Guo, M., Peng, Y., Gao, A., Du, C., & Herman, J. G.. (2019). Epigenetic heterogeneity in cancer. Biomarker Research
Plain numerical DOI: 10.1186/s40364-019-0174-y
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“Phenotypic and functional heterogeneity is one of the hallmarks of human cancers. tumor genotype variations among tumors within different patients are known as interpatient heterogeneity, and variability among multiple tumors of the same type arising in the same patient is referred to as intra-patient heterogeneity. subpopulations of cancer cells with distinct phenotypic and molecular features within a tumor are called intratumor heterogeneity (ith). since nowell proposed the clonal evolution of tumor cell populations in 1976, tumor heterogeneity, especially ith, was actively studied. research has focused on the genetic basis of cancer, particularly mutational activation of oncogenes or inactivation of tumor-suppressor genes (tsgs). the phenomenon of ith is commonly explained by darwinian-like clonal evolution of a single tumor. despite the monoclonal origin of most cancers, new clones arise during tumor progression due to the continuous acquisition of mutations. it is clear that disruption of the ‘epigenetic machinery’ plays an important role in cancer development. aberrant epigenetic changes occur more frequently than gene mutations in human cancers. the epigenome is at the intersection of the environment and genome. epigenetic dysregulation occurs in the earliest stage of cancer. the current trend of epigenetic therapy is to use epigenetic drugs to reverse and/or delay future resistance to cancer therapies. a majority of cancer therapies fail to achieve durable responses, which is often attributed to ith. epigenetic therapy may reverse drug resistance in heterogeneous cancer. complete understanding of genetic and epigenetic heterogeneity may assist in designing combinations of targeted therapies based on molecular information extracted from individual tumors.”
Levine, M. E., Lu, A. T., Quach, A., Chen, B. H., Assimes, T. L., Bandinelli, S., … Horvath, S.. (2018). An epigenetic biomarker of aging for lifespan and healthspan. Aging
Plain numerical DOI: 10.18632/aging.101414
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“Identifying reliable biomarkers of aging is a major goal in geroscience. while the first generation of epigenetic biomarkers of aging were developed using chronological age as a surrogate for biological age, we hypothesized that incorporation of composite clinical measures of phenotypic age that capture differences in lifespan and healthspan may identify novel cpgs and facilitate the development of a more powerful epigenetic biomarker of aging. using an innovative two-step process, we develop a new epigenetic biomarker of aging, dnam phenoage that strongly outperforms previous measures in regards to predictions for a variety of aging outcomes, including all-cause mortality, cancers, healthspan, physical functioning, and alzheimer’s disease. while this biomarker was developed using data from whole blood, it correlates strongly with age in every tissue and cell tested. based on an in-depth transcriptional analysis in sorted cells, we find that increased epigenetic, relative to chronological age, is associated with increased activation of pro-inflammatory and interferon pathways, and decreased activation of transcriptional/translational machinery, dna damage response, and mitochondrial signatures. overall, this single epigenetic biomarker of aging is able to capture risks for an array of diverse outcomes across multiple tissues and cells, and provide insight into important pathways in aging.”
Majchrzak-Celinska, A., Warych, A., & Szoszkiewicz, M.. (2021). Novel approaches to epigenetic therapies: From drug combinations to epigenetic editing. Genes
Plain numerical DOI: 10.3390/genes12020208
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“Cancer development involves both genetic and epigenetic alterations. aberrant epigenetic modifications are reversible, allowing excellent opportunities for therapeutic intervention. nowadays, several epigenetic drugs are used worldwide to treat, e.g., myelodysplastic syndromes and leukemias. however, overcoming resistance and widening the therapeutic profiles are the most important challenges faced by traditional epigenetic drugs. recently, novel approaches to epigenetic therapies have been proposed. next-generation epigenetic drugs, with longer half-life and better bioavailability, are being developed and tested. since epigenetic phenomena are interdependent, treatment modalities include co-administration of two different epigenetic drugs. in order to sensitize cancer cells to chemotherapy, epigenetic drugs are administered prior to chemotherapy, or both epigenetic drug and chemotherapy are used together to achieve synergistic effects and maximize treatment efficacy. the combinations of epigenetic drug with immunotherapy are being tested, because they have proved to enhance antitumor immune responses. the next approach involves targeting the metabolic causes of epigenetic changes, i.e., enzymes which, when mutated, produce oncometabolites. finally, epigenome editing makes it possible to modify individual chromatin marks at a defined region with unprecedented specificity and efficiency. this review summarizes the above attempts in fulfilling the promise of epigenetic drugs in the effective cancer treatment.”
Voisin, S., Harvey, N. R., Haupt, L. M., Griffiths, L. R., Ashton, K. J., Coffey, V. G., … Eynon, N.. (2020). An epigenetic clock for human skeletal muscle. Journal of Cachexia, Sarcopenia and Muscle
Plain numerical DOI: 10.1002/jcsm.12556
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“Background: ageing is associated with dna methylation changes in all human tissues, and epigenetic markers can estimate chronological age based on dna methylation patterns across tissues. however, the construction of the original pan-tissue epigenetic clock did not include skeletal muscle samples and hence exhibited a strong deviation between dna methylation and chronological age in this tissue. methods: to address this, we developed a more accurate, muscle-specific epigenetic clock based on the genome-wide dna methylation data of 682 skeletal muscle samples from 12 independent datasets (18–89 years old, 22% women, 99% caucasian), all generated with illumina humanmethylation (hm) arrays (hm27, hm450, or hmepic). we also took advantage of the large number of samples to conduct an epigenome-wide association study of age-associated dna methylation patterns in skeletal muscle. results: the newly developed clock uses 200 cytosine-phosphate–guanine dinucleotides to estimate chronological age in skeletal muscle, 16 of which are in common with the 353 cytosine-phosphate–guanine dinucleotides of the pan-tissue clock. the muscle clock outperformed the pan-tissue clock, with a median error of only 4.6 years across datasets (vs. 13.1 years for the pan-tissue clock, p < 0.0001) and an average correlation of ρ = 0.62 between actual and predicted age across datasets (vs. ρ = 0.51 for the pan-tissue clock). lastly, we identified 180 differentially methylated regions with age in skeletal muscle at a false discovery rate < 0.005. however, gene set enrichment analysis did not reveal any enrichment for gene ontologies. conclusions: we have developed a muscle-specific epigenetic clock that predicts age with better accuracy than the pan-tissue clock. we implemented the muscle clock in an r package called muscle epigenetic age test available on bioconductor to estimate epigenetic age in skeletal muscle samples. this clock may prove valuable in assessing the impact of environmental factors, such as exercise and diet, on muscle-specific biological ageing processes.”
Topart, C., Werner, E., & Arimondo, P. B.. (2020). Wandering along the epigenetic timeline. Clinical Epigenetics
Plain numerical DOI: 10.1186/s13148-020-00893-7
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“Background: increasing life expectancy but also healthspan seems inaccessible as of yet but it may become a reality in the foreseeable future. to extend lifespan, it is essential to unveil molecular mechanisms involved in ageing. as for healthspan, a better understanding of the mechanisms involved in age-related pathologies is crucial. main body: we focus on the epigenetic side of ageing as ageing is traced by specific epigenetic patterns and can be measured by epigenetic clocks. we discuss to what extent exposure to environmental factor, such as alcohol use, unhealthy diet, tobacco and stress, promotes age-related conditions. we focused on inflammation, cancer and alzheimer’s disease. finally, we discuss strategies to reverse time based on epigenetic reprogramming. conclusions: reversibility of the epigenetic marks makes them promising targets for rejuvenation. for this purpose, a better understanding of the epigenetic mechanisms underlying ageing is essential. epigenetic clocks were successfully designed to monitor these mechanisms and the influence of environmental factors. further studies on age-related diseases should be conducted to determine their epigenetic signature, but also to pinpoint the defect in the epigenetic machinery and thereby identify potential therapeutic targets. as for rejuvenation, epigenetic reprogramming is still at an early stage. graphical abstract: [figure not available: see fulltext.]”
Wang, T., Maden, S. K., Luebeck, G. E., Li, C. I., Newcomb, P. A., Ulrich, C. M., … Grady, W. M.. (2020). Dysfunctional epigenetic aging of the normal colon and colorectal cancer risk. Clinical Epigenetics
Plain numerical DOI: 10.1186/s13148-019-0801-3
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“Background: chronological age is a prominent risk factor for many types of cancers including colorectal cancer (crc). yet, the risk of crc varies substantially between individuals, even within the same age group, which may reflect heterogeneity in biological tissue aging between people. epigenetic clocks based on dna methylation are a useful measure of the biological aging process with the potential to serve as a biomarker of an individual’s susceptibility to age-related diseases such as crc. methods: we conducted a genome-wide dna methylation study on samples of normal colon mucosa (n = 334). subjects were assigned to three cancer risk groups (low, medium, and high) based on their personal adenoma or cancer history. using previously established epigenetic clocks (hannum, horvath, phenoage, and epitoc), we estimated the biological age of each sample and assessed for epigenetic age acceleration in the samples by regressing the estimated biological age on the individual’s chronological age. we compared the epigenetic age acceleration between different risk groups using a multivariate linear regression model with the adjustment for gender and cell-type fractions for each epigenetic clock. an epigenome-wide association study (ewas) was performed to identify differential methylation changes associated with crc risk. results: each epigenetic clock was significantly correlated with the chronological age of the subjects, and the horvath clock exhibited the strongest correlation in all risk groups (r > 0.8, p < 1 × 10-30). the phenoage clock (p = 0.0012) revealed epigenetic age deceleration in the high-risk group compared to the low-risk group. conclusions: among the four dna methylation-based measures of biological age, the horvath clock is the most accurate for estimating the chronological age of individuals. individuals with a high risk for crc have epigenetic age deceleration in their normal colons measured by the phenoage clock, which may reflect a dysfunctional epigenetic aging process.”
Gensous, N., Franceschi, C., Santoro, A., Milazzo, M., Garagnani, P., & Bacalini, M. G.. (2019). The impact of caloric restriction on the epigenetic signatures of aging. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms20082022
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“Aging is characterized by an extensive remodeling of epigenetic patterns, which has been implicated in the physiopathology of age-related diseases. nutrition plays a significant role in modulating the epigenome, and a growing amount of data indicate that dietary changes can modify the epigenetic marks associated with aging. in this review, we will assess the current advances in the relationship between caloric restriction, a proven anti-aging intervention, and epigenetic signatures of aging. we will specifically discuss the impact of caloric restriction on epigenetic regulation and how some of the favorable effects of caloric restriction on lifespan and healthspan could be mediated by epigenetic modifications.”
Bates, S. E.. (2020). Epigenetic Therapies for Cancer. New England Journal of Medicine
Plain numerical DOI: 10.1056/nejmra1805035
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“Epigenetic therapies for cancer cancer-cell biology is dictated by alterations in epigenetic regulation of gene expression. mechanisms underlying these regulators are increasingly being elucidated,…”
Phang, M., Ross, J., Raythatha, J. H., Dissanayake, H. U., McMullan, R. L., Kong, Y., … Skilton, M. R.. (2020). Epigenetic aging in newborns: Role of maternal diet. American Journal of Clinical Nutrition
Plain numerical DOI: 10.1093/ajcn/nqz326
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“Background: epigenetic aging is associated with higher risk of cardiovascular disease, cancer, and all-cause mortality and may be a mechanistic link between early-life exposures, such as maternal dietary characteristics during pregnancy, and risk of adult disease. objectives: we sought to determine the early-life risk factors for newborn epigenetic aging, specifically maternal dietary macronutrient intake, and whether epigenetic aging is associated with cardiovascular health markers in the newborn. methods: epigenetic age acceleration of 169 newborns was measured from saliva using the horvath age calculator. maternal diet during pregnancy was assessed using food-frequency questionnaires. results: newborns with positive age acceleration were more likely to be female and have greater body fatness. maternal intakes of saturated fat [6.2 wk epigenetic age acceleration (95% ci: 1.0, 11.3) per 5% of energy; p = 0.02] and monounsaturated fat [12.4 wk (95% ci: 4.2, 20.5) per 5% of energy; p = 0.003] were associated with higher epigenetic age acceleration in the newborn. the strongest association of individual fatty acids were for palmitoleic acid (25.3 wk; 95% ci: 11.4, 39.2; p = 0.0004), oleic acid (2.2 wk; 95% ci: 0.8, 3.6; p = 0.002), and palmitic acid (2.9 wk; 95% ci: 1.0, 4.9; p = 0.004) per 1% of energy intake. vitamin d supplementation was associated with lower epigenetic age acceleration (-8.1 wk; 95% ci:-14.5,-1.7; p = 0.01). epigenetic age acceleration was associated with aortic intima-media thickness in preterm infants [1.0 μm (95% ci: 0.2, 1.8) per week of epigenetic age acceleration; p = 0.01], but not among those born at term (p = 0.78). epigenetic age acceleration was not associated with heart rate variability in either preterm or term born infants (both p > 0.2). conclusions: this study provides evidence of maternal dietary characteristics that are associated with epigenetic aging in the offspring. prospective intervention studies are required to determine whether such associations are causal.”
Fardi, M., Solali, S., & Farshdousti Hagh, M.. (2018). Epigenetic mechanisms as a new approach in cancer treatment: An updated review. Genes and Diseases
Plain numerical DOI: 10.1016/j.gendis.2018.06.003
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“Epigenetic, along with genetic mechanisms, is essential for natural evolution and maintenance of specific patterns of gene expression in mammalians. global epigenetic variation is inherited somatically and unlike genetic variation, it is dynamic and reversible. they are somatically associated with known genetic variations. recent studies indicate the broad role of epigenetic mechanisms in the initiation and development of cancers, that they are including dna methylation, histone modifications, nucleosomes changes, non-coding rnas. the reversible nature of epigenetic changes has led to the emergence of novel epigenetic therapeutic approaches, so that several types of these medications have been approved by the fda so far. in this review, we discuss the concept of epigenetic changes in diseases, especially cancers, the role of these changes in the onset and progression of cancers and the potential of using this knowledge in designing novel therapeutic strategies.”
Sharma, M., Li, Y., Stoll, M. L., & Tollefsbol, T. O.. (2020). The Epigenetic Connection Between the Gut Microbiome in Obesity and Diabetes. Frontiers in Genetics
Plain numerical DOI: 10.3389/fgene.2019.01329
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“Metabolic diseases are becoming an alarming health issue due to elevated incidences of these diseases over the past few decades. various environmental factors are associated with a number of metabolic diseases and often play a crucial role in this process. amongst the factors, diet is the most important factor that can regulate these diseases via modulation of the gut microbiome. the gut microbiome participates in multiple metabolic processes in the human body and is mainly responsible for regulation of host metabolism. the alterations in function and composition of the gut microbiota have been known to be involved in the pathogenesis of metabolic diseases via induction of epigenetic changes such as dna methylation, histone modifications and regulation by noncoding rnas. these induced epigenetic modifications can also be regulated by metabolites produced by the gut microbiota including short-chain fatty acids, folates, biotin and trimethylamine-n-oxide. in addition, studies have elucidated the potential role of these microbial-produced metabolites in the pathophysiology of obesity and diabetes. hence, this review focuses on the interactions between the gut microbiome and epigenetic processes in the regulation and development of obesity and diabetes, which may have potential as a novel preventive or therapeutic approach for several metabolic and other human diseases.”
Flavahan, W. A., Gaskell, E., & Bernstein, B. E.. (2017). Epigenetic plasticity and the hallmarks of cancer. Science
Plain numerical DOI: 10.1126/science.aal2380
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“Chromatin and associated epigenetic mechanisms stabilize gene expression and cellular states while also facilitating appropriate responses to developmental or environmental cues. genetic, environmental, or metabolic insults can induce overly restrictive or overly permissive epigenetic landscapes that contribute to pathogenesis of cancer and other diseases. restrictive chromatin states may prevent appropriate induction of tumor suppressor programs or block differentiation. by contrast, permissive or ‘plastic’ states may allow stochastic oncogene activation or nonphysiologic cell fate transitions. whereas many stochastic events will be inconsequential ‘passengers,’ some will confer a fitness advantage to a cell and be selected as ‘drivers.’ we review the broad roles played by epigenetic aberrations in tumor initiation and evolution and their potential to give rise to all classic hallmarks of cancer.”
Miryeganeh, M., & Saze, H.. (2020). Epigenetic inheritance and plant evolution. Population Ecology
Plain numerical DOI: 10.1002/1438-390X.12018
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“Being sessile organisms, plants show a high degree of developmental plasticity to cope with a constantly changing environment. while plasticity in plants is largely controlled genetically, recent studies have demonstrated the importance of epigenetic mechanisms, especially dna methylation, for gene regulation and phenotypic plasticity in response to internal and external stimuli. induced epigenetic changes can be a source of phenotypic variations in natural plant populations that can be inherited by progeny for multiple generations. whether epigenetic phenotypic changes are advantageous in a given environment, and whether they are subject to natural selection is of great interest, and their roles in adaptation and evolution are an area of active research in plant ecology. this review is focused on the role of heritable epigenetic variation induced by environmental changes, and its potential influence on adaptation and evolution in plants.”
Gjaltema, R. A. F., & Rots, M. G.. (2020). Advances of epigenetic editing. Current Opinion in Chemical Biology
Plain numerical DOI: 10.1016/j.cbpa.2020.04.020
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“Epigenetic editing refers to the locus-specific targeting of epigenetic enzymes to rewrite the local epigenetic landscape of an endogenous genomic site, often with the aim of transcriptional reprogramming. implementing clustered regularly interspaced short palindromic repeat–dcas9 greatly accelerated the advancement of epigenetic editing, yielding preclinical therapeutic successes using a variety of epigenetic enzymes., crispr/dcas9 here, were review the current applications of these epigenetic editing tools in mammalians and shed light on biochemical improvements that facilitate versatile applications.”
Lacal, I., & Ventura, R.. (2018). Epigenetic Inheritance: Concepts, Mechanisms and Perspectives. Frontiers in Molecular Neuroscience
Plain numerical DOI: 10.3389/fnmol.2018.00292
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“Parents’ stressful experiences can influence an offspring’s vulnerability to many pathological conditions, including psychopathologies, and their effects may even endure for several generations. nevertheless, the cause of this phenomenon has not been determined, and only recently have scientists turned to epigenetics to answer this question. there is extensive literature on epigenetics, but no consensus exists with regard to how and what can (and must) be considered to study and define epigenetics processes and their inheritance. in this work, we aimed to clarify and systematize these concepts. to this end, we analyzed the dynamics of epigenetic changes over time in detail and defined three types of epigenetics: a direct form of epigenetics (de) and two indirect epigenetic processes—within (wie) and across (aie). de refers to changes that occur in the lifespan of an individual, due to direct experiences with his environment. wie concerns changes that occur inside of the womb, due to events during gestation. finally, aie defines changes that affect the individual’s predecessors (parents, grandparents, etc.), due to events that occur even long before conception and that are somehow (e.g., through gametes, the intrauterine environment setting) transmitted across generations. this distinction allows us to organize the main body of epigenetic evidence according to these categories and then focus on the latter (aie), referring to it as a faster route of informational transmission across generations—compared with genetic inheritance—that guides human evolution in a lamarckian (i.e., experience-dependent) manner. of the molecular processes that are implicated in this phenomenon, well-known (methylation) and novel (non-coding rna, ncrna) regulatory mechanisms are converging. our discussion of the chief methods that are used to study epigenetic inheritance highlights the most compelling technical and theoretical problems of this discipline. experimental suggestions to expand this field are provided, and their practical and ethical implications are discussed extensively.”
Carlos-Reyes, Á., López-González, J. S., Meneses-Flores, M., Gallardo-Rincón, D., Ruíz-García, E., Marchat, L. A., … López-Camarillo, C.. (2019). Dietary compounds as epigenetic modulating agents in cancer. Frontiers in Genetics
Plain numerical DOI: 10.3389/fgene.2019.00079
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“Epigenetic mechanisms control gene expression during normal development and their aberrant regulation may lead to human diseases including cancer. natural phytochemicals can largely modulate mammalian epigenome through regulation of mechanisms and proteins responsible for chromatin remodeling. phytochemicals are mainly contained in fruits, seeds, and vegetables as well as in foods supplements. these compounds act as powerful cellular antioxidants and anti-carcinogens agents. several dietary compounds such as catechins, curcumin, genistein, quercetin and resveratrol, among others, exhibit potent anti-tumor activities through the reversion of epigenetic alterations associated to oncogenes activation and inactivation of tumor suppressor genes. in this review, we summarized the actual knowledge about the role of dietary phytochemicals in the restoration of aberrant epigenetic alterations found in cancer cells with a particular focus on dna methylation and histone modifications. furthermore, we discussed the mechanisms by which these natural compounds modulate gene expression at epigenetic level and described their molecular targets in diverse types of cancer. modulation of epigenetic activities by phytochemicals will allow the discovery of novel biomarkers for cancer prevention, and highlights its potential as an alternative therapeutic approach in cancer.”
Liu, Z., Leung, D., Thrush, K., Zhao, W., Ratliff, S., Tanaka, T., … Levine, M. E.. (2020). Underlying features of epigenetic aging clocks in vivo and in vitro. Aging Cell
Plain numerical DOI: 10.1111/acel.13229
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“Epigenetic clocks, developed using dna methylation data, have been widely used to quantify biological aging in multiple tissues/cells. however, many existing epigenetic clocks are weakly correlated with each other, suggesting they may capture different biological processes. we utilize multi-omics data from diverse human tissue/cells to identify shared features across eleven existing epigenetic clocks. despite the striking lack of overlap in cpgs, multi-omics analysis suggested five clocks (horvath1, horvath2, levine, hannum, and lin) share transcriptional associations conserved across purified cd14+ monocytes and dorsolateral prefrontal cortex. the pathways enriched in the shared transcriptional association suggested links between epigenetic aging and metabolism, immunity, and autophagy. results from in vitro experiments showed that two clocks (levine and lin) were accelerated in accordance with two hallmarks of aging—cellular senescence and mitochondrial dysfunction. finally, using multi-tissue data to deconstruct the epigenetic clock signals, we developed a meta-clock that demonstrated improved prediction for mortality and robustly related to hallmarks of aging in vitro than single clocks.”
Park, M., Patel, N., Keung, A. J., & Khalil, A. S.. (2019). Engineering Epigenetic Regulation Using Synthetic Read-Write Modules. Cell
Plain numerical DOI: 10.1016/j.cell.2018.11.002
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“A synthetic, modular, and programmable read-write system allows isolated and orthogonal epigenetic control in mammalian cells.”
Sen, P., Shah, P. P., Nativio, R., & Berger, S. L.. (2016). Epigenetic Mechanisms of Longevity and Aging. Cell
Plain numerical DOI: 10.1016/j.cell.2016.07.050
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“Aging is an inevitable outcome of life, characterized by progressive decline in tissue and organ function and increased risk of mortality. accumulating evidence links aging to genetic and epigenetic alterations. given the reversible nature of epigenetic mechanisms, these pathways provide promising avenues for therapeutics against age-related decline and disease. in this review, we provide a comprehensive overview of epigenetic studies from invertebrate organisms, vertebrate models, tissues, and in vitro systems. we establish links between common operative aging pathways and hallmark chromatin signatures that can be used to identify ‘druggable’ targets to counter human aging and age-related disease.”
Baylin, S. B., & Jones, P. A.. (2016). Epigenetic determinants of cancer. Cold Spring Harbor Perspectives in Biology
Plain numerical DOI: 10.1101/cshperspect.a019505
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“Epigenetic changes are present in all human cancers and are now known to cooperate with genetic alterations to drive the cancer phenotype. these changes involve dna methylation, histone modifiers and readers, chromatin remodelers, micrornas, and other components of chromatin. cancer genetics and epigenetics are inextricably linked in generating the malignant phenotype; epigenetic changes can cause mutations in genes, and, conversely, mutations are frequently observed in genes that modify the epigenome. epigenetic therapies, in which the goal is to reverse these changes, are now one standard of care for a preleukemic disorder and form of lymphoma. the application of epigenetic therapies in the treatment of solid tumors is also emerging as a viable therapeutic route.”
Xu, R., Li, C., Liu, X., & Gao, S.. (2021). Insights into epigenetic patterns in mammalian early embryos. Protein and Cell
Plain numerical DOI: 10.1007/s13238-020-00757-z
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“Mammalian fertilization begins with the fusion of two specialized gametes, followed by major epigenetic remodeling leading to the formation of a totipotent embryo. during the development of the pre-implantation embryo, precise reprogramming progress is a prerequisite for avoiding developmental defects or embryonic lethality, but the underlying molecular mechanisms remain elusive. for the past few years, unprecedented breakthroughs have been made in mapping the regulatory network of dynamic epigenomes during mammalian early embryo development, taking advantage of multiple advances and innovations in low-input genome-wide chromatin analysis technologies. the aim of this review is to highlight the most recent progress in understanding the mechanisms of epigenetic remodeling during early embryogenesis in mammals, including dna methylation, histone modifications, chromatin accessibility and 3d chromatin organization.”
Neal, M., & Richardson, J. R.. (2018). Epigenetic regulation of astrocyte function in neuroinflammation and neurodegeneration. Biochimica et Biophysica Acta – Molecular Basis of Disease
Plain numerical DOI: 10.1016/j.bbadis.2017.11.004
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“Epigenetic mechanisms control various functions throughout the body, from cell fate determination in development to immune responses and inflammation. neuroinflammation is one of the prime contributors to the initiation and progression of neurodegeneration in a variety of diseases, including alzheimer’s and parkinson’s diseases. because astrocytes are the largest population of glial cells, they represent an important regulator of cns function, both in health and disease. only recently have studies begun to identify the epigenetic mechanisms regulating astrocyte responses in neurodegenerative diseases. these epigenetic mechanisms, along with the epigenetic marks involved in astrocyte development, could elucidate novel pathways to potentially modulate astrocyte-mediated neuroinflammation and neurotoxicity. this review examines the known epigenetic mechanisms involved in regulation of astrocyte function, from development to neurodegeneration, and links these mechanisms to potential astrocyte-specific roles in neurodegenerative disease with a focus on potential opportunities for therapeutic intervention.”
Wagner, W.. (2019). The link between epigenetic clocks for aging and senescence. Frontiers in Genetics
Plain numerical DOI: 10.3389/fgene.2019.00303
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“Replicative senescence of cells in vitro is often considered as counterpart for aging of the organism in vivo. in fact, both processes are associated with functional decay and similar molecular modifications. on epigenetic level, replicative senescence and aging evoke characteristic modifications in the dna methylation (dnam) pattern, but at different sites in the genome. various epigenetic signatures, which are often referred to as epigenetic clocks, provide useful biomarkers: senescence-associated epigenetic modifications can be used for quality control of cell preparations or to elucidate effects of culture conditions on the state of cellular aging. age-associated epigenetic modifications hold high expectations to determine chronological age in forensics or to identify parameters that impact on biological aging. despite these differences, there are some striking similarities between senescence- and age-associated dnam, such as complete rejuvenation during reprogramming into induced pluripotent stem cells (ipscs). it is yet unclear what makes epigenetic clocks tick, but there is evidence that the underlying mechanisms of both processes are related to similar modifications in the histone code or higher order chromatin. replicative senescence therefore appears to be a suitable model system to gain better insight into how organismal aging might be governed epigenetically.”
Yang, H., Cui, W., & Wang, L.. (2019). Epigenetic synthetic lethality approaches in cancer therapy. Clinical Epigenetics
Plain numerical DOI: 10.1186/s13148-019-0734-x
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“The onset and development of malignant tumors are closely related to epigenetic modifications, and this has become a research hotspot. in recent years, a variety of epigenetic regulators have been discovered, and corresponding small molecule inhibitors have been developed, but their efficacy in solid tumors is generally poor. with the introduction of the first synthetic lethal drug (the parp inhibitor olaparib in ovarian cancer with brca1 mutation), research into synthetic lethality has also become a hotspot. high-throughput screening with crispr-cas9 and shrna technology has revealed a large number of synthetic lethal pairs involving epigenetic-related synthetic lethal genes, such as those encoding swi/snf complex subunits, prc2 complex subunits, setd2, kmt2c, and mll fusion proteins. in this review, we focus on epigenetic-related synthetic lethal mechanisms, including synthetic lethality between epigenetic mutations and epigenetic inhibitors, epigenetic mutations and non-epigenetic inhibitors, and oncogene mutations and epigenetic inhibitors.”
Cheng, Y., He, C., Wang, M., Ma, X., Mo, F., Yang, S., … Wei, X.. (2019). Targeting epigenetic regulators for cancer therapy: Mechanisms and advances in clinical trials. Signal Transduction and Targeted Therapy
Plain numerical DOI: 10.1038/s41392-019-0095-0
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“Epigenetic alternations concern heritable yet reversible changes in histone or dna modifications that regulate gene activity beyond the underlying sequence. epigenetic dysregulation is often linked to human disease, notably cancer. with the development of various drugs targeting epigenetic regulators, epigenetic-targeted therapy has been applied in the treatment of hematological malignancies and has exhibited viable therapeutic potential for solid tumors in preclinical and clinical trials. in this review, we summarize the aberrant functions of enzymes in dna methylation, histone acetylation and histone methylation during tumor progression and highlight the development of inhibitors of or drugs targeted at epigenetic enzymes.”
Zhu, Z., Cao, F., & Li, X.. (2019). Epigenetic Programming and Fetal Metabolic Programming. Frontiers in Endocrinology
Plain numerical DOI: 10.3389/fendo.2019.00764
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“Fetal metabolic programming caused by the adverse intrauterine environment can induce metabolic syndrome in adult offspring. adverse intrauterine environment introduces fetal long-term relatively irreversible changes in organs and metabolism, and thus causes fetal metabolic programming leading metabolic syndrome in adult offspring. fetal metabolic programming of obesity and insulin resistance plays a key role in this process. the mechanism of fetal metabolic programming is still not very clear. it is suggested that epigenetic programming, also induced by the adverse intrauterine environment, is a critical underlying mechanism of fetal metabolic programming. fetal epigenetic programming affects gene expression changes and cellular function through epigenetic modifications without dna nucleotide sequence changes. epigenetic modifications can be relatively stably retained and transmitted through mitosis and generations, and thereby induce the development of metabolic syndrome in adult offspring. this manuscript provides an overview of the critical role of epigenetic programming in fetal metabolic programming.”
Neal, M., & Richardson, J. R.. (2018). Epigenetic regulation of astrocyte function in neuroinflammation and neurodegeneration. Biochimica et Biophysica Acta – Molecular Basis of Disease
Plain numerical DOI: 10.1016/j.bbadis.2017.11.004
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“Epigenetic mechanisms control various functions throughout the body, from cell fate determination in development to immune responses and inflammation. neuroinflammation is one of the prime contributors to the initiation and progression of neurodegeneration in a variety of diseases, including alzheimer’s and parkinson’s diseases. because astrocytes are the largest population of glial cells, they represent an important regulator of cns function, both in health and disease. only recently have studies begun to identify the epigenetic mechanisms regulating astrocyte responses in neurodegenerative diseases. these epigenetic mechanisms, along with the epigenetic marks involved in astrocyte development, could elucidate novel pathways to potentially modulate astrocyte-mediated neuroinflammation and neurotoxicity. this review examines the known epigenetic mechanisms involved in regulation of astrocyte function, from development to neurodegeneration, and links these mechanisms to potential astrocyte-specific roles in neurodegenerative disease with a focus on potential opportunities for therapeutic intervention.”
Fahy, G. M., Brooke, R. T., Watson, J. P., Good, Z., Vasanawala, S. S., Maecker, H., … Horvath, S.. (2019). Reversal of epigenetic aging and immunosenescent trends in humans. Aging Cell
Plain numerical DOI: 10.1111/acel.13028
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“Epigenetic ‘clocks’ can now surpass chronological age in accuracy for estimating biological age. here, we use four such age estimators to show that epigenetic aging can be reversed in humans. using a protocol intended to regenerate the thymus, we observed protective immunological changes, improved risk indices for many age-related diseases, and a mean epigenetic age approximately 1.5 years less than baseline after 1 year of treatment (−2.5-year change compared to no treatment at the end of the study). the rate of epigenetic aging reversal relative to chronological age accelerated from −1.6 year/year from 0–9 month to −6.5 year/year from 9–12 month. the grimage predictor of human morbidity and mortality showed a 2-year decrease in epigenetic vs. chronological age that persisted six months after discontinuing treatment. this is to our knowledge the first report of an increase, based on an epigenetic age estimator, in predicted human lifespan by means of a currently accessible aging intervention.”
Cheng, Y., He, C., Wang, M., Ma, X., Mo, F., Yang, S., … Wei, X.. (2019). Targeting epigenetic regulators for cancer therapy: Mechanisms and advances in clinical trials. Signal Transduction and Targeted Therapy
Plain numerical DOI: 10.1038/s41392-019-0095-0
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“Epigenetic alternations concern heritable yet reversible changes in histone or dna modifications that regulate gene activity beyond the underlying sequence. epigenetic dysregulation is often linked to human disease, notably cancer. with the development of various drugs targeting epigenetic regulators, epigenetic-targeted therapy has been applied in the treatment of hematological malignancies and has exhibited viable therapeutic potential for solid tumors in preclinical and clinical trials. in this review, we summarize the aberrant functions of enzymes in dna methylation, histone acetylation and histone methylation during tumor progression and highlight the development of inhibitors of or drugs targeted at epigenetic enzymes.”
Poli, G., Fabi, C., Bellet, M. M., Costantini, C., Nunziangeli, L., Romani, L., & Brancorsini, S.. (2020). Epigenetic mechanisms of inflammasome regulation. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms21165758
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“The innate immune system represents the host’s first-line defense against pathogens, dead cells or environmental factors. one of the most important inflammatory pathways is represented by the activation of the nod-like receptor (nlr) protein family. some nlrs induce the assembly of large caspase-1-activating complexes called inflammasomes. different types of inflammasomes have been identified that can respond to distinct bacterial, viral or fungal infections; sterile cell damage or other stressors, such as metabolic imbalances. epigenetic regulation has been recently suggested to provide a complementary mechanism to control inflammasome activity. this regulation can be exerted through at least three main mechanisms, including cpg dna methylation, histones post-translational modifications and noncoding rna expression. the repression or promotion of expression of different inflammasomes (nlrp1, nlrp2, nlrp3, nlrp4, nlrp6, nlrp7, nlrp12 and aim2) through epigenetic mechanisms determines the development of pathologies with variable severity. for example, our team recently explored the role of micrornas (mirnas) targeting and modulating the components of the inflammasome as potential biomarkers in bladder cancer and during therapy. this suggests that the epigenetic control of inflammasome-related genes could represent a potential target for further investigations of molecular mechanisms regulating inflammatory pathways.”
Liu, Z., Leung, D., Thrush, K., Zhao, W., Ratliff, S., Tanaka, T., … Levine, M. E.. (2020). Underlying features of epigenetic aging clocks in vivo and in vitro. Aging Cell
Plain numerical DOI: 10.1111/acel.13229
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“Epigenetic clocks, developed using dna methylation data, have been widely used to quantify biological aging in multiple tissues/cells. however, many existing epigenetic clocks are weakly correlated with each other, suggesting they may capture different biological processes. we utilize multi-omics data from diverse human tissue/cells to identify shared features across eleven existing epigenetic clocks. despite the striking lack of overlap in cpgs, multi-omics analysis suggested five clocks (horvath1, horvath2, levine, hannum, and lin) share transcriptional associations conserved across purified cd14+ monocytes and dorsolateral prefrontal cortex. the pathways enriched in the shared transcriptional association suggested links between epigenetic aging and metabolism, immunity, and autophagy. results from in vitro experiments showed that two clocks (levine and lin) were accelerated in accordance with two hallmarks of aging—cellular senescence and mitochondrial dysfunction. finally, using multi-tissue data to deconstruct the epigenetic clock signals, we developed a meta-clock that demonstrated improved prediction for mortality and robustly related to hallmarks of aging in vitro than single clocks.”
Hassan, F. U., Rehman, M. S. U., Khan, M. S., Ali, M. A., Javed, A., Nawaz, A., & Yang, C.. (2019). Curcumin as an alternative epigenetic modulator: Mechanism of action and potential effects. Frontiers in Genetics
Plain numerical DOI: 10.3389/fgene.2019.00514
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“Curcumin (a polyphenolic compound in turmeric) is famous for its potent anti-inflammatory, anti-oxidant, and anti-cancer properties, and has a great potential to act as an epigenetic modulator. the epigenetic regulatory roles of curcumin include the inhibition of dna methyltransferases (dnmts), regulation of histone modifications via the regulation of histone acetyltransferases (hats) and histone deacetylases (hdacs), regulation of micrornas (mirna), action as a dna binding agent and interaction with transcription factors. these mechanisms are interconnected and play a vital role in tumor progression. the recent research has demonstrated the role of epigenetic inactivation of pivotal genes that regulate human pathologies such as cancers. epigenetics helps to understand the mechanism of chemoprevention of cancer through different therapeutic agents. in this regard, dietary phytochemicals, such as curcumin, have emerged as a potential source to reverse epigenetic modifications and efficiently regulate the expression of genes and molecular targets that are involved in the promotion of tumorigenesis. the curcumin may also act as an epigenetic regulator in neurological disorders, inflammation, and diabetes. moreover, curcumin can induce the modifications of histones (acetylation/deacetylation), which are among the most important epigenetic changes responsible for altered expression of genes leading to modulating the risks of cancers. curcumin is an effective medicinal agent, as it regulates several important molecular signaling pathways that modulate survival, govern anti-oxidative properties like nuclear factor e2-related factor 2 (nrf2) and inflammation pathways, e.g., nuclear factor kappa b (nf-κb). curcumin is a potent proteasome inhibitor that increases p-53 level and induces apoptosis through caspase activation. moreover, the disruption of 26s proteasome activity induced by curcumin through inhibiting dyrk2 in different cancerous cells resulting in the inhibition of cell proliferation opens up a new horizon for using curcumin as a potential preventive and treatment approach in proteasome-linked cancers. this review presents a brief summary of knowledge about the mechanism of epigenetic changes induced by curcumin and the potential effects of curcumin such as anti-oxidant activity, enhancement of wound healing, modulation of angiogenesis and its interaction with inflammatory cytokines. the development of curcumin as a clinical molecule for successful ch…”
Thiebaut, F., Hemerly, A. S., & Ferreira, P. C. G.. (2019). A role for epigenetic regulation in the adaptation and stress responses of non-model plants. Frontiers in Plant Science
Plain numerical DOI: 10.3389/fpls.2019.00246
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“In recent years enormous progress has been made in understanding the role of epigenetic regulation response to environmental stimuli, especially in response to stresses. molecular mechanisms involved in chromatin dynamics and silencing have been explained, leading to an appreciation of how new phenotypes can be generated quickly in response to environmental modifications. in some cases, it has also been shown that epigenetic modifications can be stably transmitted to the next generations. despite this, the vast majority of studies have been carried out with model plants, particularly with arabidopsis, and very little is known on how native plants in their natural habitat react to changes in their environment. climate change has been affecting, sometimes drastically, the conditions of numerous ecosystems around the world, forcing populations of native species to adapt quickly. although part of the adaptation can be explained by the preexisting genetic variation in the populations, recent studies have shown that new stable phenotypes can be generated through epigenetic modifications in few generations, contributing to the stability and survival of the plants in their natural habitat. here, we review the recent data that suggest that epigenetic variation can help natural populations to cope to with change in their environments.”
Stanzione, R., Cotugno, M., Bianchi, F., Marchitti, S., Forte, M., Volpe, M., & Rubattu, S.. (2020). Pathogenesis of ischemic stroke: Role of epigenetic mechanisms. Genes
Plain numerical DOI: 10.3390/genes11010089
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“Epigenetics is the branch of molecular biology that studies modifications able to change gene expression without altering the dna sequence. epigenetic modulations include dna methylation, histone modifications, and noncoding rnas. these gene modifications are heritable and modifiable and can be triggered by lifestyle and nutritional factors. in recent years, epigenetic changes have been associated with the pathogenesis of several diseases such as diabetes, obesity, renal pathology, and different types of cancer. they have also been related with the pathogenesis of cardiovascular diseases including ischemic stroke. importantly, since epigenetic modifications are reversible processes they could assist with the development of new therapeutic approaches for the treatment of human diseases. in the present review article, we aim to collect the most recent evidence concerning the impact of epigenetic modifications on the pathogenesis of ischemic stroke in both animal models and humans.”
Xiao, B., Yin, S., Hu, Y., Sun, M., Wei, J., Huang, Z., … Jiang, L.. (2019). Epigenetic editing by CRISPR/dCas9 in Plasmodium falciparum. Proceedings of the National Academy of Sciences of the United States of America
Plain numerical DOI: 10.1073/pnas.1813542116
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“Genetic manipulation remains a major obstacle for understanding the functional genomics of the deadliest malaria parasite plasmodium falciparum. although the crispr/cas9 (clustered regularly interspaced short palindromic repeat/crispr-associated protein 9) system has been successfully applied to introduce permanent changes in the parasite genome, its use is still limited. here we show that fusing different epigenetic effector domains to a cas9 null mutant efficiently and specifically reprograms the expression of target genes in p. falciparum. by precisely writing and erasing histone acetylation at the transcription start site regions of the invasion-related genes reticulocyte binding protein homolog 4 (rh4) and erythrocyte binding protein 175 (eba-175), respectively, we achieved significant activation of rh4 and repression of eba-175, leading to the switch of the parasite invasion pathways into human erythrocytes. by using the epigenetic knockdown system, we have also characterized the effects of pfset1, previously identified as an essential gene, on expression of mainly trophozoite- and schizont-specific genes, and therefore regulation of the growth of the mature forms of p. falciparum. this epigenetic crispr/dcas9 system provides a powerful approach for regulating gene expression at the transcriptional level in p. falciparum.”
Deans, C., & Maggert, K. A.. (2015). What do you mean, “Epigenetic”?. Genetics
Plain numerical DOI: 10.1534/genetics.114.173492
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“Interest in the field of epigenetics has increased rapidly over the last decade, with the term becoming more identifiable in biomedical research, scientific fields outside of the molecular sciences, such as ecology and physiology, and even mainstream culture. it has become increasingly clear, however, that different investigators ascribe different definitions to the term. some employ epigenetics to explain changes in gene expression, others use it to refer to transgenerational effects and/or inherited expression states. this disagreement on a clear definition has made communication difficult, synthesis of epigenetic research across fields nearly impossible, and has in many ways biased methodologies and interpretations. this article discusses the history behind the multitude of definitions that have been employed since the conception of epigenetics, analyzes the components of these definitions, and offers solutions for clarifying the field and mitigating the problems that have arisen due to these definitional ambiguities.”
Yang, H., Cui, W., & Wang, L.. (2019). Epigenetic synthetic lethality approaches in cancer therapy. Clinical Epigenetics
Plain numerical DOI: 10.1186/s13148-019-0734-x
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“The onset and development of malignant tumors are closely related to epigenetic modifications, and this has become a research hotspot. in recent years, a variety of epigenetic regulators have been discovered, and corresponding small molecule inhibitors have been developed, but their efficacy in solid tumors is generally poor. with the introduction of the first synthetic lethal drug (the parp inhibitor olaparib in ovarian cancer with brca1 mutation), research into synthetic lethality has also become a hotspot. high-throughput screening with crispr-cas9 and shrna technology has revealed a large number of synthetic lethal pairs involving epigenetic-related synthetic lethal genes, such as those encoding swi/snf complex subunits, prc2 complex subunits, setd2, kmt2c, and mll fusion proteins. in this review, we focus on epigenetic-related synthetic lethal mechanisms, including synthetic lethality between epigenetic mutations and epigenetic inhibitors, epigenetic mutations and non-epigenetic inhibitors, and oncogene mutations and epigenetic inhibitors.”
Mohammad, H. P., Barbash, O., & Creasy, C. L.. (2019). Targeting epigenetic modifications in cancer therapy: erasing the roadmap to cancer. Nature Medicine
Plain numerical DOI: 10.1038/s41591-019-0376-8
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“Epigenetic dysregulation is a common feature of most cancers, often occurring directly through alteration of epigenetic machinery. over the last several years, a new generation of drugs directed at epigenetic modulators have entered clinical development, and results from these trials are now being disclosed. unlike first-generation epigenetic therapies, these new agents are selective, and many are targeted to proteins which are mutated or translocated in cancer. this review will provide a summary of the epigenetic modulatory agents currently in clinical development and discuss the opportunities and challenges in their development. as these drugs advance in the clinic, drug discovery has continued with a focus on both novel and existing epigenetic targets. we will provide an overview of these efforts and the strategies being employed.”
Chen, S., Yang, J., Wei, Y., & Wei, X.. (2020). Epigenetic regulation of macrophages: from homeostasis maintenance to host defense. Cellular and Molecular Immunology
Plain numerical DOI: 10.1038/s41423-019-0315-0
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“Macrophages are crucial members of the innate immune response and important regulators. the differentiation and activation of macrophages require the timely regulation of gene expression, which depends on the interaction of a variety of factors, including transcription factors and epigenetic modifications. epigenetic changes also give macrophages the ability to switch rapidly between cellular programs, indicating the ability of epigenetic mechanisms to affect phenotype plasticity. in this review, we focus on key epigenetic events associated with macrophage fate, highlighting events related to the maintenance of tissue homeostasis, responses to different stimuli and the formation of innate immune memory. further understanding of the epigenetic regulation of macrophages will be helpful for maintaining tissue integrity, preventing chronic inflammatory diseases and developing therapies to enhance host defense.”
Kuehner, J. N., Bruggeman, E. C., Wen, Z., & Yao, B.. (2019). Epigenetic regulations in neuropsychiatric disorders. Frontiers in Genetics
Plain numerical DOI: 10.3389/fgene.2019.00268
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“Precise genetic and epigenetic spatiotemporal regulation of gene expression is critical for proper brain development, function and circuitry formation in the mammalian central nervous system. neuronal differentiation processes are tightly regulated by epigenetic mechanisms including dna methylation, histone modifications, chromatin remodelers and non-coding rnas. dysregulation of any of these pathways is detrimental to normal neuronal development and functions, which can result in devastating neuropsychiatric disorders, such as depression, schizophrenia and autism spectrum disorders. in this review, we focus on the current understanding of epigenetic regulations in brain development and functions, as well as their implications in neuropsychiatric disorders.”
Zheng, S. C., Widschwendter, M., & Teschendorff, A. E.. (2016). Epigenetic drift, epigenetic clocks and cancer risk. Epigenomics
Plain numerical DOI: 10.2217/epi-2015-0017
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“It is well-established that the dna methylation landscape of normal cells undergoes a gradual modification with age, termed as ‘epigenetic drift’. here, we review the current state of knowledge of epigenetic drift and its potential role in cancer etiology. we propose a new terminology to help distinguish the different components of epigenetic drift, with the aim of clarifying the role of the epigenetic clock, mitotic clocks and active changes, which accumulate in response to environmental disease risk factors. we further highlight the growing evidence that epigenetic changes associated with cancer risk factors may play an important causal role in cancer development, and that monitoring these molecular changes in normal cells may offer novel risk prediction and disease prevention strategies.”
Allis, C. D., & Jenuwein, T.. (2016). The molecular hallmarks of epigenetic control. Nature Reviews Genetics
Plain numerical DOI: 10.1038/nrg.2016.59
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“Over the past 20 years, breakthrough discoveries of chromatin-modifying enzymes and associated mechanisms that alter chromatin in response to physiological or pathological signals have transformed our knowledge of epigenetics from a collection of curious biological phenomena to a functionally dissected research field. here, we provide a personal perspective on the development of epigenetics, from its historical origins to what we define as ‘the modern era of epigenetic research’. we primarily highlight key molecular mechanisms of and conceptual advances in epigenetic control that have changed our understanding of normal and perturbed development.”
Piferrer, F., Anastasiadi, D., Valdivieso, A., Sánchez-Baizán, N., Moraleda-Prados, J., & Ribas, L.. (2019). The model of the conserved epigenetic regulation of sex. Frontiers in Genetics
Plain numerical DOI: 10.3389/fgene.2019.00857
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“Epigenetics integrates genomic and environmental information to produce a given phenotype. here, the model of conserved epigenetic regulation of sex (cers) is discussed. this model is based on our knowledge on genes involved in sexual development and on epigenetic regulation of gene expression activation and silencing. this model was recently postulated to be applied to the sexual development of fish, and it states that epigenetic and gene expression patterns are more associated with the development of a particular gonadal phenotype, e.g., testis differentiation, rather than with the intrinsic or extrinsic causes that lead to the development of this phenotype. this requires the existence of genes with different epigenetic modifications, for example, changes in dna methylation levels associated with the development of a particular sex. focusing on dna methylation, the identification of cpgs, the methylation of which is linked to sex, constitutes the basis for the identification of essential epigenetic marks (eem). eems are defined as the number and identity of informative epigenetic marks that are strictly necessary, albeit perhaps not sufficient, to bring about a specific, measurable, phenotype of interest. here, we provide a summary of the genes where dna methylation has been investigated so far, focusing on fish. we found that cyp19a1a and dmrt1, two key genes for ovary and testis development, respectively, consistently show an inverse relationship between their dna methylation and expression levels, thus following cers predictions. however, in foxl2a, a pro-female gene, and amh, a pro-male gene, such relationship is not clear. the available data of other genes related to sexual development such as sox9, gsdf, and amhr2 are also discussed. next, we discuss the use of cers to make testable predictions of how sex is epigenetically regulated and to better understand sexual development, as well as the use of eems as tools for the diagnosis and prognosis of sex. we argue that cers can aid in focusing research on the epigenetic regulation of sexual development not only in fish but also in vertebrates in general, particularly in reptiles with temperature sex-determination, and can be the basis for possible practical applications including sex control in aquaculture and also in conservation biology.”
Gonzalo, S.. (2010). Epigenetic alterations in aging. Journal of Applied Physiology
Plain numerical DOI: 10.1152/japplphysiol.00238.2010
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“Aging is a multifaceted process characterized by genetic and epigenetic changes in the genome. the genetic component of aging received initially all of the attention. telomere attrition and accumulation of mutations due to a progressive deficiency in the repair of dna damage with age remain leading causes of genomic instability. however, epigenetic mechanisms have now emerged as key contributors to the alterations of genome structure and function that accompany aging. the three pillars of epigenetic regulation are dna methylation, histone modifications, and noncoding rna species. alterations of these epigenetic mechanisms affect the vast majority of nuclear processes, including gene transcription and silencing, dna replication and repair, cell cycle progression, and telomere and centromere structure and function. here, we summarize the lines of evidence indicating that these epigenetic defects might represent a major factor in the pathophysiology of aging and aging-related diseases, especially cancer. © 2010 the american physiological society.”
Thiagalingam, S.. (2020). Epigenetic memory in development and disease: Unraveling the mechanism. Biochimica et Biophysica Acta – Reviews on Cancer
Plain numerical DOI: 10.1016/j.bbcan.2020.188349
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“Epigenetic memory is an essential process of life that governs the inheritance of predestined functional characteristics of normal cells and the newly acquired properties of cells affected by cancer and other diseases from parental to progeny cells. unraveling the molecular basis of epigenetic memory dictated by protein and rna factors in conjunction with epigenetic marks that are erased and re-established during embryogenesis/development during the formation of somatic, stem and disease cells will have far reaching implications to our understanding of embryogenesis/development and various diseases including cancer. while there has been enormous progress made, there are still gaps in knowledge which includes, the identity of unique epigenetic memory factors (emfs) and epigenome coding enzymes/co-factors/scaffolding proteins involved in the assembly of defined ‘epigenetic memorysomes’ and the epigenome marks that constitute collections of gene specific epigenetic memories corresponding to specific cell types and physiological conditions. a better understanding of the molecular basis for epigenetic memory will play a central role in improving diagnostics and prognostics of disease states and aid the development of targeted therapeutics of complex diseases.”
Martin-Herranz, D. E., Aref-Eshghi, E., Bonder, M. J., Stubbs, T. M., Choufani, S., Weksberg, R., … Thornton, J. M.. (2019). Screening for genes that accelerate the epigenetic aging clock in humans reveals a role for the H3K36 methyltransferase NSD1. Genome Biology
Plain numerical DOI: 10.1186/s13059-019-1753-9
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“Background: epigenetic clocks are mathematical models that predict the biological age of an individual using dna methylation data and have emerged in the last few years as the most accurate biomarkers of the aging process. however, little is known about the molecular mechanisms that control the rate of such clocks. here, we have examined the human epigenetic clock in patients with a variety of developmental disorders, harboring mutations in proteins of the epigenetic machinery. results: using the horvath epigenetic clock, we perform an unbiased screen for epigenetic age acceleration in the blood of these patients. we demonstrate that loss-of-function mutations in the h3k36 histone methyltransferase nsd1, which cause sotos syndrome, substantially accelerate epigenetic aging. furthermore, we show that the normal aging process and sotos syndrome share methylation changes and the genomic context in which they occur. finally, we found that the horvath clock cpg sites are characterized by a higher shannon methylation entropy when compared with the rest of the genome, which is dramatically decreased in sotos syndrome patients. conclusions: these results suggest that the h3k36 methylation machinery is a key component of the epigenetic maintenance system in humans, which controls the rate of epigenetic aging, and this role seems to be conserved in model organisms. our observations provide novel insights into the mechanisms behind the epigenetic aging clock and we expect will shed light on the different processes that erode the human epigenetic landscape during aging.”
Cerna, M.. (2020). Epigenetic regulation in etiology of type 1 diabetes mellitus. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms21010036
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“Type 1 diabetes mellitus (t1dm) is caused by an autoimmune destruction of the pancreatic β-cells, a process in which autoreactive t cells play a pivotal role, an d it is characterized by islet autoantibodies. consequent hyperglycemia is requiring lifelong insulin replacement therapy. t1dm is caused by the interaction of multiple environmental an d genetic factors. the integrations of environments an d genes occur via epigenetic regulations of the genome, which allow adaptation of organism to changing life conditions by alternation of gene expression. t1dm has increased several-fold over the past half century. such a short time indicates involvement of environment factors an d excludes genetic changes. this review summarizes the most current knowledge of epigenetic changes in that process leading to autoimmune diabetes mellitus.”
Ouni, M., & Schürmann, A.. (2020). Epigenetic contribution to obesity. Mammalian Genome
Plain numerical DOI: 10.1007/s00335-020-09835-3
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“Obesity is a worldwide epidemic and contributes to global morbidity and mortality mediated via the development of nonalcoholic fatty liver disease (nafld), type 2 diabetes (t2d), cardiovascular (cvd) and other diseases. it is a consequence of an elevated caloric intake, a sedentary lifestyle and a genetic as well as an epigenetic predisposition. this review summarizes changes in dna methylation and micrornas identified in blood cells and different tissues in obese human and rodent models. it includes information on epigenetic alterations which occur in response to fat-enriched diets, exercise and metabolic surgery and discusses the potential of interventions to reverse epigenetic modifications.”
Beltrán-García, J., Osca-Verdegal, R., Mena-Mollá, S., & García-Giménez, J. L.. (2019). Epigenetic IVD tests for personalized precision medicine in cancer. Frontiers in Genetics
Plain numerical DOI: 10.3389/fgene.2019.00621
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“Epigenetic alterations play a key role in the initiation and progression of cancer. therefore, it is possible to use epigenetic marks as biomarkers for predictive and precision medicine in cancer. precision medicine is poised to impact clinical practice, patients, and healthcare systems. the objective of this review is to provide an overview of the epigenetic testing landscape in cancer by examining commercially available epigenetic-based in vitro diagnostic tests for colon, breast, cervical, glioblastoma, lung cancers, and for cancers of unknown origin. we compile current commercial epigenetic tests based on epigenetic biomarkers (i.e., dna methylation, mirnas, and histones) that can actually be implemented into clinical practice.”
Durzynska, J., Lesniewicz, K., & Poreba, E.. (2017). Human papillomaviruses in epigenetic regulations. Mutation Research – Reviews in Mutation Research
Plain numerical DOI: 10.1016/j.mrrev.2016.09.006
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“Human papillomaviruses (hpvs) are double-stranded dna viruses, that infect epithelial cells and are etiologically involved in the development of human cancer. today, over 200 types of human papillomaviruses are known. they are divided into low-risk and high-risk hpvs depending on their potential to induce carcinogenesis, driven by two major viral oncoproteins, e6 and e7. by interacting with cellular partners, these proteins are involved in interdependent viral and cell cycles in stratified differentiating epithelium, and concomitantly induce epigenetic changes in infected cells and those undergoing malignant transformation. e6 and e7 oncoproteins interact with and/or modulate expression of many proteins involved in epigenetic regulation, including dna methyltransferases, histone-modifying enzymes and subunits of chromatin remodeling complexes, thereby influencing host cell transcription program. furthermore, hpv oncoproteins modulate expression of cellular micro rnas. most of these epigenetic actions in a complex dynamic interplay participate in the maintenance of persistent infection, cell transformation, and development of invasive cancer by a considerable deregulation of tumor suppressor and oncogenes. in this study, we have undertaken to discuss a number of studies concerning epigenetic regulations in hpv-dependent cells and to focus on those that have biological relevance to cancer progression.”
Ben Maamar, M., King, S. E., Nilsson, E., Beck, D., & Skinner, M. K.. (2020). Epigenetic transgenerational inheritance of parent-of-origin allelic transmission of outcross pathology and sperm epimutations: Epigenetic transgenerational parent-of-origin allelic transmission. Developmental Biology
Plain numerical DOI: 10.1016/j.ydbio.2019.10.030
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“Epigenetic transgenerational inheritance potentially impacts disease etiology, phenotypic variation, and evolution. an increasing number of environmental factors from nutrition to toxicants have been shown to promote the epigenetic transgenerational inheritance of disease. previous observations have demonstrated that the agricultural fungicide vinclozolin and pesticide ddt (dichlorodiphenyltrichloroethane) induce transgenerational sperm epimutations involving dna methylation, ncrna, and histone modifications or retention. these two environmental toxicants were used to investigate the impacts of parent-of-origin outcross on the epigenetic transgenerational inheritance of disease. male and female rats were collected from a paternal outcross (poc) or a maternal outcross (moc) f4 generation control and exposure lineages for pathology and epigenetic analysis. this model allows the parental allelic transmission of disease and epimutations to be investigated. there was increased pathology incidence in the moc f4 generation male prostate, kidney, obesity, and multiple diseases through a maternal allelic transmission. the poc f4 generation female offspring had increased pathology incidence for kidney, obesity and multiple types of diseases through the paternal allelic transmission. some disease such as testis or ovarian pathology appear to be transmitted through the combined actions of both male and female alleles. analysis of the f4 generation sperm epigenomes identified differential dna methylated regions (dmrs) in a genome-wide analysis. observations demonstrate that ddt and vinclozolin have the potential to promote the epigenetic transgenerational inheritance of disease and sperm epimutations to the outcross f4 generation in a sex specific and exposure specific manner. the parent-of-origin allelic transmission observed appears similar to the process involved with imprinted-like genes.”
Durzynska, J., Lesniewicz, K., & Poreba, E.. (2017). Human papillomaviruses in epigenetic regulations. Mutation Research – Reviews in Mutation Research
Plain numerical DOI: 10.1016/j.mrrev.2016.09.006
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“Human papillomaviruses (hpvs) are double-stranded dna viruses, that infect epithelial cells and are etiologically involved in the development of human cancer. today, over 200 types of human papillomaviruses are known. they are divided into low-risk and high-risk hpvs depending on their potential to induce carcinogenesis, driven by two major viral oncoproteins, e6 and e7. by interacting with cellular partners, these proteins are involved in interdependent viral and cell cycles in stratified differentiating epithelium, and concomitantly induce epigenetic changes in infected cells and those undergoing malignant transformation. e6 and e7 oncoproteins interact with and/or modulate expression of many proteins involved in epigenetic regulation, including dna methyltransferases, histone-modifying enzymes and subunits of chromatin remodeling complexes, thereby influencing host cell transcription program. furthermore, hpv oncoproteins modulate expression of cellular micro rnas. most of these epigenetic actions in a complex dynamic interplay participate in the maintenance of persistent infection, cell transformation, and development of invasive cancer by a considerable deregulation of tumor suppressor and oncogenes. in this study, we have undertaken to discuss a number of studies concerning epigenetic regulations in hpv-dependent cells and to focus on those that have biological relevance to cancer progression.”
Migicovsky, Z., & Kovalchuk, I.. (2011). Epigenetic memory in mammals. Frontiers in Genetics
Plain numerical DOI: 10.3389/fgene.2011.00028
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“Epigenetic information can be passed on from one generation to another via dna methylation, histone modifications, and changes in small rnas, a process called epigenetic memory. during a mammal’s lifecycle epigenetic reprogramming, or the resetting of most epigenetic marks, occurs twice. the first instance of reprogramming occurs in primordial germ cells and the second occurs following fertilization. these processes may be both passive and active. in order for epigenetic inheritance to occur the epigenetic modifications must be able to escape reprogramming.there are several examples supporting this non-mendelian mechanism of inheritance including the prepacking of early developmental genes in histones instead of protamines in sperm, genomic imprinting via methylation marks, the retention of cenh3 in mammalian sperm and the inheritance of piwi-associated interfering rnas.the ability of mammals to pass on epigenetic information to their progeny provides clear evidence that inheritance is not restricted to dna sequence and epigenetics plays a key role in producing viable offspring. © 2011 migicovsky and kovalchuk.”
Horsthemke, B.. (2018). A critical view on transgenerational epigenetic inheritance in humans. Nature Communications
Plain numerical DOI: 10.1038/s41467-018-05445-5
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“Transgenerational epigenetic inheritance refers to the transmission of epigenetic information through the germline. while it has been observed in plants, nematodes and fruit flies, its occurrence in mammals—and humans in particular—is the matter of controversial debate, mostly because the study of transgenerational epigenetic inheritance is confounded by genetic, ecological and cultural inheritance. in this comment, i discuss the phenomenon of transgenerational epigenetic inheritance and the difficulty of providing conclusive proof for it in experimental and observational studies.”
González-Becerra, K., Ramos-Lopez, O., Barrón-Cabrera, E., Riezu-Boj, J. I., Milagro, F. I., Martínez-López, E., & Martínez, J. A.. (2019). Fatty acids, epigenetic mechanisms and chronic diseases: A systematic review. Lipids in Health and Disease
Plain numerical DOI: 10.1186/s12944-019-1120-6
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“Background: chronic illnesses like obesity, type 2 diabetes (t2d) and cardiovascular diseases, are worldwide major causes of morbidity and mortality. these pathological conditions involve interactions between environmental, genetic, and epigenetic factors. recent advances in nutriepigenomics are contributing to clarify the role of some nutritional factors, including dietary fatty acids in gene expression regulation. this systematic review assesses currently available information concerning the role of the different fatty acids on epigenetic mechanisms that affect the development of chronic diseases or induce protective effects on metabolic alterations. methods: a targeted search was conducted in the pubmed/medline databases using the keywords ‘fatty acids and epigenetic’. the data were analyzed according to the prisma-p guidelines. results: consumption fatty acids like n-3 pufa: epa and dha, and mufa: oleic and palmitoleic acid was associated with an improvement of metabolic alterations. on the other hand, fatty acids that have been associated with the presence or development of obesity, t2d, pro-inflammatory profile, atherosclerosis and ir were n-6 pufa, saturated fatty acids (stearic and palmitic), and trans fatty acids (elaidic), have been also linked with epigenetic changes. conclusions: fatty acids can regulate gene expression by modifying epigenetic mechanisms and consequently result in positive or negative impacts on metabolic outcomes.”
Liao, H. K., Hatanaka, F., Araoka, T., Reddy, P., Wu, M. Z., Sui, Y., … Izpisua Belmonte, J. C.. (2017). In Vivo Target Gene Activation via CRISPR/Cas9-Mediated Trans-epigenetic Modulation. Cell
Plain numerical DOI: 10.1016/j.cell.2017.10.025
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“Current genome-editing systems generally rely on inducing dna double-strand breaks (dsbs). this may limit their utility in clinical therapies, as unwanted mutations caused by dsbs can have deleterious effects. crispr/cas9 system has recently been repurposed to enable target gene activation, allowing regulation of endogenous gene expression without creating dsbs. however, in vivo implementation of this gain-of-function system has proven difficult. here, we report a robust system for in vivo activation of endogenous target genes through trans-epigenetic remodeling. the system relies on recruitment of cas9 and transcriptional activation complexes to target loci by modified single guide rnas. as proof-of-concept, we used this technology to treat mouse models of diabetes, muscular dystrophy, and acute kidney disease. results demonstrate that crispr/cas9-mediated target gene activation can be achieved in vivo, leading to measurable phenotypes and amelioration of disease symptoms. this establishes new avenues for developing targeted epigenetic therapies against human diseases. video abstract in vivo delivery of a cas9-based epigenetic gene activation system ameliorates disease phenotypes in mouse models of type i diabetes, acute kidney injury, and muscular dystrophy”
Kuehner, J. N., Bruggeman, E. C., Wen, Z., & Yao, B.. (2019). Epigenetic regulations in neuropsychiatric disorders. Frontiers in Genetics
Plain numerical DOI: 10.3389/fgene.2019.00268
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“Precise genetic and epigenetic spatiotemporal regulation of gene expression is critical for proper brain development, function and circuitry formation in the mammalian central nervous system. neuronal differentiation processes are tightly regulated by epigenetic mechanisms including dna methylation, histone modifications, chromatin remodelers and non-coding rnas. dysregulation of any of these pathways is detrimental to normal neuronal development and functions, which can result in devastating neuropsychiatric disorders, such as depression, schizophrenia and autism spectrum disorders. in this review, we focus on the current understanding of epigenetic regulations in brain development and functions, as well as their implications in neuropsychiatric disorders.”
Cerna, M.. (2020). Epigenetic regulation in etiology of type 1 diabetes mellitus. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms21010036
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“Type 1 diabetes mellitus (t1dm) is caused by an autoimmune destruction of the pancreatic β-cells, a process in which autoreactive t cells play a pivotal role, an d it is characterized by islet autoantibodies. consequent hyperglycemia is requiring lifelong insulin replacement therapy. t1dm is caused by the interaction of multiple environmental an d genetic factors. the integrations of environments an d genes occur via epigenetic regulations of the genome, which allow adaptation of organism to changing life conditions by alternation of gene expression. t1dm has increased several-fold over the past half century. such a short time indicates involvement of environment factors an d excludes genetic changes. this review summarizes the most current knowledge of epigenetic changes in that process leading to autoimmune diabetes mellitus.”
Leśniak, W.. (2021). Epigenetic regulation of epidermal differentiation. Epigenomes
Plain numerical DOI: 10.3390/epigenomes5010001
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“The epidermis is the outer part of the skin that protects the organism from dehydration and shields from external insults. epidermal cells, called keratinocytes, undergo a series of morphological and metabolic changes that allow them to establish the biochemical and structural elements of an effective epidermal barrier. this process, known as epidermal differentiation, is critical for the maintenance of the epidermis under physiological conditions and also under stress or in various skin pathologies. epidermal differentiation relies on a highly coordinated program of gene expression. epigenetic mechanisms, which commonly include dna methylation, covalent histone modifications, and microrna (mirna) activity, modulate various stages of gene expression by altering chromatin accessibility and mrna stability. their involvement in epidermal differentiation is a matter of intensive studies, and the results obtained thus far show a complex network of epigenetic factors, acting together with transcriptional regulators, to maintain epidermal homeostasis and counteract adverse effects of environmental stressors.”
Wang, S., Zhang, C., Hasson, D., Desai, A., SenBanerjee, S., Magnani, E., … Sadler, K. C.. (2019). Epigenetic Compensation Promotes Liver Regeneration. Developmental Cell
Plain numerical DOI: 10.1016/j.devcel.2019.05.034
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“Two major functions of the epigenome are to regulate gene expression and to suppress transposons. it is unclear how these functions are balanced during physiological challenges requiring tissue regeneration, where exquisite coordination of gene expression is essential. transcriptomic analysis of seven time points following partial hepatectomy identified the epigenetic regulator uhrf1, which is essential for dna methylation, as dynamically expressed during liver regeneration in mice. uhrf1 deletion in hepatocytes (uhrf1hepko) caused genome-wide dna hypomethylation but, surprisingly, had no measurable effect on gene or transposon expression or liver homeostasis. partial hepatectomy of uhrf1hepko livers resulted in early and sustained activation of proregenerative genes and enhanced liver regeneration. this was attributed to redistribution of h3k27me3 from promoters to transposons, effectively silencing them and, consequently, alleviating repression of liver regeneration genes, priming them for expression in uhrf1hepko livers. thus, epigenetic compensation safeguards the genome against transposon activation, indirectly affecting gene regulation. it is not clear how complex epigenetic functions are coordinated to both regulate gene expression and mitigate transposon threat. wang et al. discovered that to compensate for loss of dna methylation-mediated transposon silencing, another repressive epigenetic mark is diverted from proregenerative genes, resulting in enhanced liver regeneration.”
Tsai, K., & Cullen, B. R.. (2020). Epigenetic and epitranscriptomic regulation of viral replication. Nature Reviews Microbiology
Plain numerical DOI: 10.1038/s41579-020-0382-3
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“Eukaryotic gene expression is regulated not only by genomic enhancers and promoters, but also by covalent modifications added to both chromatin and rnas. whereas cellular gene expression may be either enhanced or inhibited by specific epigenetic modifications deposited on histones (in particular, histone h3), these epigenetic modifications can also repress viral gene expression, potentially functioning as a potent antiviral innate immune response in dna virus-infected cells. however, viruses have evolved countermeasures that prevent the epigenetic silencing of their genes during lytic replication, and they can also take advantage of epigenetic silencing to establish latent infections. by contrast, the various covalent modifications added to rnas, termed epitranscriptomic modifications, can positively regulate mrna translation and/or stability, and both dna and rna viruses have evolved to utilize epitranscriptomic modifications as a means to maximize viral gene expression. as a consequence, both chromatin and rna modifications could serve as novel targets for the development of antivirals. in this review, we discuss how host epigenetic and epitranscriptomic processes regulate viral gene expression at the levels of chromatin and rna function, respectively, and explore how viruses modify, avoid or utilize these processes in order to regulate viral gene expression.”
Izzo, S., Naponelli, V., & Bettuzzi, S.. (2020). Flavonoids as epigenetic modulators for prostate cancer prevention. Nutrients
Plain numerical DOI: 10.3390/nu12041010
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“Prostate cancer (pca) is a multifactorial disease with an unclear etiology. due to its high prevalence, long latency, and slow progression, pca is an ideal target for chemoprevention strategies. many research studies have highlighted the positive effects of natural flavonoids on chronic diseases, including pca. different classes of dietary flavonoids exhibit anti-oxidative, anti-inflammatory, anti-mutagenic, anti-aging, cardioprotective, anti-viral/bacterial and anti-carcinogenic properties. we overviewed the most recent evidence of the antitumoral effects exerted by dietary flavonoids, with a special focus on their epigenetic action in pca. epigenetic alterations have been identified as key initiating events in several kinds of cancer. many dietary flavonoids have been found to reverse dna aberrations that promote neoplastic transformation, particularly for pca. the epigenetic targets of the actions of flavonoids include oncogenes and tumor suppressor genes, indirectly controlled through the regulation of epigenetic enzymes such as dna methyltransferase (dnmt), histone acetyltransferase (hat), and histone deacetylase (hdac). in addition, flavonoids were found capable of restoring mirna and lncrna expression that is altered during diseases. the optimization of the use of flavonoids as natural epigenetic modulators for chemoprevention and as a possible treatment of pca and other kinds of cancers could represent a promising and valid strategy to inhibit carcinogenesis and fight cancer.”
Verhoeven, K. J. F., & Preite, V.. (2014). Epigenetic variation in asexually reproducing organisms. Evolution
Plain numerical DOI: 10.1111/evo.12320
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“The role that epigenetic inheritance can play in adaptation may differ between sexuals and asexuals because (1) the dynamics of adaptation differ under sexual and asexual reproduction and the opportunities offered by epigenetic inheritance may affect these dynamics differently; and (2) in asexual reproduction epigenetic reprogramming mechanisms that are associated with meiosis can be bypassed, which could promote the buildup of epigenetic variation in asexuals. here, we evaluate current evidence for an epigenetic contribution to adaptation in asexuals. we argue that two aspects of epigenetic variation should have particular relevance for asexuals, namely epigenetics-mediated phenotypic plasticity within and between generations, and heritable variation via stochastic epimutations. an evaluation of epigenetic reprogramming mechanisms suggests that some, but not all, forms of asexual reproduction enhance the likelihood of stable transmission of epigenetic marks across generations compared to sexual reproduction. however, direct tests of these predicted sexual-asexual differences are virtually lacking. stable transmission of dna methylation, transcriptomes, and phenotypes from parent to clonal offspring are demonstrated in various asexual species, and clonal genotypes from natural populations show habitat-specific dna methylation. we discuss how these initial observations can be extended to demonstrate an epigenetic contribution to adaptation. © 2013 the society for the study of evolution.”
Assenov, Y., Brocks, D., & Gerhäuser, C.. (2018). Intratumor heterogeneity in epigenetic patterns. Seminars in Cancer Biology
Plain numerical DOI: 10.1016/j.semcancer.2018.01.010
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“Analogous to life on earth, tumor cells evolve through space and time and adapt to different micro-environmental conditions. as a result, tumors are composed of millions of genetically diversified cells at the time of diagnosis. profiling these variants contributes to understanding tumors’ clonal origins and might help to better understand response to therapy. however, even genetically homogenous cell populations show remarkable diversity in their response to different environmental stimuli, suggesting that genetic heterogeneity does not explain the full spectrum of tumor plasticity. understanding epigenetic diversity across cancer cells provides important additional information about the functional state of subclones and therefore allows better understanding of tumor evolution and resistance to current therapies.”
Marini, S., Davis, K. A., Soare, T. W., Zhu, Y., Suderman, M. J., Simpkin, A. J., … Dunn, E. C.. (2020). Adversity exposure during sensitive periods predicts accelerated epigenetic aging in children. Psychoneuroendocrinology
Plain numerical DOI: 10.1016/j.psyneuen.2019.104484
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“Objectives: exposure to adversity has been linked to accelerated biological aging, which in turn has been shown to predict numerous physical and mental health problems. in recent years, measures of dna methylation-based epigenetic age––known as ‘epigenetic clocks’––have been used to estimate accelerated epigenetic aging. although a small number of studies have found an effect of adversity exposure on epigenetic age in children, none have investigated if there are ‘sensitive periods’ when adversity is most impactful. methods: using data from the avon longitudinal study of parents and children (alspac; n = 973), we tested the prospective association between repeated measures of childhood exposure to seven types of adversity on epigenetic age assessed at age 7.5 using the horvath and hannum epigenetic clocks. with a least angle regression variable selection procedure, we evaluated potential sensitive period effects. results: we found that exposure to abuse, financial hardship, or neighborhood disadvantage during sensitive periods in early and middle childhood best explained variability in the deviation of hannum-based epigenetic age from chronological age, even after considering the role of adversity accumulation and recency. secondary sex-stratified analyses identified particularly strong sensitive period effects. these effects were undetected in analyses comparing children ‘exposed’ versus ‘unexposed’ to adversity. we did not identify any associations between adversity and epigenetic age using the horvath epigenetic clock. conclusions: our results suggest that adversity may alter methylation processes in ways that either directly or indirectly perturb normal cellular aging and that these effects may be heightened during specific life stages.”
Pogribna, M., & Hammons, G.. (2021). Epigenetic Effects of Nanomaterials and Nanoparticles. Journal of Nanobiotechnology
Plain numerical DOI: 10.1186/s12951-020-00740-0
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“The rise of nanotechnology and widespread use of engineered nanomaterials in everyday human life has led to concerns regarding their potential effect on human health. adverse effects of nanomaterials and nanoparticles on various molecular and cellular alterations have been well-studied. in contrast, the role of epigenetic alterations in their toxicity remains relatively unexplored. this review summarizes current evidence of alterations in cytosine dna methylation and histone modifications in response to nanomaterials and nanoparticles exposures in vivo and in vitro. this review also highlights existing knowledge gaps regarding the role of epigenetic alterations in nanomaterials and nanoparticles toxicity. additionally, the role of epigenetic changes as potential translational biomarkers for detecting adverse effects of nanomaterials and nanoparticles is discussed.”
Akar, R. O., Selvı, S., Ulukaya, E., & Aztopal, N.. (2019). Key actors in cancer therapy: Epigenetic modifiers. Turkish Journal of Biology
Plain numerical DOI: 10.3906/biy-1903-39
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“Epigenetic reprogramming plays a crucial role in the tumorigenicity and maintenance of tumor-specific gene expression that especially occurs through dna methylation and/or histone modifications. it has well-defined mechanisms. it is known that alterations in the dna methylation pattern and/or the loss of specific histone acetylation/methylation markers are related to several hallmarks of cancer, such as drug resistance, stemness, epithelial-mesenchymal transition, and metastasis. it has also recently been highlighted that epigenetic alterations are critical for the regulation of the stemlike properties of cancer cells (tumor-initiating cells; cancer stem cells). cancer stem cells are thought to be responsible for the recurrence of cancer which makes the patient return to the clinic with metastatic tumor tissue. hence, the dysregulation of epigenetic machinery represents potential new therapeutic targets. therefore, compounds with epigenetic activities have become crucial for developing new therapy regimens (e.g., antimetastatic agents) in the fight against cancer. here, we review the epigenetic modifiers that have already been used in the clinic and/or in clinical trials, related preclinical studies in cancer therapy, and the smart combination strategies that target cancer stem cells along with the other cancer cells. the emerging role of epitranscriptome (rna epigenetic) in cancer therapy has also been included in this review as a new avenue and potential target for the better management of cancer-beneficial epigenetic machinery.”
Sarkies, P.. (2020). Molecular mechanisms of epigenetic inheritance: Possible evolutionary implications. Seminars in Cell and Developmental Biology
Plain numerical DOI: 10.1016/j.semcdb.2019.06.005
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“Recently interest in multi-generational epigenetic phenomena have been fuelled by highly reproducible intergenerational and transgenerational inheritance paradigms in several model organisms. such paradigms are essential in order to begin to use genetics to unpick the mechanistic bases of how epigenetic information may be transmitted between generations; indeed great strides have been made towards understanding these mechanisms. far less well understood is the relationship between epigenetic inheritance, ecology and evolution. in this review i focus on potential connections between laboratory studies of transgenerational epigenetic inheritance phenomena and evolutionary processes that occur in natural populations. in the first section, i consider whether transgenerational epigenetic inheritance might provide an advantage to organisms over the short term in adapting to their environment. second, i consider whether epigenetic changes can contribute to the evolution of species by contributing to stable phenotypic variation within a population. finally i discuss whether epigenetic changes could influence evolution by either directly or indirectly promoting dna sequence changes that could impact phenotypic divergence. additionally, i will discuss how epigenetic changes could influence the evolution of human cancer and thus be directly relevant for the development of this disease.”
Policarpi, C., Dabin, J., & Hackett, J. A.. (2021). Epigenetic editing: Dissecting chromatin function in context. BioEssays
Plain numerical DOI: 10.1002/bies.202000316
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“How epigenetic mechanisms regulate genome output and response to stimuli is a fundamental question in development and disease. past decades have made tremendous progress in deciphering the regulatory relationships involved by correlating aggregated (epi)genomics profiles with global perturbations. however, the recent development of epigenetic editing technologies now enables researchers to move beyond inferred conclusions, towards explicit causal reasoning, through ‚programing’ precise chromatin perturbations in single cells. here, we first discuss the major unresolved questions in the epigenetics field that can be addressed by programable epigenome editing, including the context-dependent function and memory of chromatin states. we then describe the epigenetic editing toolkit focusing on crispr-based technologies, and highlight its achievements, drawbacks and promise. finally, we consider the potential future application of epigenetic editing to the study and treatment of specific disease conditions.”
DE FREITAS, N. L., Azevedo, P. R. G., & Brandão, F.. (2020). A glance upon epigenetic and COVID-19. Anais Da Academia Brasileira de Ciencias
Plain numerical DOI: 10.1590/0001-3765202020201451
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“Epigenetics studies focused on sars-cov-2 infection to assist in the perception of pathophysiology can direct prospective approaches for the covid-19 treatment. there is an intrinsic relationship between epigenetic marks and the adaptation of the immune system, which determines the outcome of the pathogen-host interaction. recently, studies have shown that there is an increased expression of the ace2 receptor in individuals with lupus, the origin of this phenomenon is from dna’s methylation deregulation process that consequently, become this group more suitable to be infected by sars-cov-2. there is evidence for the use of some epigenetic modifiers known as epidrugs, which might be a promising approach to be deeper investigated. here we emphasize the importance of this glance upon epigenetic and its modulators in the promising therapeutic in the covid-19 disease context.”
Perez, M. F., & Lehner, B.. (2019). Intergenerational and transgenerational epigenetic inheritance in animals. Nature Cell Biology
Plain numerical DOI: 10.1038/s41556-018-0242-9
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“Animals transmit not only dna but also other molecules, such as rna, proteins and metabolites, to their progeny via gametes. it is currently unclear to what extent these molecules convey information between generations and whether this information changes according to their physiological state and environment. here, we review recent work on the molecular mechanisms by which ‘epigenetic’ information is transmitted between generations over different timescales, and the importance of this information for development and physiology.”
Van Cauwenbergh, O., Di Serafino, A., Tytgat, J., & Soubry, A.. (2020). Transgenerational epigenetic effects from male exposure to endocrine-disrupting compounds: A systematic review on research in mammals. Clinical Epigenetics
Plain numerical DOI: 10.1186/s13148-020-00845-1
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“Assessing long-term health effects from a potentially harmful environment is challenging. endocrine-disrupting compounds (edcs) have become omnipresent in our environment. individuals may or may not experience clinical health issues from being exposed to the increasing environmental pollution in daily life, but an issue of high concern is that also the non-exposed progeny may encounter consequences of these ancestral exposures. progress in understanding epigenetic mechanisms opens new perspectives to estimate the risk of man-made edcs. however, the field of epigenetic toxicology is new and its application in public health or in the understanding of disease etiology is almost non-existent, especially if it concerns future generations. in this review, we investigate the literature on transgenerational inheritance of diseases, published in the past 10 years. we question whether persistent epigenetic changes occur in the male germ line after exposure to synthesized edcs. our systematic search led to an inclusion of 43 articles, exploring the effects of commonly used synthetic edcs, such as plasticizers (phthalates and bisphenol a), pesticides (dichlorodiphenyltrichloroethane, atrazine, vinclozin, methoxychlor), dioxins, and polycyclic aromatic hydrocarbons (pahs, such as benzo(a)pyrene). most studies found transgenerational epigenetic effects, often linked to puberty- or adult-onset diseases, such as testicular or prostate abnormalities, metabolic disorders, behavioral anomalies, and tumor development. the affected epigenetic mechanisms included changes in dna methylation patterns, transcriptome, and expression of dna methyltransferases. studies involved experiments in animal models and none were based on human data. in the future, human studies are needed to confirm animal findings. if not transgenerational, at least intergenerational human studies and studies on edc-induced epigenetic effects on germ cells could help to understand early processes of inheritance. next, toxicity tests of new chemicals need a more comprehensive approach before they are introduced on the market. we further point to the relevance of epigenetic toxicity tests in regard to public health of the current population but also of future generations. finally, this review sheds a light on how the interplay of genetics and epigenetics may explain the current knowledge gap on transgenerational inheritance.”
Mancarella, D., & Plass, C.. (2021). Epigenetic signatures in cancer: proper controls, current challenges and the potential for clinical translation. Genome Medicine
Plain numerical DOI: 10.1186/s13073-021-00837-7
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“Epigenetic alterations are associated with normal biological processes such as aging or differentiation. changes in global epigenetic signatures, together with genetic alterations, are driving events in several diseases including cancer. comparative studies of cancer and healthy tissues found alterations in patterns of dna methylation, histone posttranslational modifications, and changes in chromatin accessibility. driven by sophisticated, next-generation sequencing-based technologies, recent studies discovered cancer epigenomes to be dominated by epigenetic patterns already present in the cell-of-origin, which transformed into a neoplastic cell. tumor-specific epigenetic changes therefore need to be redefined and factors influencing epigenetic patterns need to be studied to unmask truly disease-specific alterations. the underlying mechanisms inducing cancer-associated epigenetic alterations are poorly understood. studies of mutated epigenetic modifiers, enzymes that write, read, or edit epigenetic patterns, or mutated chromatin components, for example oncohistones, help to provide functional insights on how cancer epigenomes arise. in this review, we highlight the importance and define challenges of proper control tissues and cell populations to exploit cancer epigenomes. we summarize recent advances describing mechanisms leading to epigenetic changes in tumorigenesis and briefly discuss advances in investigating their translational potential.”
Liu, J., Feng, L., Li, J., & He, Z.. (2015). Genetic and epigenetic control of plant heat responses. Frontiers in Plant Science
Plain numerical DOI: 10.3389/fpls.2015.00267
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“Plants have evolved sophisticated genetic and epigenetic regulatory systems to respond quickly to unfavorable environmental conditions such as heat, cold, drought, and pathogen infections. in particular, heat greatly affects plant growth and development, immunity and circadian rhythm, and poses a serious threat to the global food supply. according to temperatures exposing, heat can be usually classified as warm ambient temperature (about 22–27°c), high temperature (27–30°c) and extremely high temperature (37–42°c, also known as heat stress) for the model plant arabidopsis thaliana. the genetic mechanisms of plant responses to heat have been well studied, mainly focusing on elevated ambient temperature-mediated morphological acclimation and acceleration of flowering, modulation of circadian clock and plant immunity by high temperatures, and thermotolerance to heat stress. recently, great progress has been achieved on epigenetic regulation of heat responses, including dna methylation, histone modifications, histone variants, atp-dependent chromatin remodeling, histone chaperones, small rnas, long non-coding rnas and other undefined epigenetic mechanisms. these epigenetic modifications regulate the expression of heat-responsive genes and function to prevent heat-related damages. this review focuses on recent progresses regarding the genetic and epigenetic control of heat responses in plants, and pays more attention to the role of the major epigenetic mechanisms in plant heat responses. further research perspectives are also discussed.”
Yan, Q., Paul, K. C., Lu, A. T., Kusters, C., Binder, A. M., Horvath, S., & Ritz, B.. (2020). Epigenetic mutation load is weakly correlated with epigenetic age acceleration. Aging
Plain numerical DOI: 10.18632/aging.103950
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“DNA methylation (dnam) age estimators are widely used to study aging-related conditions. it is not yet known whether dnam age is associated with the accumulation of stochastic epigenetic mutations (sems), which reflect dysfunctions of the epigenetic maintenance system. here, we defined epigenetic mutation load (eml) as the total number of sems per individual. we assessed associations between eml and dnam age acceleration estimators using biweight midcorrelations in four population-based studies (total n = 6,388). eml was not only positively associated with chronological age (meta r = 0.171), but also with four measures of epigenetic age acceleration: the horvath pan tissue clock, intrinsic epigenetic age acceleration, the hannum clock, and the grimage clock (meta-analysis correlation ranging from r = 0.109 to 0.179). we further conducted pathway enrichment analyses for each participant’s sems. the enrichment result demonstrated the stochasticity of epigenetic mutations, meanwhile implicated several pathways: signaling, neurogenesis, neurotransmitter, glucocorticoid, and circadian rhythm pathways may contribute to faster dnam age acceleration. finally, investigating genomic-region specific eml, we found that emls located within regions of transcriptional repression (tss1500, tss200, and 1stexon) were associated with faster age acceleration. overall, our findings suggest a role for the accumulation of epigenetic mutations in the aging process.”
Chang, Y. N., Zhu, C., Jiang, J., Zhang, H., Zhu, J. K., & Duan, C. G.. (2020). Epigenetic regulation in plant abiotic stress responses. Journal of Integrative Plant Biology
Plain numerical DOI: 10.1111/jipb.12901
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“In eukaryotic cells, gene expression is greatly influenced by the dynamic chromatin environment. epigenetic mechanisms, including covalent modifications to dna and histone tails and the accessibility of chromatin, create various chromatin states for stress-responsive gene expression that is important for adaptation to harsh environmental conditions. recent studies have revealed that many epigenetic factors participate in abiotic stress responses, and various chromatin modifications are changed when plants are exposed to stressful environments. in this review, we summarize recent progress on the cross-talk between abiotic stress response pathways and epigenetic regulatory pathways in plants. our review focuses on epigenetic regulation of plant responses to extreme temperatures, drought, salinity, the stress hormone abscisic acid, nutrient limitations and ultraviolet stress, and on epigenetic mechanisms of stress memory.”
Horvath, S., Gurven, M., Levine, M. E., Trumble, B. C., Kaplan, H., Allayee, H., … Assimes, T. L.. (2016). An epigenetic clock analysis of race/ethnicity, sex, and coronary heart disease. Genome Biology
Plain numerical DOI: 10.1186/s13059-016-1030-0
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“Background: epigenetic biomarkers of aging (the ‘epigenetic clock’) have the potential to address puzzling findings surrounding mortality rates and incidence of cardio-metabolic disease such as: (1) women consistently exhibiting lower mortality than men despite having higher levels of morbidity; (2) racial/ethnic groups having different mortality rates even after adjusting for socioeconomic differences; (3) the black/white mortality cross-over effect in late adulthood; and (4) hispanics in the united states having a longer life expectancy than caucasians despite having a higher burden of traditional cardio-metabolic risk factors. results: we analyzed blood, saliva, and brain samples from seven different racial/ethnic groups. we assessed the intrinsic epigenetic age acceleration of blood (independent of blood cell counts) and the extrinsic epigenetic aging rates of blood (dependent on blood cell counts and tracks the age of the immune system). in blood, hispanics and tsimane amerindians have lower intrinsic but higher extrinsic epigenetic aging rates than caucasians. african-americans have lower extrinsic epigenetic aging rates than caucasians and hispanics but no differences were found for the intrinsic measure. men have higher epigenetic aging rates than women in blood, saliva, and brain tissue. conclusions: epigenetic aging rates are significantly associated with sex, race/ethnicity, and to a lesser extent with chd risk factors, but not with incident chd outcomes. these results may help elucidate lower than expected mortality rates observed in hispanics, older african-americans, and women.”
Yehuda, R., & Lehrner, A.. (2018). Intergenerational transmission of trauma effects: putative role of epigenetic mechanisms. World Psychiatry
Plain numerical DOI: 10.1002/wps.20568
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“This paper reviews the research evidence concerning the intergenerational transmission of trauma effects and the possible role of epigenetic mechanisms in this transmission. two broad categories of epigenetically mediated effects are highlighted. the first involves developmentally programmed effects. these can result from the influence of the offspring’s early environmental exposures, including postnatal maternal care as well as in utero exposure reflecting maternal stress during pregnancy. the second includes epigenetic changes associated with a preconception trauma in parents that may affect the germline, and impact fetoplacental interactions. several factors, such as sex-specific epigenetic effects following trauma exposure and parental developmental stage at the time of exposure, explain different effects of maternal and paternal trauma. the most compelling work to date has been done in animal models, where the opportunity for controlled designs enables clear interpretations of transmissible effects. given the paucity of human studies and the methodological challenges in conducting such studies, it is not possible to attribute intergenerational effects in humans to a single set of biological or other determinants at this time. elucidating the role of epigenetic mechanisms in intergenerational effects through prospective, multi-generational studies may ultimately yield a cogent understanding of how individual, cultural and societal experiences permeate our biology.”
Vaiserman, A.. (2018). Developmental tuning of epigenetic clock. Frontiers in Genetics
Plain numerical DOI: 10.3389/fgene.2018.00584
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“Research in the field of gerontology has traditionally focused on later life stages. there is increasing evidence, however, that both the rate of age-related functional decline and the later-life health status can be programmed during early development. the central role of epigenetic mechanisms (methylation of dna, histone modifications and regulation by non-coding rnas) in mediating these long-term effects has been elucidated. both rate and direction of age-associated change of epigenetic patterns (‘epigenetic drift’) were shown to be largely dependent on early-life environmental conditions. inter-individual divergences in epigenetic profiles may arise following the stochastic errors in maintaining epigenetic marks, but they may also be adaptively mediated by specific environmental cues. recent cohort studies indicate that ticking rate of epigenetic clock, estimated by a dna methylation-based methods, may be developmentally adjusted, and that individual’s discrepancies among epigenetic and chronological age would be likely programmed early in development. in this perspective article, recent findings suggesting the importance of early-life determinants for life-course dynamics of epigenetic drift are summarized and discussed.”
Atlante, S., Mongelli, A., Barbi, V., Martelli, F., Farsetti, A., & Gaetano, C.. (2020). The epigenetic implication in coronavirus infection and therapy. Clinical Epigenetics
Plain numerical DOI: 10.1186/s13148-020-00946-x
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“Epigenetics is a relatively new field of science that studies the genetic and non-genetic aspects related to heritable phenotypic changes, frequently caused by environmental and metabolic factors. in the host, the epigenetic machinery can regulate gene expression through a series of reversible epigenetic modifications, such as histone methylation and acetylation, dna/rna methylation, chromatin remodeling, and non-coding rnas. the coronavirus disease 19 (covid-19) is a highly transmittable and pathogenic viral infection. the severe acute respiratory syndrome coronavirus 2 (sars-cov-2), which emerged in wuhan, china, and spread worldwide, causes it. covid-19 severity and consequences largely depend on patient age and health status. in this review, we will summarize and comparatively analyze how viruses regulate the host epigenome. mainly, we will be focusing on highly pathogenic respiratory rna virus infections such as coronaviruses. in this context, epigenetic alterations might play an essential role in the onset of coronavirus disease complications. although many therapeutic approaches are under study, more research is urgently needed to identify effective vaccine or safer chemotherapeutic drugs, including epigenetic drugs, to cope with this viral outbreak and to develop pre- and post-exposure prophylaxis against covid-19.”
Canale, M., Casadei-Gardini, A., Ulivi, P., Arechederra, M., Berasain, C., Lollini, P. L., … Avila, M. A.. (2020). Epigenetic mechanisms in gastric cancer: Potential new therapeutic opportunities. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms21155500
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“Gastric cancer (gc) is one of the deadliest malignancies worldwide. complex disease heterogeneity, late diagnosis, and suboptimal therapies result in the poor prognosis of patients. besides genetic alterations and environmental factors, it has been demonstrated that alterations of the epigenetic machinery guide cancer onset and progression, representing a hallmark of gastric malignancies. moreover, epigenetic mechanisms undergo an intricate crosstalk, and distinct epigenomic profiles can be shaped under different microenvironmental contexts. in this scenario, targeting epigenetic mechanisms could be an interesting therapeutic strategy to overcome gastric cancer heterogeneity, and the efforts conducted to date are delivering promising results. in this review, we summarize the key epigenetic events involved in gastric cancer development. we conclude with a discussion of new promising epigenetic strategies for gastric cancer treatment.”
Hanson, M. A., & Skinner, M. K.. (2016). Developmental origins of epigenetic transgenerational inheritance. Environmental Epigenetics
Plain numerical DOI: 10.1093/eep/dvw002
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“Environmental factors can induce epigenetic alterations in the germ cells that can potentially be transmitted transgenerationally. this non-genetic form of inheritance is termed epigenetic transgenerational inheritance and has been shown in a variety of species including plants, flies, worms, fish, rodents, pigs, and humans. this phenomenon operates during specific critical windows of exposure, linked to the developmental biology of the germ cells (sperm and eggs). therefore, concepts of the developmental origins of transgenerational inheritance of phenotypic variation and subsequent disease risk need to include epigenetic processes affecting the developmental biology of the germ cell. these developmental impacts on epigenetic transgenerational inheritance, in contrast to multigenerational exposures, are the focus of this perspective.”
Zhao, Z., & Shilatifard, A.. (2019). Epigenetic modifications of histones in cancer. Genome Biology
Plain numerical DOI: 10.1186/s13059-019-1870-5
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“The epigenetic modifications of histones are versatile marks that are intimately connected to development and disease pathogenesis including human cancers. in this review, we will discuss the many different types of histone modifications and the biological processes with which they are involved. specifically, we review the enzymatic machineries and modifications that are involved in cancer development and progression, and how to apply currently available small molecule inhibitors for histone modifiers as tool compounds to study the functional significance of histone modifications and their clinical implications.”
Turgut-Kara, N., Arikan, B., & Celik, H.. (2020). Epigenetic memory and priming in plants. Genetica
Plain numerical DOI: 10.1007/s10709-020-00093-4
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“In nature, plants are regularly exposed to biotic and abiotic stress conditions. these conditions create potential risks for survival. plants have evolved in order to compete with these stress conditions through physiological adjustments that are based on epigenetic background. thus, the ecological signals create different levels of stress memory. recent studies have shown that this stress-induced environmental memory is mediated by epigenetic mechanisms that have fundamental roles in the aspect of controlling gene expression via dna methylation, histone modifications and, small rnas and these modifications could be transmitted to the next generations. thus, they provide alternative mechanisms to constitute stress memories in plants. in this review, we summarized the epigenetic memory mechanisms related with biotic and abiotic stress conditions, and relationship between priming and epigenetic memory in plants by believing that it can be useful for analyzing memory mechanisms and see what is missing out in order to develop plants more resistant and productive under diverse environmental cues.”
Wang, X., Qu, J., Li, J., He, H., Liu, Z., & Huan, Y.. (2020). Epigenetic Reprogramming During Somatic Cell Nuclear Transfer: Recent Progress and Future Directions. Frontiers in Genetics
Plain numerical DOI: 10.3389/fgene.2020.00205
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“Somatic cell nuclear transfer (scnt) has broad applications but is limited by low cloning efficiency. in this review, we mainly focus on scnt-mediated epigenetic reprogramming in livestock and also describe mice data for reference. this review presents the factors contributing to low cloning efficiency, demonstrates that incomplete epigenetic reprogramming leads to the low developmental potential of cloned embryos, and further describes the regulation of epigenetic reprogramming by long non-coding rnas, which is a new research perspective in the field of scnt-mediated epigenetic reprogramming. in conclusion, this review provides new insights into the epigenetic regulatory mechanism during scnt-mediated nuclear reprogramming, which could have great implications for improving cloning efficiency.”
Mukherjee, A. K., Sharma, S., & Chowdhury, S.. (2019). Non-duplex G-Quadruplex Structures Emerge as Mediators of Epigenetic Modifications. Trends in Genetics
Plain numerical DOI: 10.1016/j.tig.2018.11.001
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“The role of non-duplex dna, the guanine-quadruplex structure in particular, is becoming widely appreciated. increasing evidence in the last decade implicates quadruplexes in important processes such as transcription and replication. interestingly, more recent work suggests roles for quadruplexes, in association with quadruplex-interacting proteins, in epigenetics through both dna and histone modifications. here, we review the effect of the quadruplex structure on post-replication epigenetic memory and quadruplex-induced promoter dna/histone modifications. furthermore, we highlight the epigenetic state of the telomerase promoter where quadruplexes could play a key regulatory role. finally, we discuss the possibility that dna structures such as quadruplexes, within a largely duplex dna background, could act as molecular anchors for locally induced epigenetic modifications.”
Zong, D., Liu, X., Li, J., Ouyang, R., & Chen, P.. (2019). The role of cigarette smoke-induced epigenetic alterations in inflammation. Epigenetics and Chromatin
Plain numerical DOI: 10.1186/s13072-019-0311-8
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“Background: exposure to cigarette smoke (cs) is a major threat to human health worldwide. it is well established that smoking increases the risk of respiratory diseases, cardiovascular diseases and different forms of cancer, including lung, liver, and colon. cs-triggered inflammation is considered to play a central role in various pathologies by a mechanism that stimulates the release of pro-inflammatory cytokines. during this process, epigenetic alterations are known to play important roles in the specificity and duration of gene transcription. main text: epigenetic alterations include three major modifications: dna modifications via methylation; various posttranslational modifications of histones, namely, methylation, acetylation, phosphorylation, and ubiquitination; and non-coding rna sequences. these modifications work in concert to regulate gene transcription in a heritable fashion. the enzymes that regulate these epigenetic modifications can be activated by smoking, which further mediates the expression of multiple inflammatory genes. in this review, we summarize the current knowledge on the epigenetic alterations triggered by cs and assess how such alterations may affect smoking-mediated inflammatory responses. conclusion: the recognition of the molecular mechanisms of the epigenetic changes in abnormal inflammation is expected to contribute to the understanding of the pathophysiology of cs-related diseases such that novel epigenetic therapies may be identified in the near future.”
Bohacek, J., & Mansuy, I. M.. (2013). Epigenetic inheritance of disease and disease risk. Neuropsychopharmacology
Plain numerical DOI: 10.1038/npp.2012.110
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“Epigenetic marks in an organism can be altered by environmental factors throughout life. although changes in the epigenetic code can be positive, some are associated with severe diseases, in particular, cancer and neuropsychiatric disorders. recent evidence has indicated that certain epigenetic marks can be inherited, and reshape developmental and cellular features over generations. this review examines the challenging possibility that epigenetic changes induced by environmental factors can contribute to some of the inheritance of disease and disease risk. this concept has immense implications for the understanding of biological functions and disease etiology, and provides potential novel strategies for diagnosis and treatment. examples of epigenetic inheritance relevant to human disease, such as the detrimental effects of traumatic stress or drug/toxic exposure on brain functions, are reviewed. different possible routes of transmission of epigenetic information involving the germline or germline-independent transfer are discussed, and different mechanisms for the maintenance and transmission of epigenetic information like chromatin remodeling and small noncoding rnas are considered. future research directions and remaining major challenges in this field are also outlined. finally, the adaptive value of epigenetic inheritance, and the cost and benefit of allowing acquired epigenetic marks to persist across generations is critically evaluated. © 2013 american college of neuropsychopharmacology. all rights reserved.”
Jiang, S., Postovit, L., Cattaneo, A., Binder, E. B., & Aitchison, K. J.. (2019). Epigenetic Modifications in Stress Response Genes Associated With Childhood Trauma. Frontiers in Psychiatry
Plain numerical DOI: 10.3389/fpsyt.2019.00808
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“Adverse childhood experiences (aces) may be referred to by other terms (e.g., early life adversity or stress and childhood trauma) and have a lifelong impact on mental and physical health. for example, childhood trauma has been associated with posttraumatic stress disorder (ptsd), anxiety, depression, bipolar disorder, diabetes, and cardiovascular disease. the heritability of ace-related phenotypes such as ptsd, depression, and resilience is low to moderate, and, moreover, is very variable for a given phenotype, which implies that gene by environment interactions (such as through epigenetic modifications) may be involved in the onset of these phenotypes. currently, there is increasing interest in the investigation of epigenetic contributions to ace-induced differential health outcomes. although there are a number of studies in this field, there are still research gaps. in this review, the basic concepts of epigenetic modifications (such as methylation) and the function of the hypothalamic-pituitary-adrenal (hpa) axis in the stress response are outlined. examples of specific genes undergoing methylation in association with ace-induced differential health outcomes are provided. limitations in this field, e.g., uncertain clinical diagnosis, conceptual inconsistencies, and technical drawbacks, are reviewed, with suggestions for advances using new technologies and novel research directions. we thereby provide a platform on which the field of ace-induced phenotypes in mental health may build.”
Han, Y., Franzen, J., Stiehl, T., Gobs, M., Kuo, C. C., Nikolić, M., … Wagner, W.. (2020). New targeted approaches for epigenetic age predictions. BMC Biology
Plain numerical DOI: 10.1186/s12915-020-00807-2
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“Background: age-associated dna methylation changes provide a promising biomarker for the aging process. while genome-wide dna methylation profiles enable robust age-predictors by integration of many age-associated cg dinucleotides (cpgs), there are various alternative approaches for targeted measurements at specific cpgs that better support standardized and cost-effective high-throughput analysis. results: in this study, we utilized 4647 illumina beadchip profiles of blood to select cpg sites that facilitate reliable age-predictions based on pyrosequencing. we demonstrate that the precision of dna methylation measurements can be further increased with droplet digital pcr (ddpcr). in comparison, bisulfite barcoded amplicon sequencing (bba-seq) gave slightly lower correlation between chronological age and dna methylation at individual cpgs, while the age-predictions were overall relatively accurate. furthermore, bba-seq data revealed that the correlation of methylation levels with age at neighboring cpg sites follows a bell-shaped curve, often associated with a ctcf binding site. we demonstrate that within individual bba-seq reads the dna methylation at neighboring cpgs is not coherently modified, but reveals a stochastic pattern. based on this, we have developed a new approach for epigenetic age predictions based on the binary sequel of methylated and non-methylated sites in individual reads, which reflects heterogeneity in epigenetic aging within a sample. conclusion: targeted dna methylation analysis at few age-associated cpgs by pyrosequencing, bba-seq, and particularly ddpcr enables high precision of epigenetic age-predictions. furthermore, we demonstrate that the stochastic evolution of age-associated dna methylation patterns in bba-seq data enables epigenetic clocks for individual dna strands.”
Duempelmann, L., Skribbe, M., & Bühler, M.. (2020). Small RNAs in the Transgenerational Inheritance of Epigenetic Information. Trends in Genetics
Plain numerical DOI: 10.1016/j.tig.2019.12.001
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“In recent years it has become evident that rna interference-related mechanisms can mediate the deposition and transgenerational inheritance of specific chromatin modifications in a truly epigenetic fashion. rapid progress has been made in identifying the rnai effector proteins and how they work together to confer long-lasting epigenetic responses, and initial studies hint at potential physiological relevance of such regulation. in this review, we highlight mechanistic studies in model organisms that advance our understanding of how small rnas trigger long-lasting epigenetic changes in gene expression and we discuss observations that lend support for the idea that small rnas might participate in mechanisms that trigger epigenetic gene expression changes in response to environmental cues and the effects these could have on population adaptation.”
Gensous, N., Garagnani, P., Santoro, A., Giuliani, C., Ostan, R., Fabbri, C., … Bacalini, M. G.. (2020). One-year Mediterranean diet promotes epigenetic rejuvenation with country- and sex-specific effects: a pilot study from the NU-AGE project. GeroScience
Plain numerical DOI: 10.1007/s11357-019-00149-0
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“Mediterranean diet has been proposed to promote healthy aging, but its effects on aging biomarkers have been poorly investigated. we evaluated the impact of a 1-year mediterranean-like diet in a pilot study including 120 elderly healthy subjects from the nu-age study (60 italians, 60 poles) by measuring the changes in their epigenetic age, assessed by horvath’s clock. we observed a trend towards epigenetic rejuvenation of participants after nutritional intervention. the effect was statistically significant in the group of polish females and in subjects who were epigenetically older at baseline. a genome-wide association study of epigenetic age changes after the intervention did not return significant (adjusted p value < 0.05) loci. however, we identified small-effect alleles (nominal p value < 10–4), mapping in genes enriched in pathways related to energy metabolism, regulation of cell cycle, and of immune functions. together, these findings suggest that mediterranean diet can promote epigenetic rejuvenation but with country-, sex-, and individual-specific effects, thus highlighting the need for a personalized approach to nutritional interventions.”
Li, M., Fu, X., Xie, W., Guo, W., Li, B., Cui, R., & Yang, W.. (2020). Effect of Early Life Stress on the Epigenetic Profiles in Depression. Frontiers in Cell and Developmental Biology
Plain numerical DOI: 10.3389/fcell.2020.00867
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“Depression is one of the most common mental disorders and has caused an overwhelming burden on world health. abundant studies have suggested that early life stress may grant depressive-like phenotypes in adults. childhood adversities that occurred in the developmental period amplified stress events in adulthood. epigenetic-environment interaction helps to explain the role of early life stress on adulthood depression. early life stress shaped the epigenetic profiles of the hpa axis, monoamine, and neuropeptides. in the context of early adversities increasing the risk of depression, early life stress decreased the activity of the glucocorticoid receptors, halted the circulation and production of serotonin, and reduced the molecules involved in modulating the neurogenesis and neuroplasticity. generally, dna methylation, histone modifications, and the regulation of non-coding rnas programmed the epigenetic profiles to react to early life stress. however, genetic precondition, subtypes of early life stress, the timing of epigenetic status evaluated, demographic characteristics in humans, and strain traits in animals favored epigenetic outcomes. more research is needed to investigate the direct evidence for how early life stress-induced epigenetic changes contribute to the vulnerability of depression.”
Tang, D., Gallusci, P., & Lang, Z.. (2020). Fruit development and epigenetic modifications. New Phytologist
Plain numerical DOI: 10.1111/nph.16724
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“Fruit development is a complex process that is regulated not only by plant hormones and transcription factors, but also requires epigenetic modifications. epigenetic modifications include dna methylation, histone post-translational modifications, chromatin remodeling and noncoding rnas. together, these epigenetic modifications, which are controlled during development and in response to the environment, determine the chromatin state of genes and contribute to the transcriptomes of an organism. recent studies have demonstrated that epigenetic regulation plays an important role in fleshy fruit ripening. dysfunction of a dna demethylase delayed ripening in tomato, and the application of a dna methylation inhibitor altered ripening process in the fruits of several species. these studies indicated that manipulating the epigenome of fruit crops could open new ways for breeding in the future. in this review, we highlight recent progress and address remaining questions and challenges concerning the epigenetic regulation of fruit development and ripening.”
Bezu, L., Chuang, A. W., Liu, P., Kroemer, G., & Kepp, O.. (2019). Immunological effects of epigenetic modifiers. Cancers
Plain numerical DOI: 10.3390/cancers11121911
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“Epigenetic alterations are associated with major pathologies including cancer. epigenetic dysregulation, such as aberrant histone acetylation, altered dna methylation, or modified chromatin organization, contribute to oncogenesis by inactivating tumor suppressor genes and activating oncogenic pathways. targeting epigenetic cancer hallmarks can be harnessed as an immunotherapeutic strategy, exemplified by the use of pharmacological inhibitors of dna methyltransferases (dnmt) and histone deacetylases (hdac) that can result in the release from the tumor of danger-associated molecular patterns (damps) on one hand and can (re-)activate the expression of tumor-associated antigens on the other hand. this finding suggests that epigenetic modifiers and more specifically the dna methylation status may change the interaction of chromatin with chaperon proteins including hmgb1, thereby contributing to the antitumor immune response. in this review, we detail how epigenetic modifiers can be used for stimulating therapeutically relevant anticancer immunity when used as stand-alone treatments or in combination with established immunotherapies.”
Ganesan, A., Arimondo, P. B., Rots, M. G., Jeronimo, C., & Berdasco, M.. (2019). The timeline of epigenetic drug discovery: From reality to dreams. Clinical Epigenetics
Plain numerical DOI: 10.1186/s13148-019-0776-0
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“The flexibility of the epigenome has generated an enticing argument to explore its reversion through pharmacological treatments as a strategy to ameliorate disease phenotypes. all three families of epigenetic proteins-readers, writers, and erasers- a re druggable targets that can be addressed through small-molecule inhibitors. at present, a few drugs targeting epigenetic enzymes as well as analogues of epigenetic modifications have been introduced into the clinic use (e.g. to treat haematological malignancies), and a wide range of epigenetic-based drugs are undergoing clinical trials. here, we describe the timeline of epigenetic drug discovery and development beginning with the early design based solely on phenotypic observations to the state-of-the-art rational epigenetic drug discovery using validated targets. finally, we will highlight some of the major aspects that need further research and discuss the challenges that need to be overcome to implement epigenetic drug discovery into clinical management of human disorders. to turn into reality, researchers from various disciplines (chemists, biologists, clinicians) need to work together to optimise the drug engineering, read-out assays, and clinical trial design.”
Maierhofer, A., Flunkert, J., Oshima, J., Martin, G. M., Haaf, T., & Horvath, S.. (2017). Accelerated epigenetic aging in Werner syndrome. Aging
Plain numerical DOI: 10.18632/aging.101217
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“Individuals suffering from werner syndrome (ws) exhibit many clinical signs of accelerated aging. while the underlying constitutional mutation leads to accelerated rates of dna damage, it is not yet known whether ws is also associated with an increased epigenetic age according to a dna methylation based biomarker of aging (the ‘epigenetic clock’). using whole blood methylation data from 18 ws cases and 18 age matched controls, we find that ws is associated with increased extrinsic epigenetic age acceleration (p=0.0072) and intrinsic epigenetic age acceleration (p=0.04), the latter of which is independent of age-related changes in the composition of peripheral blood cells. a multivariate model analysis reveals that ws is associated with an increase in dna methylation age (on average 6.4 years, p=0.011) even after adjusting for chronological age, gender, and blood cell counts. further, ws might be associated with a reduction in naïve cd8+ t cells (p=0.025) according to imputed measures of blood cell counts. overall, this study shows that ws is associated with an increased epigenetic age of blood cells which is independent of changes in blood cell composition. the extent to which this alteration is a cause or effect of ws disease phenotypes remains unknown.”
Lee, D. H., Ryu, H. W., Won, H. R., & Kwon, S. H.. (2017). Advances in epigenetic glioblastoma therapy. Oncotarget
Plain numerical DOI: 10.18632/oncotarget.14612
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“Glioblastoma multiforme (gbm) is the most lethal primary brain tumor in adults despite contemporary gold-standard first-line treatment strategies. this type of tumor recurs in virtually all patients and no commonly accepted standard treatment exists for the recurrent disease. therefore, advances in all scientific and clinical aspects of gbm are urgently needed. epigenetic mechanisms are one of the major factors contributing to the pathogenesis of cancers, including glioblastoma. epigenetic modulators that regulate gene expression by altering the epigenome and non-histone proteins are being exploited as therapeutic drug targets. over the last decade, numerous preclinical and clinical studies on histone deacetylase (hdac) inhibitors have shown promising results in various cancers. this article provides an overview of the anticancer mechanisms of hdac inhibitors and the role of hdac isoforms in gbm. we also summarize current knowledge on hdac inhibitors on the basis of preclinical studies and emerging clinical data.”
Rahat, B., Ali, T., Sapehia, D., Mahajan, A., & Kaur, J.. (2020). Circulating Cell-Free Nucleic Acids as Epigenetic Biomarkers in Precision Medicine. Frontiers in Genetics
Plain numerical DOI: 10.3389/fgene.2020.00844
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“The circulating cell-free nucleic acids (ccfnas) are a mixture of single- or double-stranded nucleic acids, released into the blood plasma/serum by different tissues via apoptosis, necrosis, and secretions. under healthy conditions, ccfnas originate from the hematopoietic system, whereas under various clinical scenarios, the concomitant tissues release ccfnas into the bloodstream. these ccfnas include dna, rna, microrna (mirna), long non-coding rna (lncrna), fetal dna/rna, and mitochondrial dna/rna, and act as potential biomarkers in various clinical conditions. these are associated with different epigenetic modifications, which show disease-related variations and so finding their role as epigenetic biomarkers in clinical settings. this field has recently emerged as the latest advance in precision medicine because of its clinical relevance in diagnostic, prognostic, and predictive values. dna methylation detected in ccfdna has been widely used in personalized clinical diagnosis; furthermore, there is also the emerging role of ccfrnas like mirna and lncrna as epigenetic biomarkers. this review focuses on the novel approaches for exploring ccfnas as epigenetic biomarkers in personalized clinical diagnosis and prognosis, their potential as therapeutic targets and disease progression monitors, and reveals the tremendous potential that epigenetic biomarkers present to improve precision medicine. we explore the latest techniques for both quantitative and qualitative detection of epigenetic modifications in ccfnas. the data on epigenetic modifications on ccfnas are complex and often milieu-specific posing challenges for its understanding. artificial intelligence and deep networks are the novel approaches for decoding complex data and providing insight into the decision-making in precision medicine.”
Bošković, A., & Rando, O. J.. (2018). Transgenerational epigenetic inheritance. Annual Review of Genetics
Plain numerical DOI: 10.1146/annurev-genet-120417-031404
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“Inheritance of genomic dna underlies the vast majority of biological inheritance, yet it has been clear for decades that additional epigenetic information can be passed on to future generations. here, we review major model systems for transgenerational epigenetic inheritance via the germline in multicellular organisms. in addition to surveying examples of epivariation that may arise stochastically or in response to unknown stimuli, we also discuss the induction of heritable epigenetic changes by genetic or environmental perturbations. mechanistically, we discuss the increasingly well-understood molecular pathways responsible for epigenetic inheritance, with a focus on the unusual features of the germline epigenome.”
Kandlur, A., Satyamoorthy, K., & Gangadharan, G.. (2020). Oxidative Stress in Cognitive and Epigenetic Aging: A Retrospective Glance. Frontiers in Molecular Neuroscience
Plain numerical DOI: 10.3389/fnmol.2020.00041
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“Brain aging is the critical and common factor among several neurodegenerative disorders and dementia. cellular, biochemical and molecular studies have shown intimate links between oxidative stress and cognitive dysfunction during aging and age-associated neuronal diseases. brain aging is accompanied by oxidative damage of nuclear as well as mitochondrial dna, and diminished repair. recent studies have reported epigenetic alterations during aging of the brain which involves reactive oxygen species (ros) that regulates various systems through distinct mechanisms. however, there are studies which depict differing roles of reactive oxidant species as a major factor during aging. in this review, we describe the evidence to show how oxidative stress is intricately linked to age-associated cognitive decline. the review will primarily focus on implications of age-associated oxidative damage on learning and memory, and the cellular events, with special emphasis on associated epigenetic machinery. a comprehensive understanding of these mechanisms may provide a perspective on the development of potential therapeutic targets within the oxidative system.”
Fila, M., Chojnacki, C., Chojnacki, J., & Blasiak, J.. (2019). Is an “epigenetic diet” for migraines justified? The case of folate and DNA methylation. Nutrients
Plain numerical DOI: 10.3390/nu11112763
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“Migraines are a common disease with limited treatment options and some dietary factors are recognized to trigger headaches. although migraine pathogenesis is not completely known, aberrant dna methylation has been reported to be associated with its occurrence. folate, an essential micronutrient involved in one-carbon metabolism anddnamethylation, was shown to have beneficial effects on migraines. moreover, the variability of the methylenetetrahydrofolate reductase gene, important in both folate metabolism and migraine pathogenesis, modulates the beneficial effects of folate for migraines. therefore, migraine could be targeted by a folate-rich, dna methylation-directed diet, but there are no data showing that beneficial effects of folate consumption result fromits epigenetic action. furthermore, contrary to epigenetic drugs, epigenetic diets contain many compounds, some yet unidentified, with poorly known or completely unknown potential to interfere with the epigenetic action of the main dietary components. the application of epigenetic diets for migraines and other diseases requires its personalization to the epigenetic profile of a patient, which is largely unknown. results obtained so far do not warrant the recommendation of any epigenetic diet as effective in migraine prevention and therapy. further studies including a folate-rich diet fortified with valproic acid, another modifier of epigenetic profile effective in migraine prophylaxis, may help to clarify this issue.”
Kabacik, S., Horvath, S., Cohen, H., & Raj, K.. (2018). Epigenetic ageing is distinct from senescence-mediated ageing and is not prevented by telomerase expression. Aging
Plain numerical DOI: 10.18632/aging.101588
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“The paramount role of senescent cells in ageing has prompted suggestions that re-expression of telomerase may prevent ageing; a proposition that is predicated on the assumption that senescent cells are the sole cause of ageing. recently, several dna methylation-based age estimators (epigenetic clocks) have been developed and they revealed that increased epigenetic age is associated with a host of age-related conditions, and is predictive of lifespan. employing these clocks to measure epigenetic age in vitro, we interrogated the relationship between epigenetic ageing and telomerase activity. although htert did not induce any perceptible change to the rate of epigenetic ageing, htert-expressing cells, which bypassed senescence, continued to age epigenetically. employment of htert mutants revealed that neither telomere synthesis nor immortalisation is necessary for the continued increase in epigenetic age by these cells. instead, the extension of their lifespan is sufficient to support continued epigenetic ageing of the cell. these characteristics, observed in cells from numerous donors and cell types, reveal epigenetic ageing to be distinct from replicative senescence. hence, while re-activation of htert may stave off physical manifestation of ageing through avoidance of replicative senescence, it would have little impact on epigenetic ageing which continues in spite of telomerase activity.”
Doroshow, D. B., Eder, J. P., & LoRusso, P. M.. (2017). BET inhibitors: A novel epigenetic approach. Annals of Oncology
Plain numerical DOI: 10.1093/annonc/mdx157
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“Epigenetics has been defined as ‘the structural adaptation of chromosomal regions so as to register, signal or perpetuate altered activity states.’ currently, several classes of anticancer drugs function at the epigenetic level, including inhibitors of dna methyltransferase, histone deacetylase (hdac), lysine-specific demethylase 1, zeste homolog 2, and bromodomain and extraterminal motif (bet) proteins. bet proteins have multiple functions, including the initiation and elongation of transcription and cell cycle regulation. in recent years, inhibitors of bet proteins have been developed as anticancer agents. these inhibitors exhibit selectivity for tumor cells by preferentially binding to superenhancers, noncoding regions of dna critical for the transcription of genes that determine a cell’s identity. preclinical research on bet inhibitors has identified them as a potential means of targeting myc. early clinical trials with bet inhibitors have had mixed results, with few responses in both hematologic and solid tumors that tend to be short-lived. toxicities have included severe, thrombocytopenia, fatigue, nausea, vomiting, and diarrhea; gi sideeffects, fatigue, and low-grade dysgeusia have limited compliance. however, preclinical data suggest that bet inhibitors may have a promising future in combination with other agents. they appear to be able to overcome resistance to targeted agents and have strong synergy with immune checkpoint inhibitors as well as with multiple epigenetic agents, particularly hdac inhibitors. in many instances, bet and hdac inhibitors were synergistic at reduced doses, suggesting a potential means of avoiding the overlapping toxicities of the two drug classes. bet inhibitors provide a novel approach to epigenetic anticancer therapy. however, to date they appear to have limited efficacy as single agents. a focus on bet inhibitors in combination with other drugs such as targeted and/or as other epigenetic agents is warranted, due to limited monotherapy activity, including pharmacodynamic correlatives differential activity amongst select drug combinations.”
Bloomer, R. H., Hutchison, C. E., Bäurle, I., Walker, J., Fang, X., Perera, P., … Dean, C.. (2020). The Arabidopsis epigenetic regulator ICU11 as an accessory protein of polycomb repressive complex 2. Proceedings of the National Academy of Sciences of the United States of America
Plain numerical DOI: 10.1073/pnas.1920621117
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“Molecular mechanisms enabling the switching and maintenance of epigenetic states are not fully understood. distinct histone modifications are often associated with on/off epigenetic states, but how these states are stably maintained through dna replication, yet in certain situations switch from one to another remains unclear. here, we address this problem through identification of arabidopsis incurvata11 (icu11) as a polycomb repressive complex 2 accessory protein. icu11 robustly immunoprecipitated in vivo with prc2 core components and the accessory proteins, embryonic flower 1 (emf1), like heterochromatin protein1 (lhp1), and telomere_repeat_binding factors (trbs). icu11 encodes a 2-oxoglutarate–dependent dioxygenase, an activity associated with histone demethylation in other organisms, and mutant plants show defects in multiple aspects of the arabidopsis epigenome. to investigate its primary molecular function we identified the arabidopsis flowering locus c (flc) as a direct target and found icu11 disrupted the cold-induced, polycomb-mediated silencing underlying vernalization. icu11 prevented reduction in h3k36me3 levels normally seen during the early cold phase, supporting a role for icu11 in h3k36me3 demethylation. this was coincident with an attenuation of h3k27me3 at the internal nucleation site in flc, and reduction in h3k27me3 levels across the body of the gene after plants were returned to the warm. thus, icu11 is required for the cold-induced epigenetic switching between the mutually exclusive chromatin states at flc, from the active h3k36me3 state to the silenced h3k27me3 state. these data support the importance of physical coupling of histone modification activities to promote epigenetic switching between opposing chromatin states.”
Sabeeha, & Hasnain, S. E.. (2019). Forensic Epigenetic Analysis: The Path Ahead. Medical Principles and Practice
Plain numerical DOI: 10.1159/000499496
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“Unlike dna fingerprinting, which scores for differences in the genome that are phenotype neutral, epigenetic variations are gaining importance in forensic investigations. methylation of dna has a broad range of effects on the lifestyle, health status, and physical appearance of individuals. dna methylation profiling of forensic samples is useful in determination of the cell or tissue type of the dna source and also for estimation of age. the quality and quantity of the biosample available from the crime scene limits the possible number of dna methylation tests and the selection of the technology that can be used. several techniques have been used for dna methylation analysis for epigenetic investigations of forensic biological samples. however, novel techniques are needed for multiplex analysis of epigenetic markers as the techniques that are currently available require a large amount of high-quality dna and are also limited in their multiplexing capacities that are often insufficient to fully resolve a forensic query of interest.”
Bertucci, E. M., & Parrott, B. B.. (2020). Is CpG Density the Link between Epigenetic Aging and Lifespan?. Trends in Genetics
Plain numerical DOI: 10.1016/j.tig.2020.06.003
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“The genetic mechanisms contributing to lifespan variation remain unresolved. based on recent conceptual advances in our understanding of epigenetic potential and the relocalization of chromatin modifiers (rcm), we hypothesize that increased cpg density is protective against age-related erosion of the epigenetic landscape and may explain interspecific variation in lifespan.”
Tough, D. F., Rioja, I., Modis, L. K., & Prinjha, R. K.. (2020). Epigenetic Regulation of T Cell Memory: Recalling Therapeutic Implications. Trends in Immunology
Plain numerical DOI: 10.1016/j.it.2019.11.008
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“Memory t cells possess functional differences from naïve t cells that powerfully contribute to the efficiency of secondary immune responses. these abilities are imprinted during the primary response, linked to the acquisition of novel patterns of gene expression. underlying this are alterations at the chromatin level (epigenetic modifications) that regulate constitutive and inducible gene transcription. t cell epigenetic memory can persist long-term, contributing to long-lasting immunity after infection or vaccination. however, acquired epigenetic states can also hinder effective tumor immunity or contribute to autoimmunity. the growing understanding of epigenetic gene regulation as it relates to both the stability and malleability of t cell memory may offer the potential to selectively modify t cell memory in disease by targeting epigenetic mechanisms.”
Bandera-Merchan, B., Boughanem, H., Crujeiras, A. B., Macias-Gonzalez, M., & Tinahones, F. J.. (2020). Ketotherapy as an epigenetic modifier in cancer. Reviews in Endocrine and Metabolic Disorders
Plain numerical DOI: 10.1007/s11154-020-09567-4
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“Epigenetic alterations in cancer play a variety of roles. aberrant dna methylation, as one of the epigenetic mechanisms, has been widely studied in both tumor and liquid biopsies and provide a useful bench mark for treatment response in cancer. recently, several studies have reported an association between the type of diet and epigenetic modifications. whereby there is a growing interest in finding the ‘anti-cancer diet formula’, if such a thing exists. in this sense, ketogenic diets (kd) have reported potentially beneficial effects, which were able to prevent malignancies and decrease tumor growth. some studies have even shown increased survival in cancer patients, reduced side effects of cytotoxic treatments, and intensified efficacy of cancer therapies. although the biological mechanisms of kd are not well understood, it has been reported that kd may affect dna methylation by modulating the expression of crucial genes involved in tumor survival and proliferation. however, there are many considerations to take into account to use ketotherapy in cancer, such as epigenetic mark, type of cancer, immunological and metabolic state or microbiota profile. in this review, we argue about ketotherapy as a potential strategy to consider as coadjuvant of cancer therapy. we will focus on mainly epigenetic mechanisms and dietary approach that could be included in the current clinical practice guidelines.”
Izquierdo, A. G., & Crujeiras, A. B.. (2019). Obesity-related epigenetic changes after bariatric surgery. Frontiers in Endocrinology
Plain numerical DOI: 10.3389/fendo.2019.00232
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“Objective: in recent years, an increasing number of studies have begun focusing on epigenetics as a link between environmental factors and a greater predisposition to the development of obesity and its comorbidities. an important challenge in this field is the evaluation of the possibility of the reversal of obesity-related epigenetic marks by means of therapy to induce weight loss and if the beneficial effects of therapy in reducing obesity are mediated by epigenetic mechanisms. we aimed to offer an outline of the current results regarding to the impact of bariatric surgery on epigenetic regulation, as well as to show if the beneficial effect of this intervention could be mediated by epigenetic mechanisms. methods: a review of the scientific publications in pubmed was performed by using key words related to obesity, epigenetics and bariatric surgery to provide an update of recent findings in this area of research. the most relevant and recently published articles and abstracts were selected to frame this review. results: previous studies have demonstrated the presence of differential dna methylation after bariatric surgery and the differential expression of non-coding rnas. therefore, epigenetic regulation could mediate the benefit of bariatric surgery on body weight and the metabolic disturbances associated with excess body weight, such as insulin resistance, hypertension, and cardiovascular disease. this evidence is relatively new as epigenetic regulation was first evaluated in the obesity field only a few years ago. however, there is an urgent need to perform longitudinal studies to evaluate the capacity of epigenetic marks in the prediction of bariatric surgery response. conclusions: bariatric surgery appears to be capable of partially reversing the obesity-related epigenome. the identification of potential epigenetic biomarkers predictive for the success of bariatric surgery may open new doors to personalized therapy for severe obesity.”
Miranda-Gonçalves, V., Lameirinhas, A., Henrique, R., & Jerónimo, C.. (2018). Metabolism and epigenetic interplay in cancer: Regulation and putative therapeutic targets. Frontiers in Genetics
Plain numerical DOI: 10.3389/fgene.2018.00427
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“Alterations in the epigenome and metabolism affect molecular rewiring of cancer cells facilitating cancer development and progression. oncogene-driven metabolic reprogramming modifies the epigenetic landscape through dna and histone modification enzymes modulation. conversely, epigenetic mechanisms regulate the expression of metabolism-related genes, promoting the well-known metabolic reprogramming of cancer cells and, consequently, changing the metabolome. thus, epigenetic-metabolomic interplay plays a critical role in tumorigenesis by co-ordinately sustaining cell proliferation, metastasis and pluripotency. in this review we emphasize the importance of tumor metabolites in the activity of most chromatin-modifying enzymes and their underlying role in tumorigenesis. furthermore, we highlight promising molecular targets in tumor metabolism as well as in the epigenetic machinery, focusing on development of small molecules or biologic inhibitors that counteract the epigenomic-metabolic interplay in cancer.”
Bonasio, R., Tu, S., & Reinberg, D.. (2010). Molecular signals of epigenetic states. Science
Plain numerical DOI: 10.1126/science.1191078
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“Epigenetic signals are responsible for the establishment, maintenance, and reversal of metastable transcriptional states that are fundamental for the cell’s ability to ‘remember’ past events, such as changes in the external environment or developmental cues. complex epigenetic states are orchestrated by several converging and reinforcing signals, including transcription factors, noncoding rnas, dna methylation, and histone modifications. although all of these pathways modulate transcription from chromatin in vivo, the mechanisms by which epigenetic information is transmitted through cell division remain unclear. because epigenetic states are metastable and change in response to the appropriate signals, a deeper understanding of their molecular framework will allow us to tackle the dysregulation of epigenetics in disease.”
van der Veeken, J., Zhong, Y., Sharma, R., Mazutis, L., Dao, P., Pe’er, D., … Rudensky, A. Y.. (2019). Natural Genetic Variation Reveals Key Features of Epigenetic and Transcriptional Memory in Virus-Specific CD8 T Cells. Immunity
Plain numerical DOI: 10.1016/j.immuni.2019.03.031
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“Van der veeken et al. use naturally occurring cis-regulatory variation in wild-derived inbred mouse strains to dissect mechanisms of stable and reversible gene regulation in cd8 t cells. their findings reveal central roles for t-box and runx transcription factors and suggest a general mechanism for the formation of transcriptional and epigenetic memory.”
Hudec, M., Dankova, P., Solc, R., Bettazova, N., & Cerna, M.. (2020). Epigenetic regulation of circadian rhythm and its possible role in diabetes mellitus. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms21083005
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“This review aims to summarize the knowledge about the relationship between circadian rhythms and their influence on the development of type 2 diabetes mellitus (t2dm) and metabolic syndrome. circadian rhythms are controlled by internal molecular feedback loops that synchronize the organism with the external environment. these loops are affected by genetic and epigenetic factors. genetic factors include polymorphisms and mutations of circadian genes. the expression of circadian genes is regulated by epigenetic mechanisms that change from prenatal development to old age. epigenetic modifications are influenced by the external environment. most of these modifications are affected by our own life style. irregular circadian rhythm and low quality of sleep have been shown to increase the risk of developing t2dm and other metabolic disorders. here, we attempt to provide a wide description of mutual relationships between epigenetic regulation, circadian rhythm, aging process and highlight new evidences that show possible therapeutic advance in the field of chrono-medicine which will be more important in the upcoming years.”
Wang, T., Morency, D. T., Harris, N., & Davis, G. W.. (2020). Epigenetic Signaling in Glia Controls Presynaptic Homeostatic Plasticity. Neuron
Plain numerical DOI: 10.1016/j.neuron.2019.10.041
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“Homeostatic plasticity stabilizes neural function throughout life and, if impaired, renders the nervous system less robust to injury, infection, and disease. wang and colleagues demonstrate that the homeostatic control of neurotransmitter release requires epigenetic signaling factors that reside in glia. their study argues for glial-dependent, epigenetic specification of the neuronal extracellular environment that is essential for the induction and maintenance of homeostatic plasticity. the data may have relevance for neurological and psychiatric disorders associated with impaired epigenetic signaling.”
Divella, R., Daniele, A., Savino, E., & Paradiso, A.. (2020). Anticancer Effects of Nutraceuticals in the Mediterranean Diet: An Epigenetic Diet Model. Cancer Genomics and Proteomics
Plain numerical DOI: 10.21873/cgp.20193
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“Epidemiological and clinical studies support the association between nutrition and development or progression of different malignancies such as colon, breast, and prostate cancer, defining these tumors as diet-associated cancer. the mediterranean diet shows inverse associations with metabolic diseases, cardiovascular pathologies and various types of cancer. many bioactive nutrients of the mediterranean diet have been identified as factors protective against these types of pathologies. the epigenome has been identified as the primary goal of modulations in gene expression related to these molecular nutrients. in fact, they can modify the epigenome and can be incorporated into the ‘epigenetic diet’, which translates into a diet regimen that can be used therapeutically for health or preventative purposes. most epigenetic changes are influenced by lifestyle and nutrition. epigenetic therapy is a new area for the development of nutraceuticals whose absence of toxicity can represent a valid asset in cancer prevention strategies. recent advances in understanding the mechanisms of nutrigenomics, nutrigenetics and nutraceuticals have led to the identification of superfoods capable of favorably conditioning gene expression. in this review, we highlight the importance of nutraceuticals present in the mediterranean diet as epigenetic modifiers both in the mechanisms of tumor onset and as protective agents.”
Li, S., Yang, D., Gao, L., Wang, Y., & Peng, Q.. (2020). Epigenetic regulation and mechanobiology. Biophysics Reports
Plain numerical DOI: 10.1007/s41048-020-00106-x
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“Mechanical force regulates a variety of cellular functions through inducing modulations in nuclear chromatin structures and epigenetic landscapes (outside in). the epigenetic modifications, in turn, regulate gene expressions and affect phenotypic outcomes, including cytoskeletal organization and cell-cell/cell-ecm interactions (inside out). while there have been significant advances in the understanding of mechanotransduction in the nucleus, there is still a lack of knowledge on the potential mechanisms through which mechanical cues affect epigenetic and chromatin regulations to determine genetic outcomes. this review firstly focuses on the current understanding of epigenetic regulations and then summarizes how mechanotransduction and epigenetic modification couple together to regulate molecular and cellular functions, eventually causing functional phenotype changes e.g., diseases. lastly, we introduce related technologies for mechanistic studies, particularly fluorescence resonance energy transfer (fret) biosensors for the visualization of dynamic epigenetic regulations in single living cells, as well as the applications of fret biosensors to visualize mechanotransduction events occurring in the nucleus. these studies could provide new insights into epigenetics in regulating the physiological and pathological processes in living cells under different mechanical environments.”
Lee, P. S., Chiou, Y. S., Ho, C. T., & Pan, M. H.. (2018). Chemoprevention by resveratrol and pterostilbene: Targeting on epigenetic regulation. BioFactors
Plain numerical DOI: 10.1002/biof.1401
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“Epigenetic mechanisms are essential in regulating normal cellular functions and play an important role during the disease developmental stages. however, aberrant epigenetic mechanisms may lead to pathological consequences such as cancer, neurological disorders, bone and skeletal diseases, cardiovascular dysfunction, and metabolic syndrome. the molecular mechanisms of epigenetic modification include dna methylation, histone modification (acetylation, methylation and phosphorylation), and micrornas (mirnas). unlike genetic modifications, epigenetic states of genes are reversible and can be altered by certain intrinsic and extrinsic factors. in the past few decades, accumulated evidence shows that dietary phytochemicals with chemopreventive effects are also potent epigenetic regulators. resveratrol and pterostilbene are stilbenoids, which have been reported to have anti-cancer, anti-inflammatory, anti-lipid, and anti-diabetic properties. stilbenoids are also reported to improve cardiovascular disease. by altering dna methylation and histone modification or by modulating mirna expression, resveratrol, and pterostilbene become potent epigenetic modifiers. in this review, we summarize these studies and underlying mechanisms of resveratrol and pterostilbene and their influence on epigenetic mechanisms. © 2017 biofactors, 44(1):26–35, 2018.”
Lu, Y., Chan, Y. T., Tan, H. Y., Li, S., Wang, N., & Feng, Y.. (2020). Epigenetic regulation in human cancer: The potential role of epi-drug in cancer therapy. Molecular Cancer
Plain numerical DOI: 10.1186/s12943-020-01197-3
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“Epigenetics is dynamic and heritable modifications to the genome that occur independently of dna sequence. it requires interactions cohesively with various enzymes and other molecular components. aberrant epigenetic alterations can lead to inappropriate onset of genetic expressions and promote tumorigenesis. as the epigenetic modifiers are susceptible to extrinsic factors and reversible, they are becoming promising targets in multiple cancer therapies. recently, various epi-drugs have been developed and implicated in clinical use. the use of epi-drugs alone, or in combination with chemotherapy or immunotherapy, has shown compelling outcomes, including augmentation of anti-tumoral effects, overcoming drug resistance, and activation of host immune response.”
Soler-Botija, C., Gálvez-Montón, C., & Bayés-Genís, A.. (2019). Epigenetic Biomarkers in Cardiovascular Diseases. Frontiers in Genetics
Plain numerical DOI: 10.3389/fgene.2019.00950
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“Cardiovascular diseases are the number one cause of death worldwide and greatly impact quality of life and medical costs. enormous effort has been made in research to obtain new tools for efficient and quick diagnosis and predicting the prognosis of these diseases. discoveries of epigenetic mechanisms have related several pathologies, including cardiovascular diseases, to epigenetic dysregulation. this has implications on disease progression and is the basis for new preventive strategies. advances in methodology and big data analysis have identified novel mechanisms and targets involved in numerous diseases, allowing more individualized epigenetic maps for personalized diagnosis and treatment. this paves the way for what is called pharmacoepigenetics, which predicts the drug response and develops a tailored therapy based on differences in the epigenetic basis of each patient. similarly, epigenetic biomarkers have emerged as a promising instrument for the consistent diagnosis and prognosis of cardiovascular diseases. their good accessibility and feasible methods of detection make them suitable for use in clinical practice. however, multicenter studies with a large sample population are required to determine with certainty which epigenetic biomarkers are reliable for clinical routine. therefore, this review focuses on current discoveries regarding epigenetic biomarkers and its controversy aiming to improve the diagnosis, prognosis, and therapy in cardiovascular patients.”
Pavlou, M. A. S., Grandbarbe, L., Buckley, N. J., Niclou, S. P., & Michelucci, A.. (2019). Transcriptional and epigenetic mechanisms underlying astrocyte identity. Progress in Neurobiology
Plain numerical DOI: 10.1016/j.pneurobio.2018.12.007
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“Astrocytes play a significant role in coordinating neural development and provide critical support for the function of the cns. they possess important adaptation capacities that range from their transition towards reactive astrocytes to their ability to undergo reprogramming, thereby revealing their potential to retain latent features of neural progenitor cells. we propose that the mechanisms underlying reactive astrogliosis or astrocyte reprogramming provide an opportunity for initiating neuronal regeneration, a process that is notably reduced in the mammalian nervous system throughout evolution. conversely, this plasticity may also affect normal astrocytic functions resulting in pathologies ranging from neurodevelopmental disorders to neurodegenerative diseases and brain tumors. we postulate that epigenetic mechanisms linking extrinsic cues and intrinsic transcriptional programs are key factors to maintain astrocyte identity and function, and critically, to control the balance of regenerative and degenerative activity. here, we will review the main evidences supporting this concept. we propose that unravelling the epigenetic and transcriptional mechanisms underlying the acquisition of astrocyte identity and plasticity, as well as understanding how these processes are modulated by the local microenvironment under specific threatening or pathological conditions, may pave the way to new therapeutic avenues for several neurological disorders including neurodegenerative diseases and brain tumors of astrocytic lineage.”
Costentin, J.. (2020). Epigenetic effects of cannabis/tetrahydrocannabinol. Bulletin de l’Academie Nationale de Medecine
Plain numerical DOI: 10.1016/j.banm.2020.04.004
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“The almost pandemic spread of cannabis among adolescents and young adults, especially in france, justifies the attention given to the consequences, not only acute but also delayed, of this intoxication. in the latter case, epigenetic mechanisms occur. we will first recall various types of epigenetic modifications involving either chromatin histones, mainly methylations or acetylations, either dna, by methylation of cytosines. such modifications caused by the tetrahydrocannabinol/thc of cannabis can intervene: either at the level of gametes before procreation, or at different points of the life cycle. these epigenetic modifications are associated with an increase in vulnerability to drug addiction, involving dopamine d2 receptors in the nucleus accumbens, overexpression of enkephalin precursor synthesis, modifications of: cb1 receptors of endocannabinoids, glutamic acid receptors, gaba receptors, proteins involved in synaptic plasticity… these changes can also affect: immune system, cognitive activities, development of psychiatric diseases, related to disturbances of brain maturation. the knowledge that accumulates in this respect is the opposite of the ambient trivialization of this drug. they impose sending an alert to the public authorities and to the public, especially young people, warning on the risks associated with this drug use and abuse.”
Roszkiewicz, M., Dopytalska, K., Szymańska, E., Jakimiuk, A., & Walecka, I.. (2020). Environmental risk factors and epigenetic alternations in psoriasis. Annals of Agricultural and Environmental Medicine
Plain numerical DOI: 10.26444/aaem/112107
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“Introduction and objective. psoriasis isa quite common, chronic and immune-mediated skin disorder. the prevalence of psoriasis differs in various countries, but it is said to affect 2% of the world’s population in general. psoriasis has many different clinical features but all lesions have the same characteristic: erythema, thickening and scale, although other clinical features are also connected, such as psoriatic arthritis, obesity and metabolic syndrome. all of these may lead to conditions impairing the quality of life. this review is an attempt to summarize recent data regarding environmental factors, together with epigenetic markers and processes playing an important role in psoriasis. state of knowledge. many different environmental factors play a role in genetically predisposed patients. this is causes epigenetic alternations which may be a linking part in the whole process. many studies have indicated a connection between psoriasis and various genes and antigens. the presence of hla-cw6 is common as well a strong link between its presence and the onset of psoriasis being observed. the main alternations are dna methylation, histone’s modifications and the role of microrna. excessive reaction is usually not present without a triggering factor. environmental factors are mostly rated, such as drugs, life style and habits (smoking, alcohol), diet, physical trauma (skin injury provoking koebner phenomenon), stress, microorganism and infections. conclusions. the correlation between pathogenesis of psoriasis and environmental risk factors, together with epigenetic alternations still require more investigation. education about diet habits, nutrition, weight loss and healthy lifestyle seems to be important during the treatment of psoriasis.”
Day, J. J., & Sweatt, J. D.. (2011). Epigenetic Mechanisms in Cognition. Neuron
Plain numerical DOI: 10.1016/j.neuron.2011.05.019
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“Although the critical role for epigenetic mechanisms in development and cell differentiation has long been appreciated, recent evidence reveals that these mechanisms are also employed in postmitotic neurons as a means of consolidating and stabilizing cognitive-behavioral memories. in this review, we discuss evidence for an ‘ epigenetic code’ in the central nervous system that mediates synaptic plasticity, learning, and memory. we consider how specific epigenetic changes are regulated and may interact with each other during memory formation and how these changes manifest functionally at the cellular and circuit levels. we also describe a central role for mitogen-activated protein kinases in controlling chromatin signaling in plasticity and memory. finally, we consider how aberrant epigenetic modifications may lead to cognitive disorders that affect learning and memory, and we review the therapeutic potential of epigenetic treatments for the amelioration of these conditions. © 2011 elsevier inc.”
Biswas, S., & Rao, C. M.. (2018). Epigenetic tools (The Writers, The Readers and The Erasers) and their implications in cancer therapy. European Journal of Pharmacology
Plain numerical DOI: 10.1016/j.ejphar.2018.08.021
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“Addition of chemical tags on the dna and modification of histone proteins impart a distinct feature on chromatin architecture. with the advancement in scientific research, the key players underlying these changes have been identified as epigenetic modifiers of the chromatin. indeed, the plethora of enzymes catalyzing these modifications, portray the diversity of epigenetic space and the intricacy in regulating gene expression. these epigenetic players are categorized as writers: that introduce various chemical modifications on dna and histones, readers: the specialized domain containing proteins that identify and interpret those modifications and erasers: the dedicated group of enzymes proficient in removing these chemical tags. research over the past few decades has established that these epigenetic tools are associated with numerous disease conditions especially cancer. besides, with the involvement of epigenetics in cancer, these enzymes and protein domains provide new targets for cancer drug development. this is certain from the volume of epigenetic research conducted in universities and r&d sector of pharmaceutical industry. here we have highlighted the different types of epigenetic enzymes and protein domains with an emphasis on methylation and acetylation. this review also deals with the recent developments in small molecule inhibitors as potential anti-cancer drugs targeting the epigenetic space.”
Fiorito, G., McCrory, C., Robinson, O., Carmeli, C., Rosales, C. O., Zhang, Y., … Zins, M.. (2019). Socioeconomic position, lifestyle habits and biomarkers of epigenetic aging: A multi-cohort analysis. Aging
Plain numerical DOI: 10.18632/aging.101900
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“Differences in health status by socioeconomic position (sep) tend to be more evident at older ages, suggesting the involvement of a biological mechanism responsive to the accumulation of deleterious exposures across the lifespan. dna methylation (dnam) has been proposed as a biomarker of biological aging that conserves memory of endogenous and exogenous stress during life. we examined the association of education level, as an indicator of sep, and lifestyle-related variables with four biomarkers of age-dependent dnam dysregulation: the total number of stochastic epigenetic mutations (sems) and three epigenetic clocks (horvath, hannum and levine), in 18 cohorts spanning 12 countries. the four biological aging biomarkers were associated with education and different sets of risk factors independently, and the magnitude of the effects differed depending on the biomarker and the predictor. on average, the effect of low education on epigenetic aging was comparable with those of other lifestyle-related risk factors (obesity, alcohol intake), with the exception of smoking, which had a significantly stronger effect. our study shows that low education is an independent predictor of accelerated biological (epigenetic) aging and that epigenetic clocks appear to be good candidates for disentangling the biological pathways underlying social inequalities in healthy aging and longevity.”
Sugiura, M., Sato, H., Kanesaka, M., Imamura, Y., Sakamoto, S., Ichikawa, T., & Kaneda, A.. (2021). Epigenetic modifications in prostate cancer. International Journal of Urology
Plain numerical DOI: 10.1111/iju.14406
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“Prostate cancer is a major cause of cancer-related deaths among men worldwide. in addition to genomic alterations, epigenetic alterations accumulated in prostate cancer have been elucidated. while aberrant deoxyribonucleic acid hypermethylation in promoter cpg islands inactivates crucial genes associated with deoxyribonucleic acid repair, cell cycle, apoptosis or cell adhesion, aberrant deoxyribonucleic acid hypomethylation can lead to oncogene activation. acetylation of histone is also deregulated in prostate cancer, which could cause aberrant super-enhancer formation and activation of genes associated with cancer development. deregulations of histone methylation, such as an increase of trimethylation at position 27 of histone h3 by enhancer of zeste homolog2 overexpression, or other modifications, such as phosphorylation and ubiquitination, are also involved in prostate cancer development, and inhibitors targeting these epigenomic aberrations might be novel therapeutic strategies. in this review, we provide an overview of epigenetic alterations in the development and progression of prostate cancer, focusing on deoxyribonucleic acid methylation and histone modifications.”
Li, S., Nguyen, T. L., Wong, E. M., Dugué, P. A., Dite, G. S., Armstrong, N. J., … Hopper, J. L.. (2020). Genetic and environmental causes of variation in epigenetic aging across the lifespan. Clinical Epigenetics
Plain numerical DOI: 10.1186/s13148-020-00950-1
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“Background: dna methylation-based biological age (dnam age) is an important biomarker for adult health. studies in specific age ranges have found widely varying results about its genetic and environmental causes of variation. however, these studies are not able to provide a comprehensive view of the causes of variation over the lifespan. results: in order to investigate the genetic and environmental causes of dnam age variation across the lifespan, we pooled genome-wide dna methylation data for 4217 people aged 0–92 years from 1871 families. dnam age was calculated using the horvath epigenetic clock. we estimated familial correlations in dnam age for monozygotic (mz) twin, dizygotic (dz) twin, sibling, parent–offspring, and spouse pairs by cohabitation status. genetic and environmental variance components models were fitted and compared. we found that twin pair correlations were − 0.12 to 0.18 around birth, not different from zero (all p > 0.29). for all pairs of relatives, their correlations increased with time spent living together (all p < 0.02) at different rates (mz > dz and siblings > parent–offspring; p < 0.001) and decreased with time spent living apart (p = 0.02) at similar rates. these correlation patterns were best explained by cohabitation-dependent shared environmental factors, the effects of which were 1.41 (95% confidence interval [ci] 1.16 to 1.66) times greater for mz pairs than for dz and sibling pairs, and the latter were 2.03 (95% ci 1.13 to 9.47) times greater than for parent–offspring pairs. genetic factors explained 13% (95% ci − 10 to 35%) of variation (p = 0.27). similar results were found for another two epigenetic clocks, suggesting that our observations are robust to how dnam age is measured. in addition, results for the other clocks were consistent with there also being a role for prenatal environmental factors in determining their variation. conclusions: variation in dnam age is mostly caused by environmental factors, including those shared to different extents by relatives while living together and whose effects persist into old age. the equal environment assumption of the classic twin study might not hold for epigenetic aging.”
Singh, P. B., & Newman, A. G.. (2018). Age reprogramming and epigenetic rejuvenation. Epigenetics and Chromatin
Plain numerical DOI: 10.1186/s13072-018-0244-7
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“Age reprogramming represents a novel method for generating patient-specific tissues for transplantation. it bypasses the de-differentiation/redifferentiation cycle that is characteristic of the induced pluripotent stem (ips) and nuclear transfer-embryonic stem (nt-es) cell technologies that drive current interest in regenerative medicine. despite the obvious potential of ips and nt-es cell-based therapies, there are several problems that must be overcome before these therapies are safe and routine. as an alternative, age reprogramming aims to rejuvenate the specialized functions of an old cell without de-differentiation; age reprogramming does not require developmental reprogramming through an embryonic stage, unlike the ips and nt-es cell-based therapies. tests of age reprogramming have largely focused on one aspect, the epigenome. epigenetic rejuvenation has been achieved in vitro in the absence of de-differentiation using ips cell reprogramming factors. studies on the dynamics of epigenetic age (eage) reprogramming have demonstrated that the separation of eage from developmental reprogramming can be explained largely by their different kinetics. age reprogramming has also been achieved in vivo and shown to increase lifespan in a premature ageing mouse model. we conclude that age and developmental reprogramming can be disentangled and regulated independently in vitro and in vivo.”
Browne, C. J., Godino, A., Salery, M., & Nestler, E. J.. (2020). Epigenetic Mechanisms of Opioid Addiction. Biological Psychiatry
Plain numerical DOI: 10.1016/j.biopsych.2019.06.027
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“Opioid use kills tens of thousands of americans each year, devastates families and entire communities, and cripples the health care system. exposure to opioids causes long-term changes to brain regions involved in reward processing and motivation, leading vulnerable individuals to engage in pathological drug seeking and drug taking that can remain a lifelong struggle. the persistence of these neuroadaptations is mediated in part by epigenetic remodeling of gene expression programs in discrete brain regions. although the majority of work examining how epigenetic modifications contribute to addiction has focused on psychostimulants such as cocaine, research into opioid-induced changes to the epigenetic landscape is emerging. this review summarizes our knowledge of opioid-induced epigenetic modifications and their consequential changes to gene expression. current evidence points toward opioids promoting higher levels of permissive histone acetylation and lower levels of repressive histone methylation as well as alterations to dna methylation patterns and noncoding rna expression throughout the brain’s reward circuitry. additionally, studies manipulating epigenetic enzymes in specific brain regions are beginning to build causal links between these epigenetic modifications and changes in addiction-related behavior. moving forward, studies must leverage advanced chromatin analysis and next-generation sequencing approaches combined with bioinformatics pipelines to identify novel gene networks regulated by particular epigenetic modifications. improved translational relevance also requires increased focus on volitional drug-intake models and standardization of opioid exposure paradigms. such work will significantly advance our understanding of how opioids cause persistent changes to brain function and will provide a platform on which to develop interventions for treating opioid addiction.”
Crimi, E., Benincasa, G., Figueroa-Marrero, N., Galdiero, M., & Napoli, C.. (2020). Epigenetic susceptibility to severe respiratory viral infections and its therapeutic implications: a narrative review. British Journal of Anaesthesia
Plain numerical DOI: 10.1016/j.bja.2020.06.060
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“The emergence of highly pathogenic strains of influenza virus and coronavirus (cov) has been responsible for large epidemic and pandemic outbreaks characterised by severe pulmonary illness associated with high morbidity and mortality. one major challenge for critical care is to stratify and minimise the risk of multi-organ failure during the stay in the intensive care unit (icu). epigenetic-sensitive mechanisms, including deoxyribonucleic acid (dna) and ribonucleic acid (rna) methylation, histone modifications, and non-coding rnas may lead to perturbations of the host immune-related transcriptional programmes by regulating chromatin structure and gene expression patterns. viruses causing severe pulmonary illness can use epigenetic-regulated mechanisms during host–pathogen interaction to interfere with innate and adaptive immunity, adequacy of inflammatory response, and overall outcome of viral infections. for example, middle east respiratory syndrome-cov and h5n1 can affect host antigen presentation through dna methylation and histone modifications. the same mechanisms would presumably occur in patients with coronavirus disease 2019, in which tocilizumab may epigenetically reduce microvascular damage. targeting epigenetic pathways by immune modulators (e.g. tocilizumab) or repurposed drugs (e.g. statins) may provide novel therapeutic opportunities to control viral–host interaction during critical illness. in this review, we provide an update on epigenetic-sensitive mechanisms and repurposed drugs interfering with epigenetic pathways which may be clinically suitable for risk stratification and beneficial for treatment of patients affected by severe viral respiratory infections.”
Skinner, M. K.. (2014). Environmental stress and epigenetic transgenerational inheritance. BMC Medicine
Plain numerical DOI: 10.1186/s12916-014-0153-y
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“Previous studies have shown a wide variety of environmental toxicants and abnormal nutrition can promote the epigenetic transgenerational inheritance of disease. more recently a number of studies have indicated environmental stress can also promote epigenetic alterations that are transmitted to subsequent generations to induce pathologies. a recent study by yao and colleagues demonstrated gestational exposure to restraint stress and forced swimming promoted preterm birth risk and adverse newborn outcomes generationally. this ancestral stress promoted the epigenetic transgenerational inheritance of abnormalities in the great-grand offspring of the exposed gestating female. several studies now support the role of environmental stress in promoting the epigenetic transgenerational inheritance of disease. observations suggest ancestral environmental stress may be a component of disease etiology in the current population.please see related article: http://www.biomedcentral.com/content/pdf/s12916-014-0121-6.pdf.”
Quach, A., Levine, M. E., Tanaka, T., Lu, A. T., Chen, B. H., Ferrucci, L., … Horvath, S.. (2017). Epigenetic clock analysis of diet, exercise, education, and lifestyle factors. Aging
Plain numerical DOI: 10.18632/aging.101168
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“Behavioral and lifestyle factors have been shown to relate to a number of health-related outcomes, yet there is a need for studies that examine their relationship to molecular aging rates. toward this end, we use recent epi genetic biomarkers of age that have previously been shown to predict all-cause mortality, chronic conditions and age-related functional decline. we analyze cross-sectional data from 4,173 postmenopausal female participants from the women’s health initiative, as well as 402 male and female participants from the italian cohort study, invecchiare nel chianti. extrinsic epigenetic age acceleration (eeaa) exhibits significant associations with fish intake (p=0.02), moderate alcohol consumption (p=0.01), education (p=3×10-5), bmi (p=0.01), and blood carotenoid levels (p=1×10-5)-an indicator of fruit and vegetable consumption, whereas intrinsic epigenetic age acceleration (ieaa) is associated with poultry intake (p=0.03) and bmi (p=0.05). both eeaa and ieaa were also found to relate to indicators of metabolic syndrome, which appear to mediate their associations with bmi. metformin-the first-line medication for the treatment of type 2 diabetes-does not delay epigenetic aging in this observational study. finally, longitudinal data suggests that an increase in bmi is associated with increase in both eeaa and ieaa. overall, the epigenetic age analysis of blood confirms the conventional wisdom regarding the benefits of eating a high plant diet with lean meats, moderate alcohol consumption, physical activity, and education, as well as the health risks of obesity and metabolic syndrome.”
Karlik, E., Ari, S., & Gozukirmizi, N.. (2019). LncRNAs: genetic and epigenetic effects in plants. Biotechnology and Biotechnological Equipment
Plain numerical DOI: 10.1080/13102818.2019.1581085
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“Long non-coding rnas (lncrnas) transcribed from the eukaryotic genome play important roles in essential biological processes, transcriptional and post-transcriptional gene regulation. lncrnas act both in the nucleus and in the cytoplasm, mostly in association with chromatin in the nucleus. lncrnas appear to be important regulators of gene expression, gene regulation and genome stability. this review outlines the major types of plant lncrnas, their genetic and epigenetic effects with a focus on plant lncrna instances, and discusses the recent advances in our understanding of their mechanism of action.”
Peng, C., Cardenas, A., Rifas-Shiman, S. L., Hivert, M. F., Gold, D. R., Platts-Mills, T. A., … DeMeo, D. L.. (2019). Epigenetic age acceleration is associated with allergy and asthma in children in Project Viva. Journal of Allergy and Clinical Immunology
Plain numerical DOI: 10.1016/j.jaci.2019.01.034
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“Background: epigenetic clocks have been suggested to capture one feature of the complexity between aging and the epigenome. however, little is known about the epigenetic clock in childhood allergy and asthma. objective: we sought to examine associations of dna methylation age (dnamage) and epigenetic age acceleration with childhood allergy and asthma. methods: we calculated dnamage and age acceleration at birth, early childhood, and midchildhood based on the illuminahumanmethylation450beadchip in project viva. we evaluated epigenetic clock associations with allergy and asthma using covariate-adjusted linear and logistic regressions. we attempted to replicate our findings in the genetics of asthma in costa rica study. results: at midchildhood (mean age, 7.8 years) in project viva, dnamage and age acceleration were cross-sectionally associated with greater total serum ige levels and greater odds of atopic sensitization. every 1-year increase in intrinsic epigenetic age acceleration was associated with a 1.22 (95% ci, 1.07-1.39), 1.17 (95% ci, 1.03-1.34), and 1.29 (95% ci, 1.12-1.49) greater odds of atopic sensitization and environmental and food allergen sensitization. dnamage and extrinsic epigenetic age acceleration were also cross-sectionally associated with current asthma at midchildhood. dnamage and age acceleration at birth and early childhood were not associated with midchildhood allergy or asthma. the midchildhood association between age acceleration and atopic sensitization were replicated in an independent data set. conclusions: because the epigenetic clock might reflect immune and developmental components of biological aging, our study suggests pathways through which molecular epigenetic mechanisms of immunity, development, and maturation can interact along the age axis and associate with childhood allergy and asthma by midchildhood.”
Thompson, M. J., Chwialkowska, K., Rubbi, L., Lusis, A. J., Davis, R. C., Srivastava, A., … Pellegrini, M.. (2018). A multi-tissue full lifespan epigenetic clock for mice. Aging
Plain numerical DOI: 10.18632/aging.101590
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“Human dna-methylation data have been used to develop highly accurate biomarkers of aging (‘epigenetic clocks’). recent studies demonstrate that similar epigenetic clocks for mice (mus musculus) can be slowed by gold standard anti-aging interventions such as calorie restriction and growth hormone receptor knock-outs. using dna methylation data from previous publications with data collected in house for a total 1189 samples spanning 193,651 cpg sites, we developed 4 novel epigenetic clocks by choosing different regression models (elastic net- versus ridge regression) and by considering different sets of cpgs (all cpgs vs highly conserved cpgs). we demonstrate that accurate age estimators can be built on the basis of highly conserved cpgs. however, the most accurate clock results from applying elastic net regression to all cpgs. while the anti-aging effect of calorie restriction could be detected with all types of epigenetic clocks, only ridge regression based clocks replicated the finding of slow epigenetic aging effects in dwarf mice. overall, this study demonstrates that there are trade-offs when it comes to epigenetic clocks in mice. highly accurate clocks might not be optimal for detecting the beneficial effects of anti-aging interventions.”
Ghorbaninejad, M., Khademi-Shirvan, M., Hosseini, S., & Baghaban Eslaminejad, M.. (2020). Epidrugs: novel epigenetic regulators that open a new window for targeting osteoblast differentiation. Stem Cell Research and Therapy
Plain numerical DOI: 10.1186/s13287-020-01966-3
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“Efficient osteogenic differentiation of mesenchymal stem cells (mscs) is a critical step in the treatment of bone defects and skeletal disorders, which present challenges for cell-based therapy and regenerative medicine. thus, it is necessary to understand the regulatory agents involved in osteogenesis. epigenetic mechanisms are considered to be the primary mediators that regulate gene expression during msc differentiation. in recent years, epigenetic enzyme inhibitors have been used as epidrugs in cancer therapy. a number of studies mentioned the role of epigenetic inhibitors in the regulation of gene expression patterns related to osteogenic differentiation. this review attempts to provide an overview of the key regulatory agents of osteogenesis: transcription factors, signaling pathways, and, especially, epigenetic mechanisms. in addition, we propose to introduce epigenetic enzyme inhibitors (epidrugs) and their applications as future therapeutic approaches for bone defect regeneration.”
Yao, Q., Chen, Y., & Zhou, X.. (2019). The roles of microRNAs in epigenetic regulation. Current Opinion in Chemical Biology
Plain numerical DOI: 10.1016/j.cbpa.2019.01.024
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“MicroRNAs (mirnas) are small noncoding rnas, approximately 18–25 nucleotides in length, now recognized as one of the major regulatory gene families in eukaryotes. recent advances have been made in understanding the complicated roles of mirnas in epigenetic regulation. mirnas, as epigenetic modulators, affect the protein levels of the target mrnas without modifying the gene sequences. moreover, mirnas can also be regulated by epigenetic modifications, including dna methylation, rna modification, and histone modifications. the reciprocal actions of mirnas and epigenetic pathway appear to form a mirna-epigenetic feedback loop and have an extensive influence on gene expression proliferation. the dysregulation of the mirna-epigenetic feedback loop interferes with the physiological and pathological processes and contributes to variety of diseases. in this review, we focus on the reciprocal interconnection of mirnas in epigenetic regulation, with the aim of offering new insights into the epigenetic regulatory mechanism that can be used to combat diseases.”
Wu, X., Huang, Q., Javed, R., Zhong, J., Gao, H., & Liang, H.. (2019). Effect of tobacco smoking on the epigenetic age of human respiratory organs. Clinical Epigenetics
Plain numerical DOI: 10.1186/s13148-019-0777-z
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“Background: smoking leads to the aging of organs. however, no studies have been conducted to quantify the effect of smoking on the aging of respiratory organs and the aging-reversing ability of smoking cessation. results: we collected genome-wide methylation datasets of buccal cells, airway cells, esophagus tissue, and lung tissue from non-smokers, smokers, and ex-smokers. we used the ‘epigenetic clock’ method to quantify the epigenetic age acceleration in the four organs. the statistical analyses showed the following: (1) smoking increased the epigenetic age of airway cells by an average of 4.9 years and lung tissue by 4.3 years. (2) after smoking ceased, the epigenetic age acceleration in airway cells (but not in lung tissue) slowed to a level that non-smokers had. (3) the epigenetic age acceleration in airway cells and lung tissue showed no gender difference. conclusions: smoking can accelerate the epigenetic age of human respiratory organs, but the effect varies among organs and can be reversed by smoking cessation. our study provides a powerful incentive to reduce tobacco consumption autonomously.”
Mondal, P., Natesh, J., Penta, D., & Meeran, S. M.. (2020). Progress and promises of epigenetic drugs and epigenetic diets in cancer prevention and therapy: A clinical update. Seminars in Cancer Biology
Plain numerical DOI: 10.1016/j.semcancer.2020.12.006
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“Epigenetic modifications are heritable yet reversible, essential for normal physiological functions and biological development. aberrant epigenetic modifications, including dna methylation, histone modification, and non-coding rna (ncrna)-mediated gene regulation play a crucial role in cancer progression. in cellular reprogramming, irregular epigenomic modulations alter cell signaling pathways and the expression of tumor suppressor genes and oncogenes, resulting in cancer growth and metastasis. therefore, alteration of epigenetic-status in cancer cells can be used as a potential target for cancer therapy. several synthetic epigenetic inhibitors (epi-drugs) and natural epigenetic modulatory bioactives (epi-diets) have been shown to have the potential to alter the aberrant epigenetic status and inhibit cancer progression. further, the use of combinatorial approaches with epigenetic drugs and diets has brought promising outcomes in cancer prevention and therapy. in this article, we have summarized the epigenetic modulatory activities of epi-drugs, epi-diets, and their combination against various cancers. we have also compiled the preclinical and clinical status of these epigenetic modulators in different cancers.”
Stewart-Morgan, K. R., Petryk, N., & Groth, A.. (2020). Chromatin replication and epigenetic cell memory. Nature Cell Biology
Plain numerical DOI: 10.1038/s41556-020-0487-y
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“Propagation of the chromatin landscape across cell divisions is central to epigenetic cell memory. mechanistic analysis of the interplay between dna replication, the cell cycle, and the epigenome has provided insights into replication-coupled chromatin assembly and post-replicative chromatin maintenance. these breakthroughs are critical for defining how proliferation impacts the epigenome during cell identity changes in development and disease. here we review these findings in the broader context of epigenetic inheritance across mitotic cell division.”
Sidler, C., Kovalchuk, O., & Kovalchuk, I.. (2017). Epigenetic regulation of cellular senescence and aging. Frontiers in Genetics
Plain numerical DOI: 10.3389/fgene.2017.00138
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“Aging is characterized by functional decline of diverse organs and an increased risk for several diseases. therefore, a high interest exists in understanding the molecular mechanisms that stimulate aging at all levels, from cells and tissues to organs and organisms, in order to develop ways to promote healthy aging. while many molecular and biochemical mechanisms are already understood in some detail, the role of changes in epigenetic regulation has only begun to be considered in recent years. the age-dependent global reduction in heterochromatin, along with site-specific changes in the patterns of dna methylation and modification of histones, have been observed in several aging model systems. however, understanding of the precise role of such changes requires further research. in this review, we will discuss the role of epigenetic regulation in aging and indicate future research directions that will help elucidate the mechanistic details of it.”
Pikaard, C. S., & Scheid, O. M.. (2014). Epigenetic regulation in plants. Cold Spring Harbor Perspectives in Biology
Plain numerical DOI: 10.1101/cshperspect.a019315
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“The study of epigenetics in plants has a long and rich history, from initial descriptions of non-mendelian gene behaviors to seminal discoveries of chromatin-modifying proteins and rnas that mediate gene silencing in most eukaryotes, including humans. genetic screens in the model plant arabidopsis have been particularly rewarding, identifying more than 130 epigenetic regulators thus far. the diversity of epigenetic pathways in plants is remarkable, presumably contributing to the phenotypic plasticity of plant postembryonic development and the ability to survive and reproduce in unpredictable environments.”
Chlamydas, S., Papavassiliou, A. G., & Piperi, C.. (2020). Epigenetic mechanisms regulating COVID-19 infection. Epigenetics
Plain numerical DOI: 10.1080/15592294.2020.1796896
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“Coronavirus disease 2019 (covid-2019) outbreak originating in december 2019 in wuhan, china has emerged as a global treat to human health. the highly contagious sars-cov-2 infection and transmission presents diversity of human host and increased disease risk with advancing age, highlighting the importance of in depth understanding of its biological properties. structural analyses have elucidated hot spots in viral binding domains, mutations and specific proteins in the host such as the receptor angiotensin-converting enzyme 2 (ace2) and the transmembrane protease serine 2 (tmprss2) to be implicated in cell entry and viral infectivity. furthermore, epigenetic changes that regulate chromatin structure have shown a major impact in genome stabilization and maintenance of cellular homeostasis and they have been implicated in the pathophysiology of the virus infection. epigenetic research has revealed that global dna methylation along with ace2 gene methylation and post-translational histone modifications may drive differences in host tissue-, biological age- and sex-biased patterns of viral infection. moreover, modulation of the host cells epigenetic landscape following infection represents a molecular tool used by viruses to antagonize cellular signaling as well as sensing components that regulate induction of the host innate immune and antiviral defense programs in order to enhance viral replication and infection efficiency. in this review, we provide an update of the main research findings at the interface of epigenetics and coronavirus infection. in particular, we highlight the epigenetic factors that interfere with viral replication and infection and may contribute to covid-19 susceptibility, offering new ways of thinking in respect to host viral response.”
Horvath, S., Stein, D. J., Phillips, N., Heany, S. J., Kobor, M. S., Lin, D. T. S., … Hoare, J.. (2018). Perinatally acquired HIV infection accelerates epigenetic aging in South African adolescents. AIDS
Plain numerical DOI: 10.1097/QAD.0000000000001854
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“Objective: recent studies demonstrate that infection with the hiv-1 is associated with accelerated aging effects in adults according to a highly accurate epigenetic biomarker of aging known as epigenetic clock. however, it is not yet known whether epigenetic age acceleration occurs as early as adolescence in perinatally hiv-infected (phiv+) youth. design: observational study of phiv and hiv-uninfected adolescents enrolled in the cape town adolescent antiretroviral cohort study. methods: the illumina epic array was used to generate blood dna methylation data from 204 phiv and 44 age-matched, uninfected (hiv-) adolescents aged 9-12 years old. the epigenetic clock software and method was used to estimate two measures of epigenetic age acceleration. each participant completed a comprehensive neuropsychological test battery upon enrollment to cape town adolescent antiretroviral cohort. results: hiv is associated with biologically older blood in phiv+ adolescents according to both measures of epigenetic age acceleration. one of the measures, extrinsic epigenetic age acceleration, is negatively correlated with measures of cognitive functioning (executive functioning, working memory, processing speed). conclusion: overall, our results indicate that epigenetic age acceleration in blood can be observed in phiv+ adolescents and that these epigenetic changes accompany poorer cognitive functioning.”
Wang, Y., Karlsson, R., Jylhävä, J., Hedman, Å. K., Almqvist, C., Karlsson, I. K., … Hägg, S.. (2019). Comprehensive longitudinal study of epigenetic mutations in aging. Clinical Epigenetics
Plain numerical DOI: 10.1186/s13148-019-0788-9
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“Background: the role of dna methylation in aging has been widely studied. however, epigenetic mutations, here defined as aberrant methylation levels compared to the distribution in a population, are less understood. hence, we investigated longitudinal accumulation of epigenetic mutations, using 994 blood samples collected at up to five time points from 375 individuals in old ages. results: we verified earlier cross-sectional evidence on the increase of epigenetic mutations with age, and identified important contributing factors including sex, cd19+ b cells, genetic background, cancer diagnosis, and technical artifacts. we further classified epigenetic mutations into high/low methylation outliers (hmo/lmo) according to their changes in methylation, and specifically studied methylation sites (cpgs) that were prone to mutate (frequently mutated cpgs). we validated four epigenetically mutated cpgs using pyrosequencing in 93 samples. furthermore, by using twins, we concluded that the age-related accumulation of epigenetic mutations was not related to genetic factors, hence driven by stochastic or environmental effects. conclusions: here we conducted a comprehensive study of epigenetic mutation and highlighted its important role in aging process and cancer development.”
Jin, N., George, T. L., Otterson, G. A., Verschraegen, C., Wen, H., Carbone, D., … He, K.. (2021). Advances in epigenetic therapeutics with focus on solid tumors. Clinical Epigenetics
Plain numerical DOI: 10.1186/s13148-021-01069-7
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“Epigenetic (‘above genetics’) modifications can alter the gene expression without altering the dna sequence. aberrant epigenetic regulations in cancer include dna methylation, histone methylation, histone acetylation, non-coding rna, and mrna methylation. epigenetic-targeted agents have demonstrated clinical activities in hematological malignancies and therapeutic potential in solid tumors. in this review, we describe mechanisms of various epigenetic modifications, discuss the food and drug administration-approved epigenetic agents, and focus on the current clinical investigations of novel epigenetic monotherapies and combination therapies in solid tumors.”
Romani, M., Pistillo, M. P., & Banelli, B.. (2018). Epigenetic targeting of glioblastoma. Frontiers in Oncology
Plain numerical DOI: 10.3389/fonc.2018.00448
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“Glioblastoma is one of the first tumors where the biological changes accompanying a single epigenetic modification, the methylation of the mgmt gene, were found to be of clinical relevance. the exploration of the epigenomic landscape of glioblastoma has allowed to identify patients carrying a diffuse hypermethylation at gene promoters and with better outcome. epigenetic and genetic data have led to the definition of major subgroups of glioma and were the basis of the current who classification of cns tumors and of a novel classification based solely on dna methylation data that shows a remarkable diagnostic precision. the reversibility of epigenetic modifications is considered a therapeutic opportunity in many tumors also because these alterations have been mechanistically linked to the biological characteristics of glioblastoma. several alterations like idh1/2 mutations that interfere with ‘epigenetic modifier’ enzymes, the mutations of the histone 3 variants h3.1 and h3.3 that alter the global h3k27me3 levels and the altered expression of histone methyltransferases and demethylases are considered potentially druggable targets in glioma and molecules targeting these alterations are being tested in preclinical and clinical trials. the recent advances on the knowledge of the players of the ‘epigenetic orchestra’ and of their mutual interactions are indicating new paths that may eventually open new therapeutic options for this invariably lethal cancer. this study was supported by the italian ministry of health, core grant ricerca corrente to the irccs ospedale policlinico san martino, by the grant from the fondazione compagnia di san paolo-torino: terapie innovative per il glioblastoma and by the grant associazione italiana ricerca sul cancro (airc) 5 × 1000 n. 21073: epigenetic modeling/remodeling of cancer metastases and tumor immune contexture to improve efficacy of immunotherapy.”
Indrio, F., Martini, S., Francavilla, R., Corvaglia, L., Cristofori, F., Mastrolia, S. A., … Loverro, G.. (2017). Epigenetic matters: The link between early nutrition, microbiome, and long-term health development. Frontiers in Pediatrics
Plain numerical DOI: 10.3389/fped.2017.00178
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“Epigenetic modifications are among the most important mechanisms by which environmental factors can influence early cellular differentiation and create new phenotypic traits during pregnancy and within the neonatal period without altering the deoxyribonucleic acid sequence. a number of antenatal and postnatal factors, such as maternal and neonatal nutrition, pollutant exposure, and the composition of microbiota, contribute to the establishment of epigenetic changes that can not only modulate the individual adaptation to the environment but also have an influence on lifelong health and disease by modifying inflammatory molecular pathways and the immune response. postnatal intestinal colonization, in turn determined by maternal flora, mode of delivery, early skin-to-skin contact and neonatal diet, leads to specific epigenetic signatures that can affect the barrier properties of gut mucosa and their protective role against later insults, thus potentially predisposing to the development of late-onset inflammatory diseases. the aim of this review is to outline the epigenetic mechanisms of programming and development acting within early-life stages and to examine in detail the role of maternal and neonatal nutrition, microbiota composition, and other environmental factors in determining epigenetic changes and their short- and long-term effects.”
Balakrishnan, L., & Milavetz, B.. (2017). Epigenetic regulation of viral biological processes. Viruses
Plain numerical DOI: 10.3390/v9110346
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“It is increasingly clear that dna viruses exploit cellular epigenetic processes to control their life cycles during infection. this review will address epigenetic regulation in members of the polyomaviruses, adenoviruses, human papillomaviruses, hepatitis b, and herpes viruses. for each type of virus, what is known about the roles of dna methylation, histone modifications, nucleosome positioning, and regulatory rna in epigenetic regulation of the virus infection will be discussed. the mechanisms used by certain viruses to dysregulate the host cell through manipulation of epigenetic processes and the role of cellular cofactors such as brd4 that are known to be involved in epigenetic regulation of host cell pathways will also be covered. specifically, this review will focus on the role of epigenetic regulation in maintaining viral episomes through the generation of chromatin, temporally controlling transcription from viral genes during the course of an infection, regulating latency and the switch to a lytic infection, and global dysregulation of cellular function.”
O’Dea, R. E., Noble, D. W. A., Johnson, S. L., Hesselson, D., & Nakagawa, S.. (2016). The role of non-genetic inheritance in evolutionary rescue: Epigenetic buffering, heritable bet hedging and epigenetic traps. Environmental Epigenetics
Plain numerical DOI: 10.1093/eep/dvv014
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“Rapid environmental change is predicted to compromise population survival, and the resulting strong selective pressure can erode genetic variation, making evolutionary rescue unlikely. non-genetic inheritance may provide a solution to this problem and help explain the current lack of fit between purely genetic evolutionary models and empirical data. we hypothesize that epigenetic modifications can facilitate evolutionary rescue through ‘epigenetic buffering’. by facilitating the inheritance of novel phenotypic variants that are generated by environmental change- a strategy we call ’heritable bet hedging’-epigenetic modifications could maintain and increase the evolutionary potential of a population. this process may facilitate genetic adaptation by preserving existing genetic variation, releasing cryptic genetic variation and/or facilitating mutations in functional loci. although we show that examples of non-genetic inheritance are often maladaptive in the short term, accounting for phenotypic variance and non-adaptive plasticity may reveal important evolutionary implications over longer time scales. we also discuss the possibility that maladaptive epigenetic responses may be due to ‘epigenetic traps’, whereby evolutionarily novel factors (e.g. endocrine disruptors) hack into the existing epigenetic machinery. we stress that more ecologically relevant work on transgenerational epigenetic inheritance is required. researchers conducting studies on transgenerational environmental effects should report measures of phenotypic variance, so that the possibility of both bet hedging and heritable bet hedging can be assessed. future empirical and theoretical work is required to assess the relative importance of genetic and epigenetic variation, and their interaction, for evolutionary rescue.”
Almouzni, G., & Cedar, H.. (2016). Maintenance of epigenetic information. Cold Spring Harbor Perspectives in Biology
Plain numerical DOI: 10.1101/cshperspect.a019372
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“The genome is subject to a diverse array of epigenetic modifications from dna methylation to histone posttranslational changes. many of these marks are somatically stable through cell division. this article focuses on our knowledge of the mechanisms governing the inheritance of epigenetic marks, particularly, repressive ones,when thednaand chromatin template are duplicated in s phase. this involves the action of histone chaperones, nucleosome-remodeling enzymes, histone and dna methylation binding proteins, and chromatin-modifying enzymes. last, the timing of dna replication is discussed, including the question of whether this constitutes an epigenetic mark that facilitates the propagation of epigenetic marks.”
R M, S. K., Wang, Y., Zhang, X., Cheng, H., Sun, L., He, S., & Hao, F.. (2020). Redox Components: Key Regulators of Epigenetic Modifications in Plants. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms21041419
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“Epigenetic modifications including dna methylation, histone modifications, and chromatin remodeling are crucial regulators of chromatin architecture and gene expression in plants. their dynamics are significantly influenced by oxidants, such as reactive oxygen species (ros) and nitric oxide (no), and antioxidants, like pyridine nucleotides and glutathione in plants. these redox intermediates regulate the activities and expression of many enzymes involved in dna methylation, histone methylation and acetylation, and chromatin remodeling, consequently controlling plant growth and development, and responses to diverse environmental stresses. in recent years, much progress has been made in understanding the functional mechanisms of epigenetic modifications and the roles of redox mediators in controlling gene expression in plants. however, the integrated view of the mechanisms for redox regulation of the epigenetic marks is limited. in this review, we summarize recent advances on the roles and mechanisms of redox components in regulating multiple epigenetic modifications, with a focus of the functions of ros, no, and multiple antioxidants in plants.”
Harman, M. F., & Martín, M. G.. (2020). Epigenetic mechanisms related to cognitive decline during aging. Journal of Neuroscience Research
Plain numerical DOI: 10.1002/jnr.24436
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“Cognitive decline is a hallmark of the aging nervous system, characterized by increasing memory loss and a deterioration of mental capacity, which in turn creates a favorable context for the development of neurodegenerative diseases. one of the most detrimental alterations that occur at the molecular level in the brain during aging is the modification of the epigenetic mechanisms that control gene expression. as a result of these epigenetic-driven changes in the transcriptome most of the functions of the brain including synaptic plasticity, learning, and memory decline with aging. the epigenetic mechanisms altered during aging include dna methylation, histone modifications, nucleosome remodeling, and microrna-mediated gene regulation. in this review, we examine the current evidence concerning the changes of epigenetic modifications together with the molecular mechanisms underlying impaired neuronal gene transcription during aging. herein, we discuss the alterations of dna methylation pattern that occur in old neurons. we will also describe the most prominent age-related histone posttranslational modifications in the brain since changes in acetylation and methylation of specific lysine residues on h3 and h4 are associated to functional decline in the old. in addition, we discuss the role that changes in the levels of certain mirnas would play in cognitive decline with aging. finally, we provide an overview about the mechanisms either extrinsic or intrinsic that would trigger epigenetic changes in the aging brain, and the consequences of these changes, i.e., altered transcriptional profile and reactivation of transposable elements in old brain.”
Coninx, E., Chew, Y. C., Yang, X., Guo, W., Coolkens, A., Baatout, S., … Quintens, R.. (2020). Hippocampal and cortical tissue-specific epigenetic clocks indicate an increased epigenetic age in a mouse model for Alzheimer’s disease. Aging
Plain numerical DOI: 10.18632/aging.104056
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“Epigenetic clocks are based on age-associated changes in dna methylation of cpg-sites, which can accurately measure chronological age in different species. recently, several studies have indicated that the difference between chronological and epigenetic age, defined as the age acceleration, could reflect biological age indicating functional decline and age-associated diseases. in humans, an epigenetic clock associated alzheimer’s disease (ad) pathology with an acceleration of the epigenetic age. in this study, we developed and validated two mouse brain region-specific epigenetic clocks from the c57bl/6j hippocampus and cerebral cortex. both clocks, which could successfully estimate chronological age, were further validated in a widely used mouse model for ad, the triple transgenic ad (3xtg-ad) mouse. we observed an epigenetic age acceleration indicating an increased biological age for the 3xtg-ad mice compared to non-pathological c57bl/6j mice, which was more pronounced in the cortex as compared to the hippocampus. genomic region enrichment analysis revealed that age-dependent cpgs were enriched in genes related to developmental, aging-related, neuronal and neurodegenerative functions. due to the limited access of human brain tissues, these epigenetic clocks specific for mouse cortex and hippocampus might be important in further unravelling the role of epigenetic mechanisms underlying ad pathology or brain aging in general.”
Saitou, M., Kagiwada, S., & Kurimoto, K.. (2012). Epigenetic reprogramming in mouse pre-implantation development and primordial germ cells. Development
Plain numerical DOI: 10.1242/dev.050849
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“Epigenetic modifications are crucial for the identity and stability of cells, and, when aberrant, can lead to disease. during mouse development, the genome-wide epigenetic states of pre-implantation embryos and primordial germ cells (pgcs) undergo extensive reprogramming. an improved understanding of the epigenetic reprogramming mechanisms that occur in these cells should provide important new information about the regulation of the epigenetic state of a cell and the mechanisms of induced pluripotency. here, we discuss recent findings about the potential mechanisms of epigenetic reprogramming, particularly genome-wide dna demethylation, in pre-implantation mouse embryos and pgcs. © 2012. published by the company of biologists ltd.”
Zeng, Z., Wei, F., & Ren, X.. (2020). Exhausted T cells and epigenetic status. Cancer Biology and Medicine
Plain numerical DOI: 10.20892/j.issn.2095-3941.2020.0338
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“Exhausted t cells are a group of dysfunctional t cells, which are present in chronic infections or tumors. the most significant characteristics of exhausted t cells are attenuated effector cytotoxicity, reduced cytokine production, and upregulation of multiple inhibitory molecular receptors (e.g., pd-1, tim-3, and lag-3). the intracellular metabolic changes, altered expression of transcription factors, and a unique epigenetic landscape constitute the exhaustion program. recently, researchers have made progress in understanding exhausted t cells, with the definition and identification of exhausted t cells changing from phenotypebased to being classified at the transcriptional and epigenetic levels. recent studies have revealed that exhausted t cells can be separated into two subgroups, namely tcf1+pd-1+ progenitor-like precursor exhausted cells and tcf1-pd-1+ terminally differentiated exhausted t cells. moreover, the progenitor-like precursor cell population may be a subset of t cells that can respond to immunotherapy. studies have also found that tox initiates and dominates the development of exhausted t cells at the transcriptional and epigenetic levels. tox also maintains t cell survival and may affect decisions regarding treatment strategies. in this review, we discuss the latest developments in t cell exhaustion in regards to definitions, subpopulations, development mechanisms, differences in diverse diseases, and treatment prospects for exhausted t cells. furthermore, we hypothesize that the epigenetic state regulated by tox might be the key point, which can determine the reversibility of exhaustion and the efficacy of immunotherapy.”
Ornelas-Ayala, D., Garay-Arroyo, A., García-Ponce, B., R. Álvarez-Buylla, E., & Sanchez, M. de la P.. (2021). The Epigenetic Faces of ULTRAPETALA1. Frontiers in Plant Science
Plain numerical DOI: 10.3389/fpls.2021.637244
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“ULTRAPETALA1 (ult1) is a versatile plant-exclusive protein, initially described as a trithorax group (trxg) factor that regulates transcriptional activation and counteracts polycomb group (pcg) repressor function. as part of trxg, ult1 interacts with arabidopsis trithorax1 (atx1) to regulate h3k4me3 activation mark deposition. however, our recent studies indicate that ult1 can also act independently of atx1. moreover, the ult1 ability to interact with transcription factors (tfs) and pcg proteins indicates that it is a versatile protein with other roles. therefore, in this work we revised recent information about the function of arabidopsis ult1 to understand the roles of ult1 in plant development. furthermore, we discuss the molecular mechanisms of ult1, highlighting its epigenetic role, in which ult1 seems to have characteristics of an epigenetic molecular switch that regulates repression and activation processes via trxg and pcg complexes.”
Killaars, A. R., Walker, C. J., & Anseth, K. S.. (2020). Nuclear mechanosensing controls MSC osteogenic potential through HDAC epigenetic remodeling. Proceedings of the National Academy of Sciences of the United States of America
Plain numerical DOI: 10.1073/pnas.2006765117
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“Cells sense mechanical cues from the extracellular matrix to regulate cellular behavior and maintain tissue homeostasis. the nucleus has been implicated as a key mechanosensor and can directly influence chromatin organization, epigenetic modifications, and gene expression. dysregulation of nuclear mechanosensing has been implicated in several diseases, including bone degeneration. here, we exploit photostiffening hydrogels to manipulate nuclear mechanosensing in human mesenchymal stem cells (hmscs) in vitro. results show that hmscs respond to matrix stiffening by increasing nuclear tension and causing an increase in histone acetylation via deactivation of histone deacetylases (hdacs). this ultimately induces osteogenic fate commitment. disrupting nuclear mechanosensing by disconnecting the nucleus from the cytoskeleton up-regulates hdacs and prevents osteogenesis. resetting hdac activity back to healthy levels rescues the epigenetic and osteogenic response in hmscs with pathological nuclear mechanosensing. notably, bone from patients with osteoarthritis displays similar defective nuclear mechanosensing. collectively, our results reveal that nuclear mechanosensing controls hmsc osteogenic potential mediated by hdac epigenetic remodeling and that this cellular mechanism is likely relevant to bone-related diseases.”
Horvath, S., Lu, A. T., Cohen, H., & Raj, K.. (2019). Rapamycin retards epigenetic ageing of keratinocytes independently of its effects on replicative senescence, proliferation and differentiation. Aging
Plain numerical DOI: 10.18632/aging.101976
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“The advent of epigenetic clocks has prompted questions about the place of epigenetic ageing within the current understanding of ageing biology. it was hitherto unclear whether epigenetic ageing represents a distinct mode of ageing or a manifestation of a known characteristic of ageing. we report here that epigenetic ageing is not affected by replicative senescence, telomere length, somatic cell differentiation, cellular proliferation rate or frequency. it is instead retarded by rapamycin, the potent inhibitor of the mtor complex which governs many pathways relating to cellular metabolism. rapamycin however, is also an effective inhibitor of cellular senescence. hence cellular metabolism underlies two independent arms of ageing – cellular senescence and epigenetic ageing. the demonstration that a compound that targets metabolism can slow epigenetic ageing provides a long-awaited point-of-entry into elucidating the molecular pathways that underpin the latter. lastly, we report here an in vitro assay, validated in humans, that recapitulates human epigenetic ageing that can be used to investigate and identify potential interventions that can inhibit or retard it.”
Rodriguez Barreto, D., Garcia De Leaniz, C., Verspoor, E., Sobolewska, H., Coulson, M., Consuegra, S., & Mulligan, C.. (2019). DNA Methylation Changes in the Sperm of Captive-Reared Fish: A Route to Epigenetic Introgression in Wild Populations. Molecular Biology and Evolution
Plain numerical DOI: 10.1093/molbev/msz135
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“Interbreeding between hatchery-reared and wild fish, through deliberate stocking or escapes from fish farms, can result in rapid phenotypic and gene expression changes in hybrids, but the underlying mechanisms are unknown. we assessed if one generation of captive breeding was sufficient to generate inter- and/or transgenerational epigenetic modifications in atlantic salmon. we found that the sperm of wild and captive-reared males differed in methylated regions consistent with early epigenetic signatures of domestication. some of the epigenetic marks that differed between hatchery and wild males affected genes related to transcription, neural development, olfaction, and aggression, and were maintained in the offspring beyond developmental reprogramming. our findings suggest that rearing in captivity may trigger epigenetic modifications in the sperm of hatchery fish that could explain the rapid phenotypic and genetic changes observed among hybrid fish. epigenetic introgression via fish sperm represents a previously unappreciated mechanism that could compromise locally adapted fish populations.”
Lee, J. H., Mazarei, M., Pfotenhauer, A. C., Dorrough, A. B., Poindexter, M. R., Hewezi, T., … Stewart, C. N.. (2020). Epigenetic Footprints of CRISPR/Cas9-Mediated Genome Editing in Plants. Frontiers in Plant Science
Plain numerical DOI: 10.3389/fpls.2019.01720
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“CRISPR/cas9 has been widely applied to various plant species accelerating the pace of plant genome editing and precision breeding in crops. unintended effects beyond off-target nucleotide mutations are still somewhat unexplored. we investigated the degree and patterns of epigenetic changes after gene editing. we examined changes in dna methylation in genome-edited promoters of naturally hypermethylated genes (at1g72350 and at1g09970) and hypomethylated genes (at3g17320 and at5g28770) from arabidopsis. transgenic plants were developed via agrobacterium-mediated floral dip transformation. homozygous edited lines were selected from segregated t2 plants by an in vitro digestion assay using ribonucleoprotein complex. bisulfite sequencing comparisons were made between paired groups of edited and non-edited plants to identify changes in dna methylation of the targeted loci. we found that directed mutagenesis via crispr/cas9 resulted in no unintended morphological or epigenetic alterations. phenotypes of wild-type, transgenic empty vector, and transgenic edited plants were similar. epigenetic profiles revealed that methylation patterns of promoter regions flanking target sequences were identical among wild-type, transgenic empty vector, and transgenic edited plants. there was no effect of mutation type on epigenetic status. we also evaluated off-target mutagenesis effects in the edited plants. potential off-target sites containing up to 4-bp mismatch of each target were sequenced. no off-target mutations were detected in candidate sites. our results showed that crispr/cas9 did not leave an epigenetic footprint on either the immediate gene-edited dna and flanking dna or introduce off-target mutations.”
Contreras, R. E., Schriever, S. C., & Pfluger, P. T.. (2019). Physiological and Epigenetic Features of Yoyo Dieting and Weight Control. Frontiers in Genetics
Plain numerical DOI: 10.3389/fgene.2019.01015
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“Obesity and being overweight have become a worldwide epidemic affecting more than 1.9 billion adults and 340 million children. efforts to curb this global health burden by developing effective long-term non-surgical weight loss interventions continue to fail due to weight regain after weight loss. weight cycling, often referred to as yoyo dieting, is driven by physiological counter-regulatory mechanisms that aim at preserving energy, i.e. decreased energy expenditure, increased energy intake, and impaired brain-periphery communication. models based on genetically determined set points explained some of the weight control mechanisms, but exact molecular underpinnings remained elusive. today, gene–environment interactions begin to emerge as likely drivers for the obesogenic memory effect associated with weight cycling. here, epigenetic mechanisms, including histone modifications and dna methylation, appear as likely factors that underpin long-lasting deleterious adaptations or an imprinted obesogenic memory to prevent weight loss maintenance. the first part summarizes our current knowledge on the physiology of weight cycling by discussing human and murine studies on the yoyo-dieting phenomenon and physiological adaptations associated with weight loss and weight re-gain. the second part provides an overview on known associations between obesity and epigenetic modifications. we further interrogate the roles of epigenetic mechanisms in the cns control of cognitive functions as well as reward and addictive behaviors, and subsequently discuss whether such mechanisms play a role in weight control. the final two parts describe major opportunities and challenges associated with studying epigenetic mechanisms in the cns with its highly heterogenous cell populations, and provide a summary of recent technological advances that will help to delineate whether an obese memory is based upon epigenetic mechanisms.”
Mohammed, S. A., Ambrosini, S., Lüscher, T., Paneni, F., & Costantino, S.. (2020). Epigenetic control of mitochondrial function in the vasculature. Frontiers in Cardiovascular Medicine
Plain numerical DOI: 10.3389/fcvm.2020.00028
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“The molecular signatures of epigenetic regulation and chromatin architecture are emerging as pivotal regulators of mitochondrial function. recent studies unveiled a complex intersection among environmental factors, epigenetic signals, and mitochondrial metabolism, ultimately leading to alterations of vascular phenotype and increased cardiovascular risk. changing environmental conditions over the lifetime induce covalent and post-translational chemical modification of the chromatin template which sensitize the genome to establish new transcriptional programs and, hence, diverse functional states. on the other hand, metabolic alterations occurring in mitochondria affect the availability of substrates for chromatin-modifying enzymes, thus leading to maladaptive epigenetic signatures altering chromatin accessibility and gene transcription. indeed, several components of the epigenetic machinery require intermediates of cellular metabolism (atp, accoa, nadh, α-ketoglutarate) for enzymatic function. in the present review, we describe the emerging role of epigenetic modifications as fine tuners of gene transcription in mitochondrial dysfunction and vascular disease. specifically, the following aspects are described in detail: (i) mitochondria and vascular function, (ii) mitochondrial ros, (iii) epigenetic regulation of mitochondrial function; (iv) the role of mitochondrial metabolites as key effectors for chromatin-modifying enzymes; (v) epigenetic therapies. understanding epigenetic routes may pave the way for new approaches to develop personalized therapies to prevent mitochondrial insufficiency and its complications.”
Kundakovic, M., & Jaric, I.. (2017). The epigenetic link between prenatal adverse environments and neurodevelopmental disorders. Genes
Plain numerical DOI: 10.3390/genes8030104
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“Prenatal adverse environments, such as maternal stress, toxicological exposures, and viral infections, can disrupt normal brain development and contribute to neurodevelopmental disorders, including schizophrenia, depression, and autism. increasing evidence shows that these short- and long-term effects of prenatal exposures on brain structure and function are mediated by epigenetic mechanisms. animal studies demonstrate that prenatal exposure to stress, toxins, viral mimetics, and drugs induces lasting epigenetic changes in the brain, including genes encoding glucocorticoid receptor (nr3c1) and brain-derived neurotrophic factor (bdnf). these epigenetic changes have been linked to changes in brain gene expression, stress reactivity, and behavior, and often times, these effects are shown to be dependent on the gestational window of exposure, sex, and exposure level. although evidence from human studies is more limited, gestational exposure to environmental risks in humans is associated with epigenetic changes in peripheral tissues, and future studies are required to understand whether we can use peripheral biomarkers to predict neurobehavioral outcomes. an extensive research effort combining well-designed human and animal studies, with comprehensive epigenomic analyses of peripheral and brain tissues over time, will be necessary to improve our understanding of the epigenetic basis of neurodevelopmental disorders.”
Linnér, A., & Almgren, M.. (2020). Epigenetic programming—The important first 1000 days. Acta Paediatrica, International Journal of Paediatrics
Plain numerical DOI: 10.1111/apa.15050
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“The perinatal period is a time of fast physiological change, including epigenetic programming. adverse events may lead to epigenetic changes, with implications for health and disease. our review covers the basics of clinical epigenetics and explores the latest research, including the role of epigenetic processes in complex disease phenotypes, such as neurodevelopmental, neurodegenerative and immunological disorders. some studies suggest that epigenetic alterations are linked to early life environmental stressors, including mode of delivery, famine, psychosocial stress, severe institutional deprivation and childhood abuse. conclusion: epigenetic modifications due to perinatal environmental exposures can lead to lifelong, but potentially reversible, phenotypic alterations and disease.”
Rodrigues, C. P., Shvedunova, M., & Akhtar, A.. (2021). Epigenetic Regulators as the Gatekeepers of Hematopoiesis. Trends in Genetics
Plain numerical DOI: 10.1016/j.tig.2020.09.015
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“Hematopoiesis is the process by which both fetal and adult organisms derive the full repertoire of blood cells from a single multipotent progenitor cell type, the hematopoietic stem cells (hscs). correct enactment of this process relies on a synergistic interplay between genetically encoded differentiation programs and a host of cell-intrinsic and cell-extrinsic factors. these include the influence of the hsc niche microenvironment, action of specific transcription factors, and alterations in intracellular metabolic state. the consolidation of these inputs with the genetically encoded program into a coherent differentiation program for each lineage is thought to rely on epigenetic modifiers. recent work has delineated the precise contributions of different classes of epigenetic modifiers to hsc self-renewal as well as lineage specification and differentiation into various cell types. here, we bring together what is currently known about chromatin status and the development of cells in the hematopoietic system under normal and abnormal conditions.”
Heard, E., & Martienssen, R. A.. (2014). Transgenerational epigenetic inheritance: Myths and mechanisms. Cell
Plain numerical DOI: 10.1016/j.cell.2014.02.045
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“Since the human genome was sequenced, the term ‘epigenetics’ is increasingly being associated with the hope that we are more than just the sum of our genes. might what we eat, the air we breathe, or even the emotions we feel influence not only our genes but those of descendants? the environment can certainly influence gene expression and can lead to disease, but transgenerational consequences are another matter. although the inheritance of epigenetic characters can certainly occur – particularly in plants – how much is due to the environment and the extent to which it happens in humans remain unclear. © 2014 elsevier inc.”
Gehring, M.. (2019). Epigenetic dynamics during flowering plant reproduction: evidence for reprogramming?. New Phytologist
Plain numerical DOI: 10.1111/nph.15856
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“Summary: over the last 10 yr there have been major advances in documenting and understanding dynamic changes to dna methylation, small rnas, chromatin modifications and chromatin structure that accompany reproductive development in flowering plants, from germline specification to seed maturation. here i highlight recent advances in the field, mostly made possible by microscopic analysis of epigenetic states or by the ability to isolate specific cell types or tissues and apply omics approaches. i consider in which contexts there is potentially reprogramming vs maintenance or reinforcement of epigenetic states.”
Baradaran, P. C., Kozovska, Z., Furdova, A., & Smolkova, B.. (2020). Targeting epigenetic modifications in uveal melanoma. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms21155314
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“Uveal melanoma (um), the most common intraocular malignancy in adults, is a rare subset of melanoma. despite effective primary therapy, around 50% of patients will develop the metastatic disease. several clinical trials have been evaluated for patients with advanced um, though outcomes remain dismal due to the lack of efficient therapies. epigenetic dysregulation consisting of aberrant dna methylation, histone modifications, and small non-coding rna expression, silencing tumor suppressor genes, or activating oncogenes, have been shown to play a significant role in um initiation and progression. given that there is no evidence any approach improves results so far, adopting combination therapies, incorporating a new generation of epigenetic drugs targeting these alterations, may pave the way for novel promising therapeutic options. furthermore, the fusion of effector enzymes with nuclease-deficient cas9 (dcas9) in clustered regularly interspaced short palindromic repeats (crispr) associated protein 9 (cas9) system equips a potent tool for locus-specific erasure or establishment of dna methylation as well as histone modifications and, therefore, transcriptional regulation of specific genes. both, crispr-dcas9 potential for driver epigenetic alterations discovery, and possibilities for their targeting in um are highlighted in this review.”
Chatterjee, A., Rodger, E. J., & Eccles, M. R.. (2018). Epigenetic drivers of tumourigenesis and cancer metastasis. Seminars in Cancer Biology
Plain numerical DOI: 10.1016/j.semcancer.2017.08.004
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“Since the completion of the first human genome sequence and the advent of next generation sequencing technologies, remarkable progress has been made in understanding the genetic basis of cancer. these studies have mainly defined genetic changes as either causal, providing a selective advantage to the cancer cell (a driver mutation) or consequential with no selective advantage (not directly causal, a passenger mutation). a vast unresolved question is how a primary cancer cell becomes metastatic and what are the molecular events that underpin this process. however, extensive sequencing efforts indicate that mutation may not be a causal factor for primary to metastatic transition. on the other hand, epigenetic changes are dynamic in nature and therefore potentially play an important role in determining metastatic phenotypes and this area of research is just starting to be appreciated. unlike genetic studies, current limitations in studying epigenetic events in cancer metastasis include a lack of conceptual understanding and an analytical framework for identifying putative driver and passenger epigenetic changes. in this review, we discuss the key concepts involved in understanding the role of epigenetic alterations in the metastatic cascade. we particularly focus on driver epigenetic events, and we describe analytical approaches and biological frameworks for distinguishing between ‘epi-driver’ and ‘epi-passenger’ events in metastasis. finally, we suggest potential directions for future research in this important area of cancer research.”
Wang, Y., Liu, H., & Sun, Z.. (2017). Lamarck rises from his grave: parental environment-induced epigenetic inheritance in model organisms and humans. Biological Reviews
Plain numerical DOI: 10.1111/brv.12322
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“Organisms can change their physiological/behavioural traits to adapt and survive in changed environments. however, whether these acquired traits can be inherited across generations through non-genetic alterations has been a topic of debate for over a century. emerging evidence indicates that both ancestral and parental experiences, including nutrition, environmental toxins, nurturing behaviour, and social stress, can have powerful effects on the physiological, metabolic and cellular functions in an organism. in certain circumstances, these effects can be transmitted across several generations through epigenetic (i.e. non-dna sequence-based rather than mutational) modifications. in this review, we summarize recent evidence on epigenetic inheritance from parental environment-induced developmental and physiological alterations in nematodes, fruit flies, zebrafish, rodents, and humans. the epigenetic modifications demonstrated to be both susceptible to modulation by environmental cues and heritable, including dna methylation, histone modification, and small non-coding rnas, are also summarized. we particularly focus on evidence that parental environment-induced epigenetic alterations are transmitted through both the maternal and paternal germlines and exert sex-specific effects. the thought-provoking data presented here raise fundamental questions about the mechanisms responsible for these phenomena. in particular, the means that define the specificity of the response to parental experience in the gamete epigenome and that direct the establishment of the specific epigenetic change in the developing embryos, as well as in specific tissues in the descendants, remain obscure and require elucidation. more precise epigenetic assessment at both the genome-wide level and single-cell resolution as well as strategies for breeding at relatively sensitive periods of development and manipulation aimed at specific epigenetic modification are imperative for identifying parental environment-induced epigenetic marks across generations. considering their diverse epigenetic architectures, the conservation and prevalence of the mechanisms underlying epigenetic inheritance in non-mammals require further investigation in mammals. interpretation of the consequences arising from epigenetic inheritance on organisms and a better understanding of the underlying mechanisms will provide insight into how gene–environment interactions shape developmental processes and physiological func…”
Kwiatkowska, K. M., Bacalini, M. G., Sala, C., Kaziyama, H., de Andrade, D. C., Terlizzi, R., … Pirazzini, C.. (2020). Analysis of Epigenetic Age Predictors in Pain-Related Conditions. Frontiers in Public Health
Plain numerical DOI: 10.3389/fpubh.2020.00172
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“Chronic pain prevalence is high worldwide and increases at older ages. signs of premature aging have been associated with chronic pain, but few studies have investigated aging biomarkers in pain-related conditions. a set of dna methylation (dnam)-based estimates of age, called ‘epigenetic clocks,’ has been proposed as biological measures of age-related adverse processes, morbidity, and mortality. the aim of this study is to assess if different pain-related phenotypes show alterations in dnam age. in our analysis, we considered three cohorts for which whole-blood dnam data were available: heat pain sensitivity (hps), including 20 monozygotic twin pairs discordant for heat pain temperature threshold; fibromyalgia (fm), including 24 cases and 20 controls; and headache, including 22 chronic migraine and medication overuse headache patients (moh), 18 episodic migraineurs (em), and 13 healthy subjects. we used the horvath’s epigenetic age calculator to obtain dnam-based estimates of epigenetic age, telomere length, levels of 7 proteins in plasma, number of smoked packs of cigarettes per year, and blood cell counts. we did not find differences in epigenetic age acceleration, calculated using five different epigenetic clocks, between subjects discordant for pain-related phenotypes. twins with high hps had increased cd8+ t cell counts (nominal p = 0.028). hps thresholds were negatively associated with estimated levels of gdf15 (nominal p = 0.008). fm patients showed decreased naive cd4+ t cell counts compared with controls (nominal p = 0.015). the severity of fm manifestations expressed through various evaluation tests was associated with decreased levels of leptin, shorter length of telomeres, and reduced cd8+ t and natural killer cell counts (nominal p < 0.05), while the duration of painful symptoms was positively associated with telomere length (nominal p = 0.034). no differences in dnam-based estimates were detected for moh or em compared with controls. in summary, our study suggests that hps, fm, and moh/em do not show signs of epigenetic age acceleration in whole blood, while hps and fm are associated with dnam-based estimates of immunological parameters, plasma proteins, and telomere length. future studies should extend these observations in larger cohorts.”
Wogan, G. O. U., Yuan, M. L., Mahler, D. L., & Wang, I. J.. (2020). Genome-wide epigenetic isolation by environment in a widespread Anolis lizard. Molecular Ecology
Plain numerical DOI: 10.1111/mec.15301
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“Epigenetic changes can provide a pathway for organisms to respond to local environmental conditions by influencing gene expression. however, we still know little about the spatial distribution of epigenetic variation in natural systems, how it relates to the distribution of genetic variation and the environmental structure of the landscape, and the processes that generate and maintain it. studies examining spatial patterns of genetic and epigenetic variation can provide valuable insights into how ecological and population processes contribute to epigenetic divergence across heterogeneous landscapes. here, we perform a comparative analysis of spatial genetic and epigenetic variation based on 8,459 single nucleotide polymorphisms (snps) and 8,580 single methylation variants (smvs) from eight populations of the puerto rican crested anole, anolis cristatellus, an abundant lizard in the adaptive radiations of anoles on the greater antilles that occupies a diverse range of habitats. using generalized dissimilarity modelling and multiple matrix regression, we found that genome-wide epigenetic differentiation is strongly correlated with environmental divergence, even after controlling for the underlying genetic structure. we also detected significant associations between key environmental variables and 96 smvs, including 42 located in promoter regions or gene bodies. our results suggest an environmental basis for population-level epigenetic differentiation in this system and contribute to better understanding how environmental gradients structure epigenetic variation in nature.”
Prado, N. A., Brown, J. L., Zoller, J. A., Haghani, A., Yao, M., Bagryanova, L. R., … Horvath, S.. (2021). Epigenetic clock and methylation studies in elephants. Aging Cell
Plain numerical DOI: 10.1111/acel.13414
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“Age-associated dna-methylation profiles have been used successfully to develop highly accurate biomarkers of age (‘epigenetic clocks’) in humans, mice, dogs, and other species. here we present epigenetic clocks for african and asian elephants. these clocks were developed using novel dna methylation profiles of 140 elephant blood samples of known age, at loci that are highly conserved between mammalian species, using a custom infinium array (horvathmammalmethylchip40). we present epigenetic clocks for asian elephants (elephas maximus), african elephants (loxodonta africana), and both elephant species combined. two additional human-elephant clocks were constructed by combining human and elephant samples. epigenome-wide association studies identified elephant age-related cpgs and their proximal genes. the products of these genes play important roles in cellular differentiation, organismal development, metabolism, and circadian rhythms. intracellular events observed to change with age included the methylation of bivalent chromatin domains, and targets of polycomb repressive complexes. these readily available epigenetic clocks can be used for elephant conservation efforts where accurate estimates of age are needed to predict demographic trends.”
Li, Y., Daniel, M., & Tollefsbol, T. O.. (2011). Epigenetic regulation of caloric restriction in aging. BMC Medicine
Plain numerical DOI: 10.1186/1741-7015-9-98
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“The molecular mechanisms of aging are the subject of much research and have facilitated potential interventions to delay aging and aging-related degenerative diseases in humans. the aging process is frequently affected by environmental factors, and caloric restriction is by far the most effective and established environmental manipulation for extending lifespan in various animal models. however, the precise mechanisms by which caloric restriction affects lifespan are still not clear. epigenetic mechanisms have recently been recognized as major contributors to nutrition-related longevity and aging control. two primary epigenetic codes, dna methylation and histone modification, are believed to dynamically influence chromatin structure, resulting in expression changes of relevant genes. in this review, we assess the current advances in epigenetic regulation in response to caloric restriction and how this affects cellular senescence, aging and potential extension of a healthy lifespan in humans. enhanced understanding of the important role of epigenetics in the control of the aging process through caloric restriction may lead to clinical advances in the prevention and therapy of human aging-associated diseases. © 2011 li et al; licensee biomed central ltd.”
Gehring, M.. (2019). Epigenetic dynamics during flowering plant reproduction: evidence for reprogramming?. New Phytologist
Plain numerical DOI: 10.1111/nph.15856
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“Summary: over the last 10 yr there have been major advances in documenting and understanding dynamic changes to dna methylation, small rnas, chromatin modifications and chromatin structure that accompany reproductive development in flowering plants, from germline specification to seed maturation. here i highlight recent advances in the field, mostly made possible by microscopic analysis of epigenetic states or by the ability to isolate specific cell types or tissues and apply omics approaches. i consider in which contexts there is potentially reprogramming vs maintenance or reinforcement of epigenetic states.”
Lee, J. H., Kim, E. W., Croteau, D. L., & Bohr, V. A.. (2020). Heterochromatin: an epigenetic point of view in aging. Experimental and Molecular Medicine
Plain numerical DOI: 10.1038/s12276-020-00497-4
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“Aging is an inevitable process of life. defined by progressive physiological and functional loss of tissues and organs, aging increases the risk of mortality for the organism. the aging process is affected by various factors, including genetic and epigenetic ones. here, we review the chromatin-specific epigenetic changes that occur during normal (chronological) aging and in premature aging diseases. taking advantage of the reversible nature of epigenetic modifications, we will also discuss possible lifespan expansion strategies through epigenetic modulation, which was considered irreversible until recently.”
Prado, N. A., Brown, J. L., Zoller, J. A., Haghani, A., Yao, M., Bagryanova, L. R., … Horvath, S.. (2021). Epigenetic clock and methylation studies in elephants. Aging Cell
Plain numerical DOI: 10.1111/acel.13414
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“Age-associated dna-methylation profiles have been used successfully to develop highly accurate biomarkers of age (‘epigenetic clocks’) in humans, mice, dogs, and other species. here we present epigenetic clocks for african and asian elephants. these clocks were developed using novel dna methylation profiles of 140 elephant blood samples of known age, at loci that are highly conserved between mammalian species, using a custom infinium array (horvathmammalmethylchip40). we present epigenetic clocks for asian elephants (elephas maximus), african elephants (loxodonta africana), and both elephant species combined. two additional human-elephant clocks were constructed by combining human and elephant samples. epigenome-wide association studies identified elephant age-related cpgs and their proximal genes. the products of these genes play important roles in cellular differentiation, organismal development, metabolism, and circadian rhythms. intracellular events observed to change with age included the methylation of bivalent chromatin domains, and targets of polycomb repressive complexes. these readily available epigenetic clocks can be used for elephant conservation efforts where accurate estimates of age are needed to predict demographic trends.”
Bertozzi, T. M., & Ferguson-Smith, A. C.. (2020). Metastable epialleles and their contribution to epigenetic inheritance in mammals. Seminars in Cell and Developmental Biology
Plain numerical DOI: 10.1016/j.semcdb.2019.08.002
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“Many epigenetic differences between individuals are driven by genetic variation. mammalian metastable epialleles are unusual in that they show variable dna methylation states between genetically identical individuals. the occurrence of such states across generations has resulted in their consideration by many as strong evidence for epigenetic inheritance in mammals, with the classic avy and axinfu mouse models – each products of repeat element insertions – being the most widely accepted examples. equally, there has been interest in exploring their use as epigenetic biosensors given their susceptibility to environmental compromise. here we review the classic murine metastable epialleles as well as more recently identified candidates, with the aim of providing a more holistic understanding of their biology. we consider the extent to which epigenetic inheritance occurs at metastable epialleles and explore the limited mechanistic insights into the establishment of their variable epigenetic states. we discuss their environmental modulation and their potential relevance in genome regulation. in light of recent whole-genome screens for novel metastable epialleles, we point out the need to reassess their biological relevance in multi-generational studies and we highlight their value as a model to study repeat element silencing as well as the mechanisms and consequences of mammalian epigenetic stochasticity.”
Raabe, F. J., & Spengler, D.. (2013). Epigenetic risk factors in PTSD and depression. Frontiers in Psychiatry
Plain numerical DOI: 10.3389/fpsyt.2013.00080
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“Epidemiological and clinical studies have shown that children exposed to adverse experiences are at increased risk for the development of depression, anxiety disorders, and posttraumatic stress disorder (ptsd). a history of child abuse and maltreatment increases the likelihood of being subsequently exposed to traumatic events or of developing ptsd as an adult. the brain is highly plastic during early life and encodes acquired information into lasting memories that normally subserve adaptation. translational studies in rodents showed that enduring sensitization of neuronal and neuroendocrine circuits in response to early life adversity are likely risk factors of life time vulnerability to stress. hereby, the hypothalamic-pituitary-adrenal (hpa) axis integrates cognitive, behavioral, and emotional responses to early-life stress and can be epigenetically programed during sensitive windows of development. epigenetic mechanisms, comprising reciprocal regulation of chromatin structure and dna methylation, are important to establish and maintain sustained, yet potentially reversible, changes in gene transcription. the relevance of these findings for the development of ptsd requires further studies in humans where experience-dependent epigenetic programing can additionally depend on genetic variation in the underlying substrates which may protect from or advance disease development. overall, identification of early-life stress-associated epigenetic risk markers informing on previous stress history can help to advance early diagnosis, personalized prevention, and timely therapeutic interventions, thus reducing long-term social and health costs. © 2013 raabe and spengler.”
Morgan, H. D., Santos, F., Green, K., Dean, W., & Reik, W.. (2005). Epigenetic reprogramming in mammals. Human Molecular Genetics
Plain numerical DOI: 10.1093/hmg/ddi114
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“Epigenetic marking systems confer stability of gene expression during mammalian development. genome-wide epigenetic reprogramming occurs at stages when developmental potency of cells changes. at fertilization, the paternal genome exchanges protamines for histones, undergoes dna demethylation, and acquires histone modifications, whereas the maternal genome appears epigenetically more static. during preimplantation development, there is passive dna demethylation and further reorganization of histone modifications. in blastocysts, embryonic and extraembryonic lineages first show different epigenetic marks. this epigenetic reprogramming is likely to be needed for totipotency, correct initiation of embryonic gene expression, and early lineage development in the embryo. comparative work demonstrates reprogramming in all mammalian species analysed, but the extent and timing varies, consistent with notable differences between species during preimplantation development. parental imprinting marks originate in sperm and oocytes and are generally protected from this genome-wide reprogramming. early primordial germ cells possess imprinting marks similar to those of somatic cells. however, rapid dna demethylation after midgestation erases these parental imprints, in preparation for sex-specific de novo methylation during gametogenesis. aberrant reprogramming of somatic epigenetic marks after somatic cell nuclear transfer leads to epigenetic defects in cloned embryos and stem cells. links between epigenetic marking systems appear to be developmentally regulated contributing to plasticity. a number of activities that confer epigenetic marks are firmly established, while for those that remove marks, particularly methylation, some interesting candidates have emerged recently which need thorough testing in vivo. a mechanistic understanding of reprogramming will be crucial for medical applications of stem cell technology. © the author 2005. published by oxford university press. all rights reserved.”
Wang, Y., Liu, H., & Sun, Z.. (2017). Lamarck rises from his grave: parental environment-induced epigenetic inheritance in model organisms and humans. Biological Reviews
Plain numerical DOI: 10.1111/brv.12322
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“Organisms can change their physiological/behavioural traits to adapt and survive in changed environments. however, whether these acquired traits can be inherited across generations through non-genetic alterations has been a topic of debate for over a century. emerging evidence indicates that both ancestral and parental experiences, including nutrition, environmental toxins, nurturing behaviour, and social stress, can have powerful effects on the physiological, metabolic and cellular functions in an organism. in certain circumstances, these effects can be transmitted across several generations through epigenetic (i.e. non-dna sequence-based rather than mutational) modifications. in this review, we summarize recent evidence on epigenetic inheritance from parental environment-induced developmental and physiological alterations in nematodes, fruit flies, zebrafish, rodents, and humans. the epigenetic modifications demonstrated to be both susceptible to modulation by environmental cues and heritable, including dna methylation, histone modification, and small non-coding rnas, are also summarized. we particularly focus on evidence that parental environment-induced epigenetic alterations are transmitted through both the maternal and paternal germlines and exert sex-specific effects. the thought-provoking data presented here raise fundamental questions about the mechanisms responsible for these phenomena. in particular, the means that define the specificity of the response to parental experience in the gamete epigenome and that direct the establishment of the specific epigenetic change in the developing embryos, as well as in specific tissues in the descendants, remain obscure and require elucidation. more precise epigenetic assessment at both the genome-wide level and single-cell resolution as well as strategies for breeding at relatively sensitive periods of development and manipulation aimed at specific epigenetic modification are imperative for identifying parental environment-induced epigenetic marks across generations. considering their diverse epigenetic architectures, the conservation and prevalence of the mechanisms underlying epigenetic inheritance in non-mammals require further investigation in mammals. interpretation of the consequences arising from epigenetic inheritance on organisms and a better understanding of the underlying mechanisms will provide insight into how gene–environment interactions shape developmental processes and physiological func…”
Gaździcka, J., Gołąbek, K., Strzelczyk, J. K., & Ostrowska, Z.. (2020). Epigenetic Modifications in Head and Neck Cancer. Biochemical Genetics
Plain numerical DOI: 10.1007/s10528-019-09941-1
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“Head and neck squamous cell carcinoma (hnscc) is the sixth most common human malignancy in the world, with high mortality and poor prognosis for patients. among the risk factors are tobacco and alcohol intake, human papilloma virus, and also genetic and epigenetic modifications. many studies show that epigenetic events play an important role in hnscc development and progression, including dna methylation, chromatin remodeling, histone posttranslational covalent modifications, and effects of non-coding rna. epigenetic modifications may influence silencing of tumor suppressor genes by promoter hypermethylation, regulate transcription by micrornas and changes in chromatin structure, or induce genome instability through hypomethylation. moreover, getting to better understand aberrant patterns of methylation may provide biomarkers for early detection and diagnosis, while knowledge about target genes of micrornas may improve the therapy of hnscc and extend overall survival. the aim of this review is to present recent studies which demonstrate the role of epigenetic regulation in the development of hnscc.”
van der Pol, Y., & Mouliere, F.. (2019). Toward the Early Detection of Cancer by Decoding the Epigenetic and Environmental Fingerprints of Cell-Free DNA. Cancer Cell
Plain numerical DOI: 10.1016/j.ccell.2019.09.003
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“Widespread adaptation of liquid biopsy for the early detection of cancer has yet to reach clinical utility. circulating tumor dna is commonly detected though the presence of genetic alterations, but only a minor fraction of tumor-derived cell-free dna (cfdna) fragments exhibit mutations. the cellular processes occurring in cancer development mark the chromatin. these epigenetic marks are reflected by modifications in the cfdna methylation, fragment size, and structure. in this review, we describe how going beyond dna sequence information alone, by analyzing cfdna epigenetic and immune signatures, boosts the potential of liquid biopsy for the early detection of cancer.”
Wang, T., Tsui, B., Kreisberg, J. F., Robertson, N. A., Gross, A. M., Yu, M. K., … Ideker, T.. (2017). Epigenetic aging signatures in mice livers are slowed by dwarfism, calorie restriction and rapamycin treatment. Genome Biology
Plain numerical DOI: 10.1186/s13059-017-1186-2
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“Background: global but predictable changes impact the dna methylome as we age, acting as a type of molecular clock. this clock can be hastened by conditions that decrease lifespan, raising the question of whether it can also be slowed, for example, by conditions that increase lifespan. mice are particularly appealing organisms for studies of mammalian aging; however, epigenetic clocks have thus far been formulated only in humans. results: we first examined whether mice and humans experience similar patterns of change in the methylome with age. we found moderate conservation of cpg sites for which methylation is altered with age, with both species showing an increase in methylome disorder during aging. based on this analysis, we formulated an epigenetic-aging model in mice using the liver methylomes of 107 mice from 0.2 to 26.0 months old. to examine whether epigenetic aging signatures are slowed by longevity-promoting interventions, we analyzed 28 additional methylomes from mice subjected to lifespan-extending conditions, including prop1df/df dwarfism, calorie restriction or dietary rapamycin. we found that mice treated with these lifespan-extending interventions were significantly younger in epigenetic age than their untreated, wild-type age-matched controls. conclusions: this study shows that lifespan-extending conditions can slow molecular changes associated with an epigenetic clock in mice livers.”
Cruz-Almeida, Y., Sinha, P., Rani, A., Huo, Z., Fillingim, R. B., & Foster, T.. (2019). Epigenetic aging is associated with clinical and experimental pain in community-dwelling older adults. Molecular Pain
Plain numerical DOI: 10.1177/1744806919871819
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“Gerontological research reveals considerable interindividual variability in aging phenotypes, which has motivated research efforts to identify ‘aging biomarkers.’ aging biomarkers are used to calculate biological age, which are better predictors of disease risk and residual lifespan when compared to chronological age alone. emerging evidence using the epigenetic clock as an aging biomarker supports highly reliable individualized predictions about future health. this study aimed to determine whether an epigenetic aging biomarker was associated with chronic pain in older adults (60–83 years old). a subset of participants (n = 29) in the neuromodulatory examination of pain and mobility across the lifespan study underwent a blood draw, demographic, psychological, cognitive, and pain assessments. we estimated horvath’s epigenetic clock and calculated the difference between epigenetic age and chronological age that has been previously reported to predict overall mortality risk. older individuals without chronic pain (n = 9) had significantly ‘younger’ epigenetic age compared to those with chronic pain (n = 20, p < 0.05). older epigenetic age was associated with greater pain during daily activities (r = 0.494, p = 0.010) and anatomical pain sites (r = 0.741, p < 0.001) but not pain frequency/duration. an older epigenetic age was also associated with higher vibratory detection thresholds (r = 0.490, p = 0.021), heat pain thresholds (r = −0.478, p = 0.028), and pressure pain thresholds at the trapezius (r = −0.571, p = 0.006) but not thermal detection, pressure pain at the quadriceps or pain inhibition (p’s > 0.05). epigenetic aging was associated with greater emotional stability (r = −0.461, p = 0.027), conscientiousness (r = −0.549, p = 0.007), and lower extraversion (r = 0.414, p = 0.049) but not depression or affect (p’s > 0.05). epigenetic aging was also associated with lower episodic (r = −0.698, p = 0.001) and working memory (r = −0.760, p < 0.001). our findings suggest that chronic pain is associated with accelerated epigenetic aging in healthy, community-dwelling older individuals, and future studies with larger samples are needed to confirm our findings. an aging biomarker such as the epigenetic clock may help identify people with chronic pain at greater risk of functional decline and poorer health outcomes.”
Holla, S., Dhakshnamoorthy, J., Folco, H. D., Balachandran, V., Xiao, H., Sun, L. ling, … Grewal, S. I. S.. (2020). Positioning Heterochromatin at the Nuclear Periphery Suppresses Histone Turnover to Promote Epigenetic Inheritance. Cell
Plain numerical DOI: 10.1016/j.cell.2019.12.004
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“In eukaryotes, heterochromatin is generally located at the nuclear periphery. this study investigates the biological significance of perinuclear positioning for heterochromatin maintenance and gene silencing. we identify the nuclear rim protein amo1nupl2 as a factor required for the propagation of heterochromatin at endogenous and ectopic sites in the fission yeast genome. amo1 associates with the rix1pelp1-containing rna processing complex rixc and with the histone chaperone complex fact. rixc, which binds to heterochromatin protein swi6hp1 across silenced chromosomal domains and to surrounding boundary elements, connects heterochromatin with amo1 at the nuclear periphery. in turn, the amo1-enriched subdomain is critical for swi6 association with fact that precludes histone turnover to promote gene silencing and preserve epigenetic stability of heterochromatin. in addition to uncovering conserved factors required for perinuclear positioning of heterochromatin, these analyses elucidate a mechanism by which a peripheral subdomain enforces stable gene repression and maintains heterochromatin in a heritable manner.”
Chatterjee, A., Rodger, E. J., & Eccles, M. R.. (2018). Epigenetic drivers of tumourigenesis and cancer metastasis. Seminars in Cancer Biology
Plain numerical DOI: 10.1016/j.semcancer.2017.08.004
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“Since the completion of the first human genome sequence and the advent of next generation sequencing technologies, remarkable progress has been made in understanding the genetic basis of cancer. these studies have mainly defined genetic changes as either causal, providing a selective advantage to the cancer cell (a driver mutation) or consequential with no selective advantage (not directly causal, a passenger mutation). a vast unresolved question is how a primary cancer cell becomes metastatic and what are the molecular events that underpin this process. however, extensive sequencing efforts indicate that mutation may not be a causal factor for primary to metastatic transition. on the other hand, epigenetic changes are dynamic in nature and therefore potentially play an important role in determining metastatic phenotypes and this area of research is just starting to be appreciated. unlike genetic studies, current limitations in studying epigenetic events in cancer metastasis include a lack of conceptual understanding and an analytical framework for identifying putative driver and passenger epigenetic changes. in this review, we discuss the key concepts involved in understanding the role of epigenetic alterations in the metastatic cascade. we particularly focus on driver epigenetic events, and we describe analytical approaches and biological frameworks for distinguishing between ‘epi-driver’ and ‘epi-passenger’ events in metastasis. finally, we suggest potential directions for future research in this important area of cancer research.”
Kwiatkowska, K. M., Bacalini, M. G., Sala, C., Kaziyama, H., de Andrade, D. C., Terlizzi, R., … Pirazzini, C.. (2020). Analysis of Epigenetic Age Predictors in Pain-Related Conditions. Frontiers in Public Health
Plain numerical DOI: 10.3389/fpubh.2020.00172
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“Chronic pain prevalence is high worldwide and increases at older ages. signs of premature aging have been associated with chronic pain, but few studies have investigated aging biomarkers in pain-related conditions. a set of dna methylation (dnam)-based estimates of age, called ‘epigenetic clocks,’ has been proposed as biological measures of age-related adverse processes, morbidity, and mortality. the aim of this study is to assess if different pain-related phenotypes show alterations in dnam age. in our analysis, we considered three cohorts for which whole-blood dnam data were available: heat pain sensitivity (hps), including 20 monozygotic twin pairs discordant for heat pain temperature threshold; fibromyalgia (fm), including 24 cases and 20 controls; and headache, including 22 chronic migraine and medication overuse headache patients (moh), 18 episodic migraineurs (em), and 13 healthy subjects. we used the horvath’s epigenetic age calculator to obtain dnam-based estimates of epigenetic age, telomere length, levels of 7 proteins in plasma, number of smoked packs of cigarettes per year, and blood cell counts. we did not find differences in epigenetic age acceleration, calculated using five different epigenetic clocks, between subjects discordant for pain-related phenotypes. twins with high hps had increased cd8+ t cell counts (nominal p = 0.028). hps thresholds were negatively associated with estimated levels of gdf15 (nominal p = 0.008). fm patients showed decreased naive cd4+ t cell counts compared with controls (nominal p = 0.015). the severity of fm manifestations expressed through various evaluation tests was associated with decreased levels of leptin, shorter length of telomeres, and reduced cd8+ t and natural killer cell counts (nominal p < 0.05), while the duration of painful symptoms was positively associated with telomere length (nominal p = 0.034). no differences in dnam-based estimates were detected for moh or em compared with controls. in summary, our study suggests that hps, fm, and moh/em do not show signs of epigenetic age acceleration in whole blood, while hps and fm are associated with dnam-based estimates of immunological parameters, plasma proteins, and telomere length. future studies should extend these observations in larger cohorts.”
Iwasaki, M., & Paszkowski, J.. (2014). Epigenetic memory in plants. The EMBO Journal
Plain numerical DOI: 10.15252/embj.201488883
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“Epigenetics refers to heritable changes in patterns of gene expression that occur without alterations in dna sequence. the epigenetic mechanisms involve covalent modifications of dna and histones, which affect transcriptional activity of chromatin. since chromatin states can be propagated through mitotic and meiotic divisions, epigenetic mechanisms are thought to provide heritable ‘cellular memory’. here, we review selected examples of epigenetic memory in plants and briefly discuss underlying mechanisms.”
Wajda, A., Łapczuk-Romańska, J., & Paradowska-Gorycka, A.. (2020). Epigenetic regulations of ahr in the aspect of immunomodulation. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms21176404
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“Environmental factors contribute to autoimmune disease manifestation, and as regarded today, ahr has become an important factor in studies of immunomodulation. besides immunological aspects, ahr also plays a role in pharmacological, toxicological and many other physiological processes such as adaptive metabolism. in recent years, epigenetic mechanisms have provided new insight into gene regulation and reveal a new contribution to autoimmune disease pathogenesis. dna methylation, histone modifications, chromatin alterations, microrna and consequently non-genetic changes in phenotypes connect with environmental factors. increasing data reveals ahr cross-roads with the most significant in immunology pathways. although study on epigenetic modulations in autoimmune diseases is still not well understood, therefore future research will help us understand their pathophysiology and help to find new therapeutic strategies. present literature review sheds the light on the common ground between remodeling chromatin compounds and autoimmune antibodies used in diagnostics. in the proposed review we summarize recent findings that describe epigenetic factors which regulate ahr activity and impact diverse immunological responses and pathological changes.”
Martinez-Moreno, J. M., Fontecha-Barriuso, M., Martin-Sanchez, D., Guerrero-Mauvecin, J., Goma-Garces, E., Fernandez-Fernandez, B., … Sanz, A. B.. (2020). Epigenetic modifiers as potential therapeutic targets in diabetic kidney disease. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms21114113
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“Diabetic kidney disease is one of the fastest growing causes of death worldwide. epigenetic regulators control gene expression and are potential therapeutic targets. there is functional interventional evidence for a role of dna methylation and the histone post-translational modifications—histone methylation, acetylation and crotonylation—in the pathogenesis of kidney disease, including diabetic kidney disease. readers of epigenetic marks, such as bromodomain and extra terminal (bet) proteins, are also therapeutic targets. thus, the bd2 selective bet inhibitor apabetalone was the first epigenetic regulator to undergo phase-3 clinical trials in diabetic kidney disease with an endpoint of kidney function. the direct therapeutic modulation of epigenetic features is possible through pharmacological modulators of the specific enzymes involved and through the therapeutic use of the required substrates. of further interest is the characterization of potential indirect effects of nephroprotective drugs on epigenetic regulation. thus, sglt2 inhibitors increase the circulating and tissue levels of β-hydroxybutyrate, a molecule that generates a specific histone modification, β-hydroxybutyrylation, which has been associated with the beneficial health effects of fasting. to what extent this impact on epigenetic regulation may underlie or contribute to the so-far unclear molecular mechanisms of cardio-and nephroprotection offered by sglt2 inhibitors merits further in-depth studies.”
Peedicayil, J.. (2020). The potential role of epigenetic drugs in the treatment of anxiety disorders. Neuropsychiatric Disease and Treatment
Plain numerical DOI: 10.2147/NDT.S242040
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“There is increasing evidence that abnormalities in epigenetic mechanisms of gene expression contribute to the pathogenesis of anxiety disorders (ads). this article discusses the role of epigenetic mechanisms of gene expression in the pathogenesis of ads. it also discusses the data so far obtained from preclinical and clinical trials on the use of epigenetic drugs for treating ads. most drug trials investigating the use of epigenetic drugs for treating ads have used histone deacetylase inhibitors (hdaci). hdaci are showing favorable results in both preclinical and clinical drug trials for treating ads. however, at present the mode of action of hdaci in ads is not clear. more work needs to be done to elucidate how epigenetic dysregulation contributes to the pathogenesis of ads. more work also needs to be done on the mode of action of hdaci in alleviating the signs and symptoms of ads.”
Donkin, I., & Barrès, R.. (2018). Sperm epigenetics and influence of environmental factors. Molecular Metabolism
Plain numerical DOI: 10.1016/j.molmet.2018.02.006
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“Background: developmental programming of the embryo is controlled by genetic information but also dictated by epigenetic information contained in spermatozoa. lifestyle and environmental factors not only influence health in one individual but can also affect the phenotype of the following generations. this is mediated via epigenetic inheritance i.e., gametic transmission of environmentally-driven epigenetic information to the offspring. evidence is accumulating that preconceptional exposure to certain lifestyle and environmental factors, such as diet, physical activity, and smoking, affects the phenotype of the next generation through remodeling of the epigenetic blueprint of spermatozoa. scope of review: this review will summarize current knowledge about the different epigenetic signals in sperm that are responsive to environmental and lifestyle factors and are capable of affecting embryonic development and the phenotype of the offspring later in life. major conclusions: like somatic cells, the epigenome of spermatozoa has proven to be dynamically reactive to a wide variety of environmental and lifestyle stressors. the functional consequence on embryogenesis and phenotype of the next generation remains largely unknown. however, strong evidence of environmentally-driven sperm-borne epigenetic factors, which are capable of altering the phenotype of the next generation, is emerging on a large scale.”
Kronholm, I., Bassett, A., Baulcombe, D., & Collins, S.. (2017). Epigenetic and genetic contributions to adaptation in chlamydomonas. Molecular Biology and Evolution
Plain numerical DOI: 10.1093/molbev/msx166
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“Epigenetic modifications, such as dna methylation or histone modifications, can be transmitted between cellular or organismal generations. however, there are no experiments measuring their role in adaptation, so here we use experimental evolution to investigate how epigenetic variation can contribute to adaptation. we manipulated dna methylation and histone acetylation in the unicellular green alga chlamydomonas reinhardtii both genetically and chemically to change the amount of epigenetic variation generated or transmitted in adapting populations in three different environments (salt stress, phosphate starvation, and high co2) for two hundred asexual generations. we find that reducing the amount of epigenetic variation available to populations can reduce adaptation in environments where it otherwise happens. from genomic and epigenomic sequences from a subset of the populations, we see changes in methylation patterns between the evolved populations over-represented in some functional categories of genes, which is consistent with some of these differences being adaptive. based on whole genome sequencing of evolved clones, themajority of dna methylation changes do not appear to be linked to cis-acting genetic mutations. our results show that transgenerational epigenetic effects play a role in adaptive evolution, and suggest that the relationship between changes in methylation patterns and differences in evolutionary outcomes, at least for quantitative traits such as cell division rates, is complex.”
Feng, S., Jacobsen, S. E., & Reik, W.. (2010). Epigenetic reprogramming in plant and animal development. Science
Plain numerical DOI: 10.1126/science.1190614
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“Epigenetic modifications of the genome are generally stable in somatic cells of multicellular organisms. in germ cells and early embryos, however, epigenetic reprogramming occurs on a genome-wide scale, which includes demethylation of dna and remodeling of histones and their modifications. the mechanisms of genome-wide erasure of dna methylation, which involve modifications to 5-methylcytosine and dna repair, are being unraveled. epigenetic reprogramming has important roles in imprinting, the natural as well as experimental acquisition of totipotency and pluripotency, control of transposons, and epigenetic inheritance across generations. small rnas and the inheritance of histone marks may also contribute to epigenetic inheritance and reprogramming. reprogramming occurs in flowering plants and in mammals, and the similarities and differences illuminate developmental and reproductive strategies.”
Zhao, R., Choi, B. Y., Lee, M. H., Bode, A. M., & Dong, Z.. (2016). Implications of Genetic and Epigenetic Alterations of CDKN2A (p16INK4a) in Cancer. EBioMedicine
Plain numerical DOI: 10.1016/j.ebiom.2016.04.017
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“Aberrant gene silencing is highly associated with altered cell cycle regulation during carcinogenesis. in particular, silencing of the cdkn2a tumor suppressor gene, which encodes the p16ink4a protein, has a causal link with several different types of cancers. the p16ink4a protein plays an executional role in cell cycle and senescence through the regulation of the cyclin-dependent kinase (cdk) 4/6 and cyclin d complexes. several genetic and epigenetic aberrations of cdkn2a lead to enhanced tumorigenesis and metastasis with recurrence of cancer and poor prognosis. in these cases, the restoration of genetic and epigenetic reactivation of cdkn2a is a practical approach for the prevention and therapy of cancer. this review highlights the genetic status of cdkn2a as a prognostic and predictive biomarker in various cancers.”
Marečková, K., Pačínková, A., Klasnja, A., Shin, J., Andrýsková, L., Stano-Kozubík, K., … Paus, T.. (2020). Epigenetic clock as a correlate of anxiety. NeuroImage: Clinical
Plain numerical DOI: 10.1016/j.nicl.2020.102458
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“DNA methylation changes consistently throughout life and age-dependent alterations in dna methylation can be used to estimate one’s epigenetic age. post-mortem studies revealed higher epigenetic age in brains of patients with major depressive disorder, as compared with controls. since mdd is highly correlated with anxiety, we hypothesized that symptoms of anxiety, as well as lower volume of grey matter (gm) in depression-related cortical regions, will be associated with faster epigenetic clock in a community-based sample of young adults. participants included 88 young adults (53% men; 23–24 years of age) from the european longitudinal study of pregnancy and childhood (elspac) who participated in its neuroimaging follow-up and provided saliva samples for epigenetic analysis. epigenetic age was calculated according to horvath (horvath, 2013). women had slower epigenetic clock than men (cohen’s d = 0.48). in women (but not men), slower epigenetic clock was associated with less symptoms of anxiety. in the brain, women (but not men) with slower epigenetic clock had greater gm volume in the cerebral cortex (brain size-corrected; r2 = 0.07). lobe-specific analyses showed that in women (but not men), slower epigenetic clock was associated with greater gm volume in frontal lobe (r2 = 0.16), and that gm volume in frontal lobe mediated the relationship between the speed of epigenetic clock and anxiety trait (ab = 0.15, se = 0.15, 95% ci [0.007; 0.369]). these findings were not replicated, however, in a community-based sample of adolescents (n = 129; 49% men; 12–19 years of age), possibly due to the different method of tissue collection (blood vs. saliva) or additional sources of variability in the cohort of adolescents (puberty stages, socioeconomic status, prenatal exposure to maternal smoking during pregnancy).”
Richetto, J., & Meyer, U.. (2021). Epigenetic Modifications in Schizophrenia and Related Disorders: Molecular Scars of Environmental Exposures and Source of Phenotypic Variability. Biological Psychiatry
Plain numerical DOI: 10.1016/j.biopsych.2020.03.008
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“Epigenetic modifications are increasingly recognized to play a role in the etiology and pathophysiology of schizophrenia and other psychiatric disorders with developmental origins. here, we summarize clinical and preclinical findings of epigenetic alterations in schizophrenia and relevant disease models and discuss their putative origin. recent findings suggest that certain schizophrenia risk loci can influence stochastic variation in gene expression through epigenetic processes, highlighting the intricate interaction between genetic and epigenetic control of neurodevelopmental trajectories. in addition, a substantial portion of epigenetic alterations in schizophrenia and related disorders may be acquired through environmental factors and may be manifested as molecular ‘scars.’ some of these scars can influence brain functions throughout the entire lifespan and may even be transmitted across generations via epigenetic germline inheritance. epigenetic modifications, whether caused by genetic or environmental factors, are plausible molecular sources of phenotypic heterogeneity and offer a target for therapeutic interventions. the further elucidation of epigenetic modifications thus may increase our knowledge regarding schizophrenia’s heterogeneous etiology and pathophysiology and, in the long term, may advance personalized treatments through the use of biomarker-guided epigenetic interventions.”
Marioni, R. E., Harris, S. E., Shah, S., McRae, A. F., von Zglinicki, T., Martin-Ruiz, C., … Deary, I. J.. (2016). The epigenetic clock and telomere length are independently associated with chronological age and mortality. International Journal of Epidemiology
Plain numerical DOI: 10.1093/ije/dyw041
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“Background: telomere length and dna methylation have been proposed as biological clock measures that track chronological age. whether they change in tandem, or contribute independently to the prediction of chronological age, is not known. methods: we address these points using data from two scottish cohorts: the lothian birth cohorts of 1921 (lbc1921) and 1936 (lbc1936). telomere length and epigenetic clock estimates from dna methylation were measured in 920 lbc1936 participants (ages 70, 73 and 76 years) and in 414 lbc1921 participants (ages 79, 87 and 90 years). results: the epigenetic clock changed over time at roughly the same rate as chronological age in both cohorts. telomere length decreased at 48-67 base pairs per year on average. weak, non-significant correlations were found between epigenetic clock estimates and telomere length. telomere length explained 6.6% of the variance in age in lbc1921, the epigenetic clock explained 10.0%, and combined they explained 17.3% (all p < 1 × 10-7). corresponding figures for the lbc1936 cohort were 14.3%, 11.7% and 19.5% (all p < 1 × 10-12). in a combined cohorts analysis, the respective estimates were 2.8%, 28.5% and 29.5%. also in a combined cohorts analysis, a one standard deviation increase in baseline epigenetic age was linked to a 22% increased mortality risk (p = 2.6 × 10-4) whereas, in the same model, a one standard deviation increase in baseline telomere length was independently linked to an 11% decreased mortality risk (p = 0.06). conclusions: these results suggest that telomere length and epigenetic clock estimates are independent predictors of chronological age and mortality risk.”
Li, J., Li, W. X., Bai, C., & Song, Y.. (2017). Particulate matter-induced epigenetic changes and lung cancer. Clinical Respiratory Journal
Plain numerical DOI: 10.1111/crj.12389
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“Background and aims: lung cancer is the leading cause of cancer death worldwide. cigarette smoking is the well-known risk factor for lung cancer. epidemiological studies suggest that air pollution, especially particulate matter (pm) exposure, is associated with increased lung cancer risk and mortality independent of cigarette smoking. methods: english-language publications focusing on pm, epigenetic changes, and lung cancer were reviewed. the epigenome serves as an interface between the environment and the genome. pm is one of the environmental factors that can cause epigenetic changes. the epigenome serves as an interface between the environment and the genome. some of the epigenetic changes lead to increased disease susceptibility and progression. in cardiovascular disease and asthma, the association between pm exposure and the disease specific epigenetic changes has been identified. in lung cancer, the epigenetic changes in dna methylation, histone modification and microrna expression are commonly found, but the specific link between pm exposure and lung cancer remains incompletely understood. results: the results of epidemiological studies indicate the important effects of pm exposure on lung cancer. pm2.5 is consistently associated with the increased lung cancer risk and mortality. based on the epidemiological associations between pm exposure and lung cancer, pm-induced epigenetic changes may play important roles in the pathogenesis of lung cancer. conclusion: in this review, we focus on the current knowledge of epigenetic changes associated with pm exposure and lung cancer. better understanding of the link between pm exposure and lung cancer at the epigenomic level by comprehensive comparison approach may identify lung cancer early detection biomarkers and novel therapeutic targets.”
Espinas, N. A., Saze, H., & Saijo, Y.. (2016). Epigenetic control of defense signaling and priming in plants. Frontiers in Plant Science
Plain numerical DOI: 10.3389/fpls.2016.01201
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“Immune recognition of pathogen-associated molecular patterns or effectors leads to defense activation at the pathogen challenged sites. this is followed by systemic defense activation at distant non-challenged sites, termed systemic acquired resistance (sar). these inducible defenses are accompanied by extensive transcriptional reprogramming of defense-related genes. sar is associated with priming, in which a subset of these genes is kept at a poised state to facilitate subsequent transcriptional regulation. transgenerational inheritance of defense-related priming in plants indicates the stability of such primed states. recent studies have revealed the importance and dynamic engagement of epigenetic mechanisms, such as dna methylation and histone modifications that are closely linked to chromatin reconfiguration, in plant adaptation to different biotic stresses. herein we review current knowledge regarding the biological significance and underlying mechanisms of epigenetic control for immune responses in plants. we also argue for the importance of host transposable elements as critical regulators of interactions in the evolutionary ‘arms race’ between plants and pathogens.”
Park, J. W., & Turcan, Ş.. (2019). Epigenetic reprogramming for targeting IDH-mutant malignant gliomas. Cancers
Plain numerical DOI: 10.3390/cancers11101616
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“Targeting the epigenome has been considered a compelling treatment modality for several cancers, including gliomas. nearly 80% of the lower-grade gliomas and secondary glioblastomas harbor recurrent mutations in isocitrate dehydrogenase (idh). mutant idh generates high levels of 2-hydroxyglutarate (2-hg) that inhibit various components of the epigenetic machinery, including histone and dna demethylases. the encouraging results from current epigenetic therapies in hematological malignancies have reinvigorated the interest in solid tumors and gliomas, both preclinically and clinically. here, we summarize the recent advancements in epigenetic therapy for lower-grade gliomas and discuss the challenges associated with current treatment options. aparticular focus is placed on therapeutic mechanisms underlying favorable outcome with epigenetic-based drugs in basic and translational research of gliomas. this review also highlights emerging bridges to combination treatment with respect to epigenetic drugs. given that epigenetic therapies, particularly dna methylation inhibitors, increase tumor immunogenicity and antitumor immune responses, appropriate drug combinations with immune checkpoint inhibitors may lead to improvement of treatment effectiveness of immunotherapy, ultimately leading to tumor cell eradication.”
Furrow, R. E., & Feldman, M. W.. (2014). Genetic variation and the evolution of epigenetic regulation. Evolution
Plain numerical DOI: 10.1111/evo.12225
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“Epigenetic variation has been observed in a range of organisms, leading to questions of the adaptive significance of this variation. in this study, we present a model to explore the ecological and genetic conditions that select for epigenetic regulation. we find that the rate of temporal environmental change is a key factor controlling the features of this evolution. when the environment fluctuates rapidly between states with different phenotypic optima, epigenetic regulation may evolve but we expect to observe low transgenerational inheritance of epigenetic states, whereas when this fluctuation occurs over longer time scales, regulation may evolve to generate epigenetic states that are inherited faithfully for many generations. in all cases, the underlying genetic variation at the epigenetically regulated locus is a crucial factor determining the range of conditions that allow for evolution of epigenetic mechanisms. © 2013 the society for the study of evolution.”
Morgado-Pascual, J. L., Rayego-Mateos, S., Tejedor, L., Suarez-Alvarez, B., & Ruiz-Ortega, M.. (2019). Bromodomain and extraterminal proteins as novel epigenetic targets for renal diseases. Frontiers in Pharmacology
Plain numerical DOI: 10.3389/fphar.2019.01315
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“Epigenetic mechanisms, especially dna methylation and histone modifications, are dynamic processes that regulate the gene expression transcriptional program in normal and diseased states. the bromodomain and extraterminal (bet) protein family (brd2, brd3, brd4, and brdt) are epigenetic readers that, via bromodomains, regulate gene transcription by binding to acetylated lysine residues on histones and master transcriptional factors. experimental data have demonstrated the involvement of some bet proteins in many pathological conditions, including tumor development, infections, autoimmunity, and inflammation. selective bromodomain inhibitors are epigenetic drugs that block the interaction between bet proteins and acetylated proteins, thus exerting beneficial effects. recent data have described the beneficial effect of bet inhibition on experimental renal diseases. emerging evidence underscores the importance of environmental modifications in the origin of pathological features in chronic kidney diseases (ckd). several cellular processes such as oxidation, metabolic disorders, cytokines, inflammation, or accumulated uremic toxins may induce epigenetic modifications that regulate key processes involved in renal damage and in other pathological conditions observed in ckd patients. here, we review how targeting bromodomains in bet proteins may regulate essential processes involved in renal diseases and in associated complications found in ckd patients, such as cardiovascular damage, highlighting the potential of epigenetic therapeutic strategies against bet proteins for ckd treatment and associated risks.”
Chan, A. K. N., & Chen, C. W.. (2019). Rewiring the epigenetic networks in MLL-rearranged leukemias: Epigenetic dysregulation and pharmacological interventions. Frontiers in Cell and Developmental Biology
Plain numerical DOI: 10.3389/fcell.2019.00081
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“Leukemias driven by chromosomal translocation of the mixed-lineage leukemia gene (mll or kmt2a) are highly prevalent in pediatric oncology. the poor survival rate and lack of an effective targeted therapy for patients with mll-rearranged (mll-r) leukemias emphasize an urgent need for improved knowledge and novel therapeutic approaches for these malignancies. the resulting chimeric products of mll gene rearrangements, i.e., mll-fusion proteins (mll-fps), are capable of transforming hematopoietic stem/progenitor cells (hspcs) into leukemic blasts. the ability of mll-fps to reprogram hspcs toward leukemia requires the involvement of multiple chromatin effectors, including the histone 3 lysine 79 methyltransferase dot1l, the chromatin epigenetic reader brd4, and the super elongation complex. these epigenetic regulators constitute a complicated network that dictates maintenance of the leukemia program, and therefore represent an important cluster of therapeutic opportunities. in this review, we will discuss the role of mll and its fusion partners in normal hspcs and hematopoiesis, including the links between chromatin effectors, epigenetic landscapes, and leukemia development, and summarize current approaches to therapeutic targeting of mll-r leukemias.”
Yoshida, K., Maekawa, T., Ly, N. H., Fujita, S. ichiro, Muratani, M., Ando, M., … Ishii, S.. (2020). ATF7-Dependent Epigenetic Changes Are Required for the Intergenerational Effect of a Paternal Low-Protein Diet. Molecular Cell
Plain numerical DOI: 10.1016/j.molcel.2020.02.028
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“Paternal dietary conditions may contribute to metabolic disorders in offspring. we have analyzed the role of the stress-dependent epigenetic regulator cyclic amp-dependent transcription factor 7 (atf7) in paternal low-protein diet (plpd)-induced gene expression changes in mouse liver. atf7+/– mutations cause an offspring phenotype similar to that caused by plpd, and the effect of plpd almost vanished when paternal atf7+/– mice were used. atf7 binds to the promoter regions of ∼2,300 genes, including cholesterol biosynthesis-related and trna genes in testicular germ cells (tgcs). lpd induces atf7 phosphorylation by p38 via reactive oxygen species (ros) in tgcs. this leads to the release of atf7 and a decrease in histone h3k9 dimethylation (h3k9me2) on its target genes. these epigenetic changes are maintained and induce expression of some trna fragments in spermatozoa. these results indicate that lpd-induced and atf7-dependent epigenetic changes in tgcs play an important role in paternal diet-induced metabolic reprograming in offspring.”
Nicorescu, I., Dallinga, G. M., de Winther, M. P. J., Stroes, E. S. G., & Bahjat, M.. (2019). Potential epigenetic therapeutics for atherosclerosis treatment. Atherosclerosis
Plain numerical DOI: 10.1016/j.atherosclerosis.2018.10.006
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“Notwithstanding the intense efforts into the understanding and prevention of cardiovascular disease (cvd), its complex pathology remains the leading cause of mortality worldwide. the pivotal role of epigenetic changes in the control of gene expression has been profiled in several diseases, such as cancer and inflammatory disorders. in the last decade, increasing evidence has also linked aberrant epigenetic modulation as a contributor to cvd development. differential profiles of dna methylation, histone methylation and acetylation have consistently been observed in tissues and cells (comprising the aortic lesions, vascular endothelium and monocytes) from patients with cvd. this highlights the therapeutic potential of epigenetic drugs for cardiovascular treatment.”
Wang, T., Zhang, J., & Xu, Y.. (2020). Epigenetic basis of lead-induced neurological disorders. International Journal of Environmental Research and Public Health
Plain numerical DOI: 10.3390/ijerph17134878
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“Environmental lead (pb) exposure is closely associated with pathogenesis of a range of neurological disorders, including alzheimer’s disease (ad), parkinson’s disease (pd), amyotrophic lateral sclerosis (als), attention deficit/hyperactivity disorder (adhd), etc. epigenetic machinery modulates neural development and activities, while faulty epigenetic regulation contributes to the diverse forms of cns (central nervous system) abnormalities and diseases. as a potent epigenetic modifier, lead is thought to cause neurological disorders through modulating epigenetic mechanisms. specifically, increasing evidence linked aberrant dna methylations, histone modifications as well as ncrnas (non-coding rnas) with ad cases, among which circrna (circular rna) stands out as a new and promising field for association studies. in 23-year-old primates with developmental lead treatment, zawia group discovered a variety of epigenetic changes relating to ad pathogenesis. this is a direct evidence implicating epigenetic basis in lead-induced ad animals with an entire lifespan. additionally, some epigenetic molecules associated with ad etiology were also known to respond to chronic lead exposure in comparable disease models, indicating potentially interlaced mechanisms with respect to the studied neurotoxic and pathological events. of note, epigenetic molecules acted via globally or selectively influencing the expression of disease-related genes. compared to ad, the association of lead exposure with other neurological disorders were primarily supported by epidemiological survey, with fewer reports connecting epigenetic regulators with lead-induced pathogenesis. some pharmaceuticals, such as hdac (histone deacetylase) inhibitors and dna methylation inhibitors, were developed to deal with cns disease by targeting epigenetic components. still, understandings are insufficient regarding the cause–consequence relations of epigenetic factors and neurological illness. therefore, clear evidence should be provided in future investigations to address detailed roles of novel epigenetic factors in lead-induced neurological disorders, and efforts of developing specific epigenetic therapeutics should be appraised.”
Gáspár, B., Bossdorf, O., & Durka, W.. (2019). Structure, stability and ecological significance of natural epigenetic variation: a large-scale survey in Plantago lanceolata. New Phytologist
Plain numerical DOI: 10.1111/nph.15487
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“Within-species diversity is an important driver of ecological and evolutionary processes. recent research has found that plants can harbour significant epigenetic diversity, but its extent, stability and ecological significance in natural populations is largely unexplored. we analysed genetic, epigenetic and phenotypic variation in a large number of natural grassland populations of plantago lanceolata, covering a broad geographical and environmental range. within-population diversity and among-population differentiation were calculated from genetic and epigenetic marker data and from measurements of phenotypic traits, both for plants in the field and for the f 1 generation grown in a common environment. we found weak but significant epigenetic population structure. a large part of the epigenetic population differences observed in the field was maintained in a common environment. epigenetic differences were consistently related to genetic and environmental variation, and to a lesser degree to phenotypic variation and land use, with more grazed populations harbouring greater epigenetic diversity. our study demonstrates that epigenetic diversity exists in natural populations of a common grassland species, and that at least part of this epigenetic diversity is stable, nonrandom and related to environmental variation. experimental and more detailed molecular studies are needed to elucidate the mechanistic basis of these observed patterns.”
Vachharajani, V., & McCall, C. E.. (2019). Epigenetic and metabolic programming of innate immunity in sepsis. Innate Immunity
Plain numerical DOI: 10.1177/1753425919842320
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“Sepsis, the 10th leading cause of death, is the most expensive condition in the united states. the immune response in sepsis transitions from hyperinflammatory to a hypoinflammatory and immunosuppressive phase; individual variations regarding timing and overlap between hyper- and hypoinflammation exist in a number of patients. while one third of the sepsis-related deaths occur during hyperinflammation, majority of the sepsis-mortality occurs during the hypoinflammatory phase. currently, no phase-specific molecular-based therapies exist to treat sepsis. coordinated epigenetic and metabolic perturbations orchestrate this shift from hyper- to hypoinflammation in innate immune cells during sepsis. these epigenetic and metabolic changes during sepsis progression and therapeutic opportunities they pose are described in this review.”
Kundakovic, M., & Jaric, I.. (2017). The epigenetic link between prenatal adverse environments and neurodevelopmental disorders. Genes
Plain numerical DOI: 10.3390/genes8030104
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“Prenatal adverse environments, such as maternal stress, toxicological exposures, and viral infections, can disrupt normal brain development and contribute to neurodevelopmental disorders, including schizophrenia, depression, and autism. increasing evidence shows that these short- and long-term effects of prenatal exposures on brain structure and function are mediated by epigenetic mechanisms. animal studies demonstrate that prenatal exposure to stress, toxins, viral mimetics, and drugs induces lasting epigenetic changes in the brain, including genes encoding glucocorticoid receptor (nr3c1) and brain-derived neurotrophic factor (bdnf). these epigenetic changes have been linked to changes in brain gene expression, stress reactivity, and behavior, and often times, these effects are shown to be dependent on the gestational window of exposure, sex, and exposure level. although evidence from human studies is more limited, gestational exposure to environmental risks in humans is associated with epigenetic changes in peripheral tissues, and future studies are required to understand whether we can use peripheral biomarkers to predict neurobehavioral outcomes. an extensive research effort combining well-designed human and animal studies, with comprehensive epigenomic analyses of peripheral and brain tissues over time, will be necessary to improve our understanding of the epigenetic basis of neurodevelopmental disorders.”
Teschendorff, A. E., West, J., & Beck, S.. (2013). Age-associated epigenetic drift: Implications, and a case of epigenetic thrift?. Human Molecular Genetics
Plain numerical DOI: 10.1093/hmg/ddt375
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“It is now well established that the genomic landscape of dna methylation (dnam) gets altered as a function of age, a process we here call ‘epigenetic drift’. the biological, functional, clinical and evolutionary significance of this epigenetic drift, however, remains unclear.wehere provide a brief review of epigenetic drift, focusingonthe potential implications for ageing, stem cell biology and disease risk prediction. it has been demonstrated that epigenetic drift affectsmost of thegenome, suggesting a global deregulationofdnampatterns with age.acomponent of this drift is tissue-specific, allowing remarkably accurate age-predictive models to be constructed. another component is tissue-independent, targeting stem cell differentiation pathways and affecting stem cells, which may explain the observed decline of stem cell function with age. age-associated increases in dnam target developmental genes, overlapping those associated with environmental disease risk factors and with disease itself, notably cancer. in particular, cancers and precursor cancer lesions exhibit aggravated age dnam signatures. epigenetic drift is also influenced by genetic factors. thus, drift emerges as a promising biomarker for premature or biological ageing, and could potentially be used in geriatrics for disease risk prediction. finally, we propose, in the context of human evolution, that epigenetic driftmay represent a case of epigenetic thrift, or bet-hedging. in summary, this review demonstrates the growing importance of the ‘ageing epigenome’, with potentially far-reaching implications for understanding the effect of age on stem cell function and differentiation, as well as for disease prevention. © the author 2013. published by oxford university press.”
Dong, Z., & Cui, H.. (2019). Epigenetic modulation of metabolism in glioblastoma. Seminars in Cancer Biology
Plain numerical DOI: 10.1016/j.semcancer.2018.09.002
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“Epigenetic and metabolic alterations incancer cells are highly associated. glioblastoma multiforme (gbm) is a complicated pathological process with dysregulated methylation and histone modifications. metabolic modulation of epigenetics in gliomas was previously summarized. however, epigenetic modulation is also important in metabolic decision. recently, there has been a tremendous increase in understanding of dna methylation, chromatin modulation, and non-coding rnas in the regulation of cell metabolism, especially glycolytic metabolism in gbm. in this review, we summarize dna methylation, histone alteration, and non-coding rna mediated epigenetic modulation of metabolism in gbm and discuss the future research directions in this area and its applications in gbm treatment.”
Choi, J. Y., & Lee, Y. C. G.. (2020). Double-edged sword: The evolutionary consequences of the epigenetic silencing of transposable elements. PLoS Genetics
Plain numerical DOI: 10.1371/journal.pgen.1008872
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“Transposable elements (tes) are genomic parasites that selfishly replicate at the expense of host fitness. fifty years of evolutionary studies of tes have concentrated on the deleterious genetic effects of tes, such as their effects on disrupting genes and regulatory sequences. however, a flurry of recent work suggests that there is another important source of tes’ harmful effects epigenetic silencing. host genomes typically silence tes by the deposition of repressive epigenetic marks. while this silencing reduces the selfish replication of tes and should benefit hosts, a picture is emerging that the epigenetic silencing of tes triggers inadvertent spreading of repressive marks to otherwise expressed neighboring genes, ultimately jeopardizing host fitness. in this review, we provide a long-overdue overview of the recent genome-wide evidence for the presence and prevalence of tes’ epigenetic effects, highlighting both the similarities and differences across mammals, insects, and plants. we lay out the current understanding of the functional and fitness consequences of tes’ epigenetic effects, and propose possible influences of such effects on the evolution of both hosts and tes themselves. these unique evolutionary consequences indicate that tes’ epigenetic effect is not only a crucial component of te biology but could also be a significant contributor to genome function and evolution.”
Aldiri, I., Xu, B., Wang, L., Chen, X., Hiler, D., Griffiths, L., … Dyer, M. A.. (2017). The Dynamic Epigenetic Landscape of the Retina During Development, Reprogramming, and Tumorigenesis. Neuron
Plain numerical DOI: 10.1016/j.neuron.2017.04.022
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“In the developing retina, multipotent neural progenitors undergo unidirectional differentiation in a precise spatiotemporal order. here we profile the epigenetic and transcriptional changes that occur during retinogenesis in mice and humans. although some progenitor genes and cell cycle genes were epigenetically silenced during retinogenesis, the most dramatic change was derepression of cell-type-specific differentiation programs. we identified developmental-stage-specific super-enhancers and showed that most epigenetic changes are conserved in humans and mice. to determine how the epigenome changes during tumorigenesis and reprogramming, we performed integrated epigenetic analysis of murine and human retinoblastomas and induced pluripotent stem cells (ipscs) derived from murine rod photoreceptors. the retinoblastoma epigenome mapped to the developmental stage when retinal progenitors switch from neurogenic to terminal patterns of cell division. the epigenome of retinoblastomas was more similar to that of the normal retina than that of retina-derived ipscs, and we identified retina-specific epigenetic memory.”
Wahane, S., Halawani, D., Zhou, X., & Zou, H.. (2019). Epigenetic regulation of axon regeneration and glial activation in injury responses. Frontiers in Genetics
Plain numerical DOI: 10.3389/fgene.2019.00640
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“Injury to the nervous system triggers a multicellular response in which epigenetic mechanisms play an important role in regulating cell type-specific transcriptional changes. here, we summarize recent progress in characterizing neuronal intrinsic and extrinsic chromatin reconfigurations and epigenetic changes triggered by axonal injury that shape neuroplasticity and glial functions. we specifically discuss regeneration-associated transcriptional modules comprised of transcription factors and epigenetic regulators that control axon growth competence. we also review epigenetic regulation of neuroinflammation and astroglial responses that impact neural repair. these advances provide a framework for developing epigenetic strategies to maximize adaptive alterations while minimizing maladaptive stress responses in order to enhance axon regeneration and achieve functional recovery after injury.”
Ideta-Otsuka, M., Igarashi, K., Narita, M., & Hirabayashi, Y.. (2017). Epigenetic toxicity of environmental chemicals upon exposure during development – Bisphenol A and valproic acid may have epigenetic effects. Food and Chemical Toxicology
Plain numerical DOI: 10.1016/j.fct.2017.09.014
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“As of 2017, chemical substances registered in chemical abstracts service (cas) exceed 100 million, which is increasing yearly. the safety of chemical substances is adequately managed by regulations based on scientific information from toxicity tests. however, there are substances reported to have ‘biological effects’ even though they are judged to be nontoxic in conventional toxicity tests. therefore, it is necessary to consider a new concept on toxicity, ‘epigenetic toxicity’. in this review, we explain about epigenetic toxicity using bisphenol a (bpa) and valproic acid (vpa) as examples. we also discuss the problems associated with the judgment of epigenetic toxicity. currently, epigenetic changes can only be detected by biochemical methods, which are labor-intensive. therefore, we are developing reporter mice that can be used to detect epigenetic toxicity during conventional toxicity tests. in addition, we consider that linking epigenomic changes with phenotypic changes is important, because causality is important for toxicity evaluation. therefore, we are developing an artificial epigenome-editing technology. if we can develop a safety-assessment system by incorporating epigenetic evaluation into toxicity tests, we can increase the safety of both food and environmental chemical substances. the practical application of such a new safety-assessment system will be increasingly important in the future.”
Perna, L., Zhang, Y., Mons, U., Holleczek, B., Saum, K. U., & Brenner, H.. (2016). Epigenetic age acceleration predicts cancer, cardiovascular, and all-cause mortality in a German case cohort. Clinical Epigenetics
Plain numerical DOI: 10.1186/s13148-016-0228-z
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“Background: previous studies have developed models predicting methylation age from dna methylation in blood and other tissues (epigenetic clock) and suggested the difference between dna methylation and chronological ages as a marker of healthy aging. the goal of this study was to confirm and expand such observations by investigating whether different concepts of the epigenetic clocks in a population-based cohort are associated with cancer, cardiovascular, and all-cause mortality. results: dna methylation age was estimated in a cohort of 1863 older people, and the difference between age predicted by dna methylation and chronological age (δage) was calculated. a case-cohort design and weighted proportional cox hazard models were used to estimate associations of δage with cancer, cardiovascular, and all-cause mortality. hazard ratios for δage (per 5 years) calculated using the epigenetic clock developed by horvath were 1.23 (95 % ci 1.10–1.38) for all-cause mortality, 1.22 (95 % ci 1.03–1.45) for cancer mortality, and 1.19 (95 % ci 0.98–1.43) for cardiovascular mortality after adjustment for batch effects, age, sex, educational level, history of chronic diseases, hypertension, smoking status, body mass index, and leucocyte distribution. associations were similar but weaker for δage calculated using the epigenetic clock developed by hannum. conclusions: these results show that age acceleration in terms of the difference between age predicted by dna methylation and chronological age is an independent predictor of all-cause and cause-specific mortality and may be useful as a general marker of healthy aging.”
Bartlett, A. A., Lapp, H. E., & Hunter, R. G.. (2019). Epigenetic Mechanisms of the Glucocorticoid Receptor. Trends in Endocrinology and Metabolism
Plain numerical DOI: 10.1016/j.tem.2019.07.003
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“The glucocorticoid receptor (gr) has been shown to be important for mediating cellular responses to stress and circulating glucocorticoids. ligand-dependent transcriptional changes induced by gr are observed across numerous tissues. however, the mechanisms by which gr achieves cell and tissue-specific effects are less clear. epigenetic mechanisms have been proposed to explain some of these differences as well as some of the lasting, even transgenerational, effects of stress and glucocorticoid action. gr functions in tandem with epigenetic cellular machinery to coordinate transcription and shape chromatin structure. here, we describe gr interactions with these effectors and how gr acts to reshape the epigenetic landscape in response to the environment.”
Xue, B., Zhao, J., Feng, P., Xing, J., Wu, H., & Li, Y.. (2019). Epigenetic mechanism and target therapy of uhrf1 protein complex in malignancies. OncoTargets and Therapy
Plain numerical DOI: 10.2147/OTT.S192234
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“Ubiquitin-like with plant homeodomain and really interesting new gene finger domains 1 (uhrf1) functions as an epigenetic regulator recruiting pcna, dnmt1, histone deacetylase 1, g9a, suv39h, herpes virus-associated ubiquitin-specific protease, and tat-interactive protein by multiple corresponding domains of dna and h3 to maintain dna methylation and histone modifications. overexpression of uhrf1 has been found as a potential biomarker in various cancers resulting in either dna hypermethylation or global dna hypomethylation, which participates in the occurrence, progression, and invasion of cancer. the role of uhrf1 in the reciprocal interaction between dna methylation and histone modifications, the dynamic structural transformation of uhrf1 protein within epigenetic code replication machinery in epigenetic regulations, as well as modifications during cell cycle and chemotherapy targeting uhrf1 are evaluated in this study.”
Wang, R., & Liu, X.. (2020). Epigenetic regulation of prostate cancer. Genes and Diseases
Plain numerical DOI: 10.1016/j.gendis.2019.10.018
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“Prostate cancer is (pca) the second leading cause of cancer death in males in the united state, with 174,650 new cases and 31,620 deaths estimated in 2019. it has been documented that epigenetic deregulation such as histone modification and dna methylation contributes to pca initiation and progression. ezh2 (enhancer of zeste homolog 2), the catalytic subunit of the polycomb repressive complex (prc2) responsible for h3k27me3 and gene repression, has been identified as a promising target in pca. in addition, overexpression of other epigenetic regulators such as dna methyltransferases (dnmt) is also observed in pca. these epigenetic regulators undergo extensive post-translational modifications, in particular, phosphorylation. akt, cdks, plk1, pka, atr and dna-pk are the established kinases responsible for phosphorylation of various epigenetic regulators.”
Afrin, F., Khan, I., & Hemeg, H. A.. (2019). Leishmania-host interactions-an epigenetic paradigm. Frontiers in Immunology
Plain numerical DOI: 10.3389/fimmu.2019.00492
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“Leishmaniasis is one of the major neglected tropical diseases, for which no vaccines exist. chemotherapy is hampered by limited efficacy coupled with development of resistance and other side effects. leishmania parasites elude the host defensive mechanisms by modulating their surface proteins as well as dampening the host’s immune responses. the parasites use the conventional rna polymerases peculiarly under different environmental cues or pressures such as the host’s milieu or the drugs. the mechanisms that restructure post-translational modifications are poorly understood but altered epigenetic histone modifications are believed to be instrumental in influencing the chromatin remodeling in the parasite. interestingly, the parasite also modulates gene expression of the hosts, thereby hijacking or dampening the host immune response. epigenetic factor such as dna methylation of cytosine residues has been incriminated in silencing of macrophage-specific genes responsible for defense against these parasites. although there is dearth of information regarding the epigenetic alterations-mediated pathogenesis in these parasites and the host, the unique epigenetic marks may represent targets for potential anti-leishmanial drug candidates. this review circumscribes the epigenetic changes during leishmania infection, and the epigenetic modifications they enforce upon the host cells to ensure a safe haven. the non-coding micro rnas as post-transcriptional regulators and correlates of wound healing and toll-like receptor signaling, as well as prognostic biomarkers of therapeutic failure and healing time are also explored. finally, we highlight the recent advances on how the epigenetic perturbations may impact leishmaniasis vaccine development as biomarkers of safety and immunogenicity.”
Moreira-silva, F., Camilo, V., Gaspar, V., Mano, J. F., Henrique, R., & Jerónimo, C.. (2020). Repurposing old drugs into new epigenetic inhibitors: Promising candidates for cancer treatment?. Pharmaceutics
Plain numerical DOI: 10.3390/pharmaceutics12050410
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“Epigenetic alterations, as a cancer hallmark, are associated with cancer initiation, progression and aggressiveness. considering, however, that these alterations are reversible, drugs that target epigenetic machinery may have an inhibitory effect upon cancer treatment. the traditional drug discovery pathway is time-consuming and expensive, and thus, new and more effective strategies are required. drug repurposing (dr) comprises the discovery of a new medical indication for a drug that is approved for another indication, which has been recalled, that was not accepted or failed to prove efficacy. dr presents several advantages, mainly reduced resources, absence of the initial target discovery process and the reduced time necessary for the drug to be commercially available. there are numerous old drugs that are under study as repurposed epigenetic inhibitors which have demonstrated promising results in in vitro tumor models. herein, we summarize the dr process and explore several repurposed drugs with different epigenetic targets that constitute promising candidates for cancer treatment, highlighting their mechanisms of action.”
Kordowitzki, P., Haghani, A., Zoller, J. A., Li, C. Z., Raj, K., Spangler, M. L., & Horvath, S.. (2021). Epigenetic clock and methylation study of oocytes from a bovine model of reproductive aging. Aging Cell
Plain numerical DOI: 10.1111/acel.13349
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“Cattle are an attractive animal model of fertility in women due to their high degree of similarity relative to follicle selection, embryo cleavage, blastocyst formation, and gestation length. to facilitate future studies of the epigenetic underpinnings of aging effects in the female reproductive axis, several dna methylation-based biomarkers of aging (epigenetic clocks) for bovine oocytes are presented. one such clock was germane to only oocytes, while a dual-tissue clock was highly predictive of age in both oocytes and blood. dual species clocks that apply to both humans and cattle were also developed and evaluated. these epigenetic clocks can be used to accurately estimate the biological age of oocytes. both epigenetic clock studies and epigenome-wide association studies revealed that blood and oocytes differ substantially with respect to aging and the underlying epigenetic signatures that potentially influence the aging process. the rate of epigenetic aging was found to be slower in oocytes compared to blood; however, oocytes appeared to begin at an older epigenetic age. the epigenetic clocks for oocytes are expected to address questions in the field of reproductive aging, including the central question: how to slow aging of oocytes.”
Wen, Y., Mirji, N., & Irudayaraj, J.. (2020). Epigenetic toxicity of PFOA and GenX in HepG2 cells and their role in lipid metabolism. Toxicology in Vitro
Plain numerical DOI: 10.1016/j.tiv.2020.104797
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“Perfluorooctanoic acid (pfoa), an extremely persistent perfluoroalkyl substance (pfas), and 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy) propanoic acid (genx), its shorter chain alternative, have been implicated in hepatocellular damage with unusual fat deposit and liver enlargement. in this study we explored the underlying mechanisms of pfoa and genx induced hepatocellular damage. liver hepatocellular carcinoma cell line hepg2 was used as a model to study induced liver inflammation in vitro at the cellular, genetic, and epigenetic levels. hepg2 cells were exposed to pfoa or genx for 48 h and the dna and rna were extracted and analyzed. mrna expression analysis of pfoa exposed cells showed that cell cycle homeostasis genes were affected significantly, as well as the ten-eleven translocation methylcytosine dioxygenases (tets) and the essential lipid metabolism genes. genx did not have as significant an effect. global methylation levels of hepg2 cells were found to be inversely proportional to pfoa exposure levels. with genx, the global methylation level decreased and then increased. our work points to the fact that pfoa may contribute to higher overall epigenetic toxicity than genx, and its induced epigenetic changes may play a major role in lipid metabolism gene regulation and fat deposits.”
Schmid, M. W., Heichinger, C., Coman Schmid, D., Guthörl, D., Gagliardini, V., Bruggmann, R., … Grossniklaus, U.. (2018). Contribution of epigenetic variation to adaptation in Arabidopsis. Nature Communications
Plain numerical DOI: 10.1038/s41467-018-06932-5
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“In plants, transgenerational inheritance of some epialleles has been demonstrated but it remains controversial whether epigenetic variation is subject to selection and contributes to adaptation. simulating selection in a rapidly changing environment, we compare phenotypic traits and epigenetic variation between arabidopsis thaliana populations grown for five generations under selection and their genetically nearly identical ancestors. selected populations of two distinct genotypes show significant differences in flowering time and plant architecture, which are maintained for at least 2–3 generations in the absence of selection. while we cannot detect consistent genetic changes, we observe a reduction of epigenetic diversity and changes in the methylation state of about 50,000 cytosines, some of which are associated with phenotypic changes. thus, we propose that epigenetic variation is subject to selection and can contribute to rapid adaptive responses, although the extent to which epigenetics plays a role in adaptation is still unclear.”
Lee, K., & Seo, P. J.. (2018). Dynamic Epigenetic Changes during Plant Regeneration. Trends in Plant Science
Plain numerical DOI: 10.1016/j.tplants.2017.11.009
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“Plants have the remarkable ability to drive cellular dedifferentiation and regeneration. changes in epigenetic landscapes accompany the cell fate transition. notably, modifications of chromatin structure occur primarily during callus formation via an in vitro tissue culture process and, thus, pluripotent callus cells have unique epigenetic signatures. here, we highlight the latest progress in epigenetic regulation of callus formation in plants, which addresses fundamental questions related to cell fate changes and pluripotency establishment. global and local modifications of chromatin structure underlie callus formation, and the combination and sequence of epigenetic modifications further shape intricate cell fate changes. this review illustrates how a series of chromatin marks change dynamically during callus formation and their biological relevance in plant regeneration.”
Lazaris, C., Aifantis, I., & Tsirigos, A.. (2020). On Epigenetic Plasticity and Genome Topology. Trends in Cancer
Plain numerical DOI: 10.1016/j.trecan.2020.01.006
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“Mounting evidence links genetic lesions with genome topology alterations and aberrant gene activation. however, the role of epigenetic plasticity remains elusive. emerging studies implicate dna methylation, transcriptional elongation, long noncoding rnas (lncrnas), and ccctc-binding factor (ctcf)–rna interactions, but systematic approaches are needed to fully decipher the role of epigenetic plasticity in genome integrity and function.”
Mannavola, F., D’oronzo, S., Cives, M., Stucci, L. S., Ranieri, G., Silvestris, F., & Tucci, M.. (2020). Extracellular vesicles and epigenetic modifications are hallmarks of melanoma progression. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms21010052
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“Cutaneous melanoma shows a high metastatic potential based on its ability to overcome the immune system’s control. the mechanisms activated for these functions vary extremely and are also represented by the production of a number of extracellular vesicles including exosomes. other vesicles showing a potential role in the melanoma progression include oncosomes and melanosomes and the majority of them mediate tumor processes including angiogenesis, immune regulation, and modifications of the micro-environment. moreover, a number of epigenetic modifications have been described in melanoma and abundant production of altered micrornas (mi-rnas), non-coding rnas, histones, and abnormal dna methylation have been associated with different phases of melanoma progression. in addition, exosomes, mirnas, and other molecular factors have been used as potential biomarkers reflecting disease evolution while others have been suggested to be potential druggable molecules for therapeutic application.”
Kong, L., Liu, Y., Wang, X., & Chang, C.. (2020). Insight into the role of epigenetic processes in abiotic and biotic stress response in wheat and barley. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms21041480
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“Environmental stresses such as salinity, drought, heat, freezing, heavy metal and even pathogen infections seriously threaten the growth and yield of important cereal crops including wheat and barley. there is growing evidence indicating that plants employ sophisticated epigenetic mechanisms to fine‐tune their responses to environmental stresses. here, we provide an overview of recent developments in understanding the epigenetic processes and elements—such as dna methylation, histone modification, chromatin remodeling, and non‐coding rnas—involved in plant responses to abiotic and biotic stresses in wheat and barley. potentials of exploiting epigenetic variation for the improvement of wheat and barley are discussed.”
Reik, W., Dean, W., & Walter, J.. (2001). Epigenetic reprogramming in mammalian development. Science
Plain numerical DOI: 10.1126/science.1063443
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“DNA methylation is a major epigenetic modification of the genome that regulates crucial aspects of its function. genomic methylation patterns in somatic differentiated cells are generally stable and heritable. however, in mammals there are at least two developmental periods – in germ cells and in preimplantation embryos – in which methylation patterns are reprogrammed genome wide, generating cells with a broad developmental potential epigenetic reprogramming in germ cells is critical for imprinting; reprogramming in early embryos also affects imprinting. reprogramming is likely to have a crucial role in establishing nuclear totipotency in normal development and in cloned animals, and in the erasure of acquired epigenetic information. a role of reprogramming in stem cell differentiation is also envisaged.”
Elliott, H. R., Sharp, G. C., Relton, C. L., & Lawlor, D. A.. (2019). Epigenetics and gestational diabetes: a review of epigenetic epidemiology studies and their use to explore epigenetic mediation and improve prediction. Diabetologia
Plain numerical DOI: 10.1007/s00125-019-05011-8
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“Epigenetics encapsulates a group of molecular mechanisms including dna methylation, histone modification and micrornas (mirnas). gestational diabetes (gdm) increases the risk of adverse perinatal outcomes and is associated with future offspring risk of obesity and type 2 diabetes. it has been hypothesised that epigenetic mechanisms mediate an effect of gdm on offspring adiposity and type 2 diabetes and this could provide a modifiable mechanism to reduce type 2 diabetes in the next generation. evidence for this hypothesis is lacking. epigenetic epidemiology could also contribute to reducing type 2 diabetes by identifying biomarkers that accurately predict risk of gdm and its associated future adverse outcomes. we reviewed published human studies that explored associations between any of maternal gdm, type 2 diabetes, gestational fasting or post-load glucose and any epigenetic marker (dna methylation, histone modification or mirna). of the 81 relevant studies we identified, most focused on the potential role of epigenetic mechanisms in mediating intrauterine effects of gdm on offspring outcomes. studies were small (median total number of participants 58; median number of gdm cases 27) and most did not attempt replication. the most common epigenetic measure analysed was dna methylation. most studies that aimed to explore epigenetic mediation examined associations of in utero exposure to gdm with offspring cord or infant blood/placenta dna methylation. exploration of any causal effect, or effect on downstream offspring outcomes, was lacking. there is a need for more robust methods to explore the role of epigenetic mechanisms as possible mediators of effects of exposure to gdm on future risk of obesity and type 2 diabetes. research to identify epigenetic biomarkers to improve identification of women at risk of gdm and its associated adverse (maternal and offspring) outcomes is currently rare but could contribute to future tools for accurate risk stratification.”
Patrizi, B., & de Cumis, M. S.. (2018). TCDD toxicity mediated by epigenetic mechanisms. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms19124101
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“Dioxins are highly toxic and persistent halogenated organic pollutants belonging to two families i.e., polychlorinated dibenzo-p-dioxins (pcdds) and polychlorinated dibenzo furans (pcdfs). they can cause cancer, reproductive and developmental issues, damage to the immune system, and can deeply interfere with the endocrine system. dioxins toxicity is mediated by the aryl-hydrocarbon receptor (ahr) which mediates the cellular metabolic adaptation to these planar aromatic xenobiotics through the classical transcriptional regulation pathway, including ahr binding of ligand in the cytosol, translocation of the receptor to the nucleus, dimerization with the ahr nuclear translocator, and the binding of this heterodimeric transcription factor to dioxin-responsive elements which regulate the expression of genes involved in xenobiotic metabolism. 2,3,7,8-tcdd is the most toxic among dioxins showing the highest affinity toward the ahr receptor. beside this classical and well-studied pathway, a number of papers are dealing with the role of epigenetic mechanisms in the response to environmental xenobiotics. in this review, we report on the potential role of epigenetic mechanisms in dioxins-induced cellular response by inspecting recent literature and focusing our attention on epigenetic mechanisms induced by the most toxic 2,3,7,8-tcdd.”
Hogg, S. J., Beavis, P. A., Dawson, M. A., & Johnstone, R. W.. (2020). Targeting the epigenetic regulation of antitumour immunity. Nature Reviews Drug Discovery
Plain numerical DOI: 10.1038/s41573-020-0077-5
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“Dysregulation of the epigenome drives aberrant transcriptional programmes that promote cancer onset and progression. although defective gene regulation often affects oncogenic and tumour-suppressor networks, tumour immunogenicity and immune cells involved in antitumour responses may also be affected by epigenomic alterations. this could have important implications for the development and application of both epigenetic therapies and cancer immunotherapies, and combinations thereof. here, we review the role of key aberrant epigenetic processes — dna methylation and post-translational modification of histones — in tumour immunogenicity, as well as the effects of epigenetic modulation on antitumour immune cell function. we emphasize opportunities for small-molecule inhibitors of epigenetic regulators to enhance antitumour immune responses, and discuss the challenges of exploiting the complex interplay between cancer epigenetics and cancer immunology to develop treatment regimens combining epigenetic therapies with immunotherapies.”
Delcuve, G. P., Rastegar, M., & Davie, J. R.. (2009). Epigenetic control. Journal of Cellular Physiology
Plain numerical DOI: 10.1002/jcp.21678
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“Epigenetics refers to mitotically and/or meiotically heritable variations in gene expression that are not caused by changes in dna sequence. epigenetic mechanisms regulate all biological processes from conception to death, including genome reprogramming during early embryogenesis and gametogenesis, cell differentiation and maintenance of a committed lineage. key epigenetic players are dna methylation and histone post-translational modifications, which interplay with each other, with regulatory proteins and with non-coding rnas, to remodel chromatin into domains such as euchromatin, constitutive or facultative heterochromatin and to achieve nuclear compartmentalization. besides epigenetic mechanisms such as imprinting, chromosome x inactivation or mitotic bookmarking which establish heritable states, other rapid and transient mechanisms, such as histone h3 phosphorylation, allow cells to respond and adapt to environmental stimuli. however, these epigenetic marks can also have long-term effects, for example in learning and memory formation or in cancer. erroneous epigenetic marks are responsible for a whole gamut of diseases including diseases evident at birth or infancy or diseases becoming symptomatic later in life. moreover, although epigenetic marks are deposited early in development, adaptations occurring through life can lead to diseases and cancer. with epigenetic marks being reversible, research has started to focus on epigenetic therapy which has had encouraging success. as we witness an explosion of knowledge in the field of epigenetics, we are forced to revisit our dogma. for example, recent studies challenge the idea that dna methylation is irreversible. further, research on rett syndrome has revealed an unforeseen role for methyl-cpg-binding protein 2 (mecp2) in neurons. © 2009 wiley-liss, inc.”
Sansam, C. G., Pietrzak, K., Majchrzycka, B., Kerlin, M. A., Chen, J., Rankin, S., & Sansam, C. L.. (2018). A mechanism for epigenetic control of DNA replication. Genes and Development
Plain numerical DOI: 10.1101/gad.306464.117
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“DNA replication origins in hyperacetylated euchromatin fire preferentially during early s phase. however, how acetylation controls dna replication timing is unknown. ticrr/treslin is an essential protein required for the initiation of dna replication. here, we report that ticrr physically interacts with the acetyl-histone binding bromodomain (brd) and extraterminal (bet) proteins brd2 and brd4. abrogation of this interaction impairs ticrr binding to acetylated chromatin and disrupts normal s-phase progression. our data reveal a novel function for bet proteins and establish the ticrr–bet interaction as a potential mechanism for epigenetic control of dna replication.”
Ning, B., Li, W., Zhao, W., & Wang, R.. (2015). Targeting epigenetic regulations in cancer. Acta Biochimica et Biophysica Sinica
Plain numerical DOI: 10.1093/abbs/gmv116
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“Epigenetic regulation of gene expression is a dynamic and reversible process with dna methylation, histone modifications, and chromatin remodeling. recently, groundbreaking studies have demonstrated the importance of dna and chromatin regulatory proteins from different aspects, including stem cell, development, and tumor genesis. abnormal epigenetic regulation is frequently associated with diseases and drugs targeting dna methylation and histone acetylation have been approved for cancer therapy. although the network of epigenetic regulation is more complex than people expect, new potential druggable chromatin-associated proteins are being discovered and tested for clinical application. here we review the key proteins that mediate epigenetic regulations through dna methylation, the acetylation and methylation of histones, and the reader proteins that bind to modified histones. we also discuss cancer associations and recent progress of pharmacological development of these proteins.”
Dieckmann, L., Lahti-Pulkkinen, M., Kvist, T., Lahti, J., DeWitt, P. E., Cruceanu, C., … Czamara, D.. (2021). Characteristics of epigenetic aging across gestational and perinatal tissues. Clinical Epigenetics
Plain numerical DOI: 10.1186/s13148-021-01080-y
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“Background: epigenetic clocks have been used to indicate differences in biological states between individuals of same chronological age. however, so far, only few studies have examined epigenetic aging in newborns—especially regarding different gestational or perinatal tissues. in this study, we investigated which birth- and pregnancy-related variables are most important in predicting gestational epigenetic age acceleration or deceleration (i.e., the deviation between gestational epigenetic age estimated from the dna methylome and chronological gestational age) in chorionic villus, placenta and cord blood tissues from two independent study cohorts (itu, n = 639 and predo, n = 966). we further characterized the correspondence of epigenetic age deviations between these tissues. results: among the most predictive factors of epigenetic age deviations in single tissues were child sex, birth length, maternal smoking during pregnancy, maternal mental disorders until childbirth, delivery mode and parity. however, the specific factors related to epigenetic age deviation and the direction of association differed across tissues. in individuals with samples available from more than one tissue, relative epigenetic age deviations were not correlated across tissues. conclusion: gestational epigenetic age acceleration or deceleration was not related to more favorable or unfavorable factors in one direction in the investigated tissues, and the relative epigenetic age differed between tissues of the same person. this indicates that epigenetic age deviations associate with distinct, tissue specific, factors during the gestational and perinatal period. our findings suggest that the epigenetic age of the newborn should be seen as a characteristic of a specific tissue, and less as a general characteristic of the child itself.”
Sharma, S., & Bhonde, R.. (2020). Genetic and epigenetic stability of stem cells: Epigenetic modifiers modulate the fate of mesenchymal stem cells. Genomics
Plain numerical DOI: 10.1016/j.ygeno.2020.04.022
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“Stem cell research has progressed widely and has been receiving a considerable attention for its advantages and drawbacks. despite their extensive therapeutic potential in regenerative medicine, they are debatable for their genetic and epigenetic stability. in fact lineage specific differentiation is mediated via epigenetic changes in dna methylation, acetylation, histone modifications etc. thus epigenetics plays an important role in stem cell biology. for therapeutic interventions stem cells need to be genetically and epigenetically stable for their maximum paracrine secretions for bringing about expected tissue repair and regeneration. in this review we have focused on the current status of genetic and epigenetic stability in stem cells and their importance in regenerative medicine. we have also touched upon the possibility of considering tissue resident mesenchymal stem cells as epigenetic modifiers. this is likely to open a new era in stem cell therapeutic intervention by reversing disease inducing epigenetic changes.”
Hou, Y. C., Lu, C. L., Yuan, T. H., Liao, M. T., Chao, C. Ter, & Lu, K. C.. (2020). The epigenetic landscape of vascular calcification: An integrative perspective. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms21030980
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“Vascular calcification (vc) is an important complication among patients of advanced age, those with chronic kidney disease, and those with diabetes mellitus. the pathophysiology of vc encompasses passive occurrence of physico-chemical calcium deposition, active cellular secretion of osteoid matrix upon exposure to metabolically noxious stimuli, or a variable combination of both processes. epigenetic alterations have been shown to participate in this complex environment, through mechanisms including dna methylation, non-coding rnas, histone modifications, and chromatin changes. despite such importance, existing reviews fail to provide a comprehensive view of all relevant reports addressing epigenetic processes in vc, and cross-talk between different epigenetic machineries is rarely examined. we conducted a systematic review based on pubmed and medline databases up to 30 september 2019, to identify clinical, translational, and experimental reports addressing epigenetic processes in vc; we retrieved 66 original studies, among which 60.6% looked into the pathogenic role of non-coding rna, followed by dna methylation (12.1%), histone modification (9.1%), and chromatin changes (4.5%). nine (13.6%) reports examined the discrepancy of epigenetic signatures between subjects or tissues with and without vc, supporting their applicability as biomarkers. assisted by bioinformatic analyses blending in each epigenetic component, we discovered prominent interactions between micrornas, dna methylation, and histone modification regarding potential influences on vc risk.”
Larionova, I., Kazakova, E., Patysheva, M., & Kzhyshkowska, J.. (2020). Transcriptional, epigenetic and metabolic programming of tumor-associated macrophages. Cancers
Plain numerical DOI: 10.3390/cancers12061411
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“Macrophages are key innate immune cells in the tumor microenvironment (tme) that regulate primary tumor growth, vascularization, metastatic spread and tumor response to various types of therapies. the present review highlights the mechanisms of macrophage programming in tumor microenvironments that act on the transcriptional, epigenetic and metabolic levels. we summarize the latest knowledge on the types of transcriptional factors and epigenetic enzymes that control the direction of macrophage functional polarization and their pro-and anti-tumor activities. we also focus on the major types of metabolic programs of macrophages (glycolysis and fatty acid oxidation), and their interaction with cancer cells and complex tme. we have discussed how the regulation of macrophage polarization on the transcriptional, epigenetic and metabolic levels can be used for the efficient therapeutic manipulation of macrophage functions in cancer.”
Li, K., Liu, Y., Cao, H., Zhang, Y., Gu, Z., Liu, X., … Xu, J.. (2020). Interrogation of enhancer function by enhancer-targeting CRISPR epigenetic editing. Nature Communications
Plain numerical DOI: 10.1038/s41467-020-14362-5
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“Tissue-specific gene expression requires coordinated control of gene-proximal and -distal cis-regulatory elements (cres), yet functional analysis of gene-distal cres such as enhancers remains challenging. here we describe crispr/dcas9-based enhancer-targeting epigenetic editing systems, encrispra and encrispri, for efficient analysis of enhancer function in situ and in vivo. using dual effectors capable of re-writing enhancer-associated chromatin modifications, we show that encrispra and encrispri modulate gene transcription by remodeling local epigenetic landscapes at sgrna-targeted enhancers and associated genes. comparing with existing methods, the improved systems display more robust perturbations of enhancer activity and gene transcription with minimal off-targets. allele-specific targeting of encrispra to oncogenic tal1 super-enhancer modulates tal1 expression and cancer progression in xenotransplants. single or multi-loci perturbations of lineage-specific enhancers using an encrispri knock-in mouse establish in vivo evidence for lineage-restricted essentiality of developmental enhancers during hematopoiesis. hence, enhancer-targeting crispr epigenetic editing provides opportunities for interrogating enhancer function in native biological contexts.”
Villanueva, L., Álvarez-Errico, D., & Esteller, M.. (2020). The Contribution of Epigenetics to Cancer Immunotherapy. Trends in Immunology
Plain numerical DOI: 10.1016/j.it.2020.06.002
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“Effective anticancer immunotherapy treatments constitute a qualitative leap in cancer management. nonetheless, not all patients benefit from such therapies because they fail to achieve complete responses, suffer frequent relapses, or develop potentially life-threatening toxicities. epigenomic signatures in immune and cancer cells appear to be accurate and promising predictors of patient outcomes with immunotherapy. in addition, combined treatments with epigenetic drugs can exploit the dynamic nature of epigenetic changes to potentially modulate responses to immunotherapy. candidate epigenetic biomarkers may provide a rationale for patient stratification and precision medicine, thus maximizing the chances of treatment success while minimizing unwanted effects. we present a comprehensive up-to-date view of potential epigenetic biomarkers in immunotherapy and discuss their advantages over other indicators.”
Müller, M. R., Skowron, M. A., Albers, P., & Nettersheim, D.. (2021). Molecular and epigenetic pathogenesis of germ cell tumors. Asian Journal of Urology
Plain numerical DOI: 10.1016/j.ajur.2020.05.009
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“The development of germ cell tumors (gcts) is a unique pathogenesis occurring at an early developmental stage during specification, migration or colonization of primordial germ cells (pgcs) in the genital ridge. since driver mutations could not be identified so far, the involvement of the epigenetic machinery during the pathogenesis seems to play a crucial role. currently, it is investigated whether epigenetic modifications occurring between the omnipotent two-cell stage and the pluripotent implanting pgcs might result in disturbances eventually leading to gcts. although progress in understanding epigenetic mechanisms during pgc development is ongoing, little is known about the complete picture of its involvement during gct development and eventual classification into clinical subtypes. this review will shed light into the current knowledge of the complex epigenetic and molecular contribution during pathogenesis of gcts by emphasizing on early developmental stages until arrival of late pgcs in the gonads. we questioned how misguided migrating and/or colonizing pgcs develop to either type i or type ii gcts. additionally, we asked how pluripotency can be regulated during pgc development and which epigenetic changes contribute to gct pathogenesis. we propose that sox2 and sox17 determine either embryonic stem cell-like (embryonal carcinoma) or pgc-like cell fate (seminoma). finally, we suggest that factors secreted by the microenvironment, i.e. bmps and bmp inhibiting molecules, dictate the fate decision of germ cell neoplasia in situ (into seminoma and embryonal carcinoma) and seminomas (into embryonal carcinoma or extraembryonic lineage), indicating an important role of the microenvironment on gct plasticity.”
Skinner, M. K., Ben Maamar, M., Sadler-Riggleman, I., Beck, D., Nilsson, E., McBirney, M., … Yan, W.. (2018). Alterations in sperm DNA methylation, non-coding RNA and histone retention associate with DDT-induced epigenetic transgenerational inheritance of disease. Epigenetics and Chromatin
Plain numerical DOI: 10.1186/s13072-018-0178-0
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“Background: environmental toxicants such as ddt have been shown to induce the epigenetic transgenerational inheritance of disease (e.g., obesity) through the germline. the current study was designed to investigate the ddt-induced concurrent alterations of a number of different epigenetic processes including dna methylation, non-coding rna (ncrna) and histone retention in sperm. methods: gestating females were exposed transiently to ddt during fetal gonadal development, and then, the directly exposed f1 generation, the directly exposed germline f2 generation and the transgenerational f3 generation sperm were investigated. results: dna methylation and ncrna were altered in each generation sperm with the direct exposure f1 and f2 generations being predominantly distinct from the f3 generation epimutations. the pirna and small trna were the most predominant classes of ncrna altered. a highly conserved set of histone retention sites were found in the control lineage generations which was not significantly altered between generations, but a large number of new histone retention sites were found only in the transgenerational generation ddt lineage sperm. conclusions: therefore, all three different epigenetic processes were concurrently altered as ddt induced the epigenetic transgenerational inheritance of sperm epimutations. the direct exposure generations sperm epigenetic alterations were distinct from the transgenerational sperm epimutations. the genomic features and gene associations with the epimutations were investigated to help elucidate the integration of these different epigenetic processes. observations demonstrate all three epigenetic processes are involved in transgenerational inheritance. the different epigenetic processes appear to be integrated in mediating the epigenetic transgenerational inheritance phenomenon.”
Camacho-Ordonez, N., Ballestar, E., Timmers, H. T. M., & Grimbacher, B.. (2021). What can clinical immunology learn from inborn errors of epigenetic regulators?. Journal of Allergy and Clinical Immunology
Plain numerical DOI: 10.1016/j.jaci.2021.01.035
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“The epigenome is at the interface between environmental factors and the genome, regulating gene transcription, dna repair, and replication. epigenetic modifications play a crucial role in establishing and maintaining cell identity and are especially crucial for neurology, musculoskeletal integrity, and the function of the immune system. mutations in genes encoding for the components of the epigenetic machinery lead to the development of distinct disorders, especially involving the central nervous system and host defense. in this review, we focus on the role of epigenetic modifications for the function of the immune system. by studying the immune phenotype of patients with monogenic mutations in components of the epigenetic machinery (inborn errors of epigenetic regulators), we demonstrate the importance of dna methylation, histone modifications, chromatin remodeling, noncoding rnas, and mrna processing for immunity. moreover, we give a short overview on therapeutic strategies targeting the epigenome.”
Theodoropoulou, E., Alfredsson, L., Piehl, F., Marabita, F., & Jagodic, M.. (2019). Different epigenetic clocks reflect distinct pathophysiological features of multiple sclerosis. Epigenomics
Plain numerical DOI: 10.2217/epi-2019-0102
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“Aim: accumulating evidence links epigenetic age to diseases and age-related conditions, but little is known about its association with multiple sclerosis (ms). materials & methods: we estimated epigenetic age acceleration measures using dna methylation from blood or sorted cells of ms patients and controls. results: in blood, sex (p = 4.39e-05) and ms (p = 2.99e-03) explained the variation in age acceleration, and isolated blood cell types showed different epigenetic age. intrinsic epigenetic age acceleration and extrinsic epigenetic age acceleration were only associated with sex (p = 2.52e-03 and p = 1.58e-04, respectively), while phenoage acceleration displayed positive association with ms (p = 3.40e-02). conclusion: different age acceleration measures are distinctly influenced by phenotypic factors, and they might measure separate pathophysiological aspects of ms. data deposition: dna methylation data can be accessed at gene expression omnibus database under accession number gse35069, gse43976, gse106648, gse130029, gse130030.”
Rajnović, T., Vokurka, A., & Bolarić, S.. (2020). Epigenetics in plant breeding. Journal of Central European Agriculture
Plain numerical DOI: 10.5513/JCEA01/21.1.2765
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“Current farming technology and advanced techniques of plant breeding are tending to enable high yields and cropping intensity, trying to alleviate the limitations of available arable land. however, rise in global population and climate changes could strain the ability to provide a stable food supply. genetic diversity, which might be used for development of new, more resilient cultivars, could be a key for achieving better performance in agricultural production. new findings about how genes work and express, including the principles of epigenetics, could allow the advancements in breeding methods, and provide a new source of variability originating from epialleles. this paper provides a synopsis of the most significant epigenetic modifications, and particularities of plant species that impact epigenetic mechanisms, although it is mainly focused on application of epigenetics on plant breeding. epigenetic aspects of breeding are described for increased yield in brassica napus due to recursive selection for an epigenetic compound. future application might be based on epigenetic recombinant inbred lines, similar to those in arabidopsis thaliana, inhibition of dna methylation in oryza sativa, discovery of msh1 system in glycine max and solanum lycopersicon. it also outlines the current issues and limitations of epigenetic breeding such as a lack of understanding of epigenetic mechanisms, interaction of epigenetic and stress responsive mechanisms, and the development of statistical models able to predict the impact and outcome of epigenetic modifications.”
Henning, A. N., Roychoudhuri, R., & Restifo, N. P.. (2018). Epigenetic control of CD8+ T’cell differentiation. Nature Reviews Immunology
Plain numerical DOI: 10.1038/nri.2017.146
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“Upon stimulation, small numbers of naive cd8 t cells proliferate and differentiate into a variety of memory and effector cell types. cd8+ t cells can persist for years and kill tumour cells and virally infected cells. the functional and phenotypic changes that occur during cd8 t cell differentiation are well characterized, but the epigenetic states that underlie these changes are incompletely understood. here, we review the epigenetic processes that direct cd8 t cell differentiation and function. we focus on epigenetic modification of dna and associated histones at genes and their regulatory elements. we also describe structural changes in chromatin organization that affect gene expression. finally, we examine the translational potential of epigenetic interventions to improve cd8 t cell function in individuals with chronic infections and cancer.”
Ding, G. L., Liu, Y., Liu, M. E., Pan, J. X., Guo, M. X., Sheng, J. Z., & Huang, H. F.. (2015). The effects of diabetes on male fertility and epigenetic regulation during spermatogenesis. Asian Journal of Andrology
Plain numerical DOI: 10.4103/1008-682X.150844
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“The effects of diabetes mellitus include long-term damages, dysfunctions, and failures of various organs. an important complication of diabetes is the disturbance in the male reproductive system. glucose metabolism is an important event in spermatogenesis. moreover, glucose metabolism is also important for maintaining basic cell activity, as well as specific functions, such as motility and fertilization ability in mature sperm. diabetic disease and experimentally induced diabetes both demonstrated that either type 1 diabetes or type 2 diabetes could have detrimental effects on male fertility, especially on sperm quality, such as sperm motility, sperm dna integrity, and ingredients of seminal plasma. epigenetic modifications are essential during spermatogenesis. the epigenetic regulation represents chromatin modifications including dna methylation, histone modifications, remodeling of nucleosomes and the higher-order chromatin reorganization and noncoding rnas. if spermatogenesis is affected during the critical developmental window, embryonic gonadal development, and germline differentiation, environmentally-induced epigenetic modifications may become permanent in the germ line epigenome and have a potential impact on subsequent generations through epigenetic transgenerational inheritance. diabetes may influence the epigenetic modification during sperm spermatogenesis and that these epigenetic dysregulation may be inherited through the male germ line and passed onto more than one generation, which in turn may increase the risk of diabetes in offspring.”
Breiling, A., & Lyko, F.. (2015). Epigenetic regulatory functions of DNA modifications: 5-methylcytosine and beyond. Epigenetics and Chromatin
Plain numerical DOI: 10.1186/s13072-015-0016-6
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“The chemical modification of dna bases plays a key role in epigenetic gene regulation. while much attention has been focused on the classical epigenetic mark, 5-methylcytosine, the field garnered increased interest through the recent discovery of additional modifications. in this review, we focus on the epigenetic regulatory roles of dna modifications in animals. we present the symmetric modification of 5-methylcytosine on cpg dinucleotide as a key feature, because it permits the inheritance of methylation patterns through dna replication. however, the distribution patterns of cytosine methylation are not conserved in animals and independent molecular functions will likely be identified. furthermore, the discovery of enzymes that catalyse the hydroxylation of 5-methylcytosine to 5-hydroxymethylcytosine not only identified an active demethylation pathway, but also a candidate for a new epigenetic mark associated with activated transcription. most recently, n6-methyladenine was described as an additional eukaryotic dna modification with epigenetic regulatory potential. interestingly, this modification is also present in genomes that lack canonical cytosine methylation patterns, suggesting independent functions. this newfound diversity of dna modifications and their potential for combinatorial interactions indicates that the epigenetic dna code is substantially more complex than previously thought.”
Chatterjee, P., Roy, D., & Rathi, N.. (2018). Epigenetic Drug Repositioning for Alzheimer’s Disease Based on Epigenetic Targets in Human Interactome. Journal of Alzheimer’s Disease
Plain numerical DOI: 10.3233/JAD-161104
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“Background: epigenetics has emerged as an important field in drug discovery. alzheimer’s disease (ad), the leading neurodegenerative disorder throughout the world, is shown to have an epigenetic basis. currently, there are very few effective epigenetic drugs available for ad. objective: in this work, for the first time we have proposed 14 ad repositioning epigenetic drugs and identified their targets from extensive human interactome. methods: interacting partners of theadepigenetic proteins were identified from the extensive human interactome to construct epigenetic protein-protein interaction network (ep-ppin). epigenetic drug-target network (ep-dtn)was constructed with the drugs associated with the proteins of ep-ppin. regulation of non-coding rnas associated with the target proteins of these drugs was also studied. ad related target proteins, epigenetic targets, enriched pathways, and functional categories of the proposed repositioning drugs were also studied. results: the proposed 14 ad epigenetic repositioning drugs have overlapping targets and mirs with known ad epigenetic targets and mirs. furthermore, several shared functional categories and enriched pathways were obtained for these drugs with fda approved epigenetic drugs and known ad drugs. conclusions: the findings of our work might provide insight into future ad epigenetic-therapeutics.”
Marioni, R. E., Suderman, M., Chen, B. H., Horvath, S., Bandinelli, S., Morris, T., … Hägg, S.. (2019). Tracking the epigenetic clock across the human life course: A meta-analysis of longitudinal cohort data. Journals of Gerontology – Series A Biological Sciences and Medical Sciences
Plain numerical DOI: 10.1093/gerona/gly060
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“Background epigenetic clocks based on dna methylation yield high correlations with chronological age in cross-sectional data. due to a paucity of longitudinal data, it is not known how δ age (epigenetic age-chronological age) changes over time or if it remains constant from childhood to old age. here, we investigate this using longitudinal dna methylation data from five datasets, covering most of the human life course. methods two measures of the epigenetic clock (hannum and horvath) are used to calculate δ age in the following cohorts: avon longitudinal study of parents and children (alspac) offspring (n = 986, total age-range 7-19 years, 2 waves), alspac mothers (n = 982, 16-60 years, 2 waves), inchianti (n = 460, 21-100 years, 2 waves), satsa (n = 373, 48-99 years, 5 waves), lothian birth cohort 1936 (n = 1,054, 70-76 years, 3 waves), and lothian birth cohort 1921 (n = 476, 79-90 years, 3 waves). linear mixed models were used to track longitudinal change in δ age within each cohort. results for both epigenetic age measures, δ age showed a declining trend in almost all of the cohorts. the correlation between δ age across waves ranged from 0.22 to 0.82 for horvath and 0.25 to 0.71 for hannum, with stronger associations in samples collected closer in time. conclusions epigenetic age increases at a slower rate than chronological age across the life course, especially in the oldest population. some of the effect is likely driven by survival bias, where healthy individuals are those maintained within a longitudinal study, although other factors like the age distribution of the underlying training population may also have influenced this trend.”
Devaux, C. A., & Raoult, D.. (2018). The microbiological memory, an epigenetic regulator governing the balance between good health and metabolic disorders. Frontiers in Microbiology
Plain numerical DOI: 10.3389/fmicb.2018.01379
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“If the transmission of biological information from one generation to the next is based on dna, most heritable phenotypic traits such as chronic metabolic diseases, are not linked to genetic variation in dna sequences. non-genetic heritability might have several causes including epigenetic, parental effect, adaptive social learning, and influence of the ecological environment. distinguishing among these causes is crucial to resolve major phenotypic enigmas. strong evidence indicates that changes in dna expression through various epigenetic mechanisms can be linked to parent-offspring resemblance in terms of sensitivity to metabolic diseases. among non-genetic heritable traits, early nutrition could account for a long term deviant programming of genes expression responsible for metabolic diseases in adulthood. nutrition could shape an inadequate gut microbiota (dysbiosis), triggering epigenetic deregulation of transcription which can be observed in chronic metabolic diseases. we review herein the evidence that dysbiosis might be a major cause of heritable epigenetic patterns found to be associated with metabolic diseases. by taking into account the recent advances on the gut microbiome, we have aggregated together different observations supporting the hypothesis that the gut microbiota could promote the molecular crosstalk between bacteria and surrounding host cells which controls the pathological epigenetic signature. we introduce for the first time the concept of ‘microbiological memory’ as the main regulator of the epigenetic signatures, thereby indicating that different causes of non-genetic heritability can interact in complex pathways to produce inheritance.”
Lu, W., Xiao, L., Quan, M., Wang, Q., El-Kassaby, Y. A., Du, Q., & Zhang, D.. (2020). Linkage-linkage disequilibrium dissection of the epigenetic quantitative trait loci (epiQTLs) underlying growth and wood properties in Populus. New Phytologist
Plain numerical DOI: 10.1111/nph.16220
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“Increasing evidence indicates that dna methylation is heritable and serves as an essential marker contributing to phenotypic variation. linkage-linkage disequilibrium mapping was used to decipher the epigenetic architecture underlying nine growth and wood property traits in a linkage population (550 f1 progeny) and a natural population (435 unrelated individuals) of populus using methylation-sensitive amplification polymorphism (msap)-based analysis. the interactions between genetic and epigenetic variants in the causative genes was further unveiled using expression quantitative trait methylation (eqtm) and nucleotide (eqtn) mapping strategies. a total of 163 epigenetic quantitative trait loci (epiqtls; lod ≥ 3.0), explaining 1.7–44.5% of phenotypic variations, were mapped to a high-resolution epigenetic map with 19 linkage groups, which was supported by the significant msap associations (p < 0.001) in the two populations. there were 23 causal genes involved in growth regulation and wood formation, whose markers were located in epiqtls and associated with the same traits in both populations. further eqtn and eqtm mapping showed that causal genetic and epigenetic variants within the 23 candidate genes may interact more in trans in gene expression and phenotype. the present study provides strategies for investigating epigenetic architecture and the interaction between genetic and epigenetic variants modulating complex traits in forest trees.”
Luo, X., Song, R., Moreno, D. F., Ryu, H. Y., Hochstrasser, M., & Acar, M.. (2020). Epigenetic Mechanisms Contribute to Evolutionary Adaptation of Gene Network Activity under Environmental Selection. Cell Reports
Plain numerical DOI: 10.1016/j.celrep.2020.108306
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“How evolution can be facilitated by epigenetic mechanisms has received refreshed attention recently. to explore the role epigenetic inheritance plays in evolution, we subject isogenic wild-type yeast cells expressing pgal1-yfp (yellow fluorescent protein) to selection by daily sorting based on reporter expression. we observe expression-level reductions in multiple replicates sorted for the lowest expression that persist for several days, even after lifting the selection pressure. reduced expression is due to factors in the galactose (gal) network rather than global factors. results using a constitutively active gal network are in overall agreement with findings with the wild-type network. we find that the local chromatin environment of the reporter has a significant effect on the observed phenotype. genome sequencing, chromatin immunoprecipitation (chip)-qpcr, and sporulation analysis provide further insights into the epigenetic and genetic contributors to the expression changes observed. our work provides a comprehensive example of the role played by epigenetic mechanisms on gene network evolution.”
Ocker, M., Al Bitar, S., Monteiro, A. C., Gali-Muhtasib, H., & Schneider-Stock, R.. (2019). Epigenetic regulation of p21cip1/waf1 in human cancer. Cancers
Plain numerical DOI: 10.3390/cancers11091343
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“P21cip1/waf1 is a central regulator of cell cycle control and survival. while mutations are rare, it is commonly dysregulated in several human cancers due to epigenetic mechanisms influencing its transcriptional control. these mechanisms include promoter hypermethylation as well as additional pathways such as histone acetylation or methylation. the epigenetic regulators include writers, such as dna methyltransferases (dnmts); histone acetyltransferases (hats) and histone lysine methyltransferases; erasers, such as histone deacetylases (hdacs); histone lysine demethylases [e.g., the lysine demethylase (kdm) family]; dna hydroxylases; readers, such as the methyl-cpg-binding proteins (mbps); and bromodomain-containing proteins, including the bromo-and extraterminal domain (bet) family. we further discuss the roles that long noncoding rnas (lncrnas) and micrornas (mirnas) play in the epigenetic control of p21cip1/waf1 expression and its function in human cancers.”
Liang, Z., Riaz, A., Chachar, S., Ding, Y., Du, H., & Gu, X.. (2019). Epigenetic Modifications of mRNA and DNA in Plants. Molecular Plant
Plain numerical DOI: 10.1016/j.molp.2019.12.007
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“Advances in the detection and mapping of messenger rna (mrna) n6-methyladenosine (m6a) and 5-methylcytosine (m5c), and dna n6-methyldeoxyadenosine (6ma) redefined our understanding of these modifications as additional tiers of epigenetic regulation. in plants, the most prevalent internal mrna modifications, m6a and m5c, play crucial and dynamic roles in many processes, including embryo development, stem cell fate determination, trichome branching, leaf morphogenesis, floral transition, stress responses, fruit ripening, and root development. the newly identified and widespread epigenetic marker 6ma dna methylation is associated with gene expression, plant development, and stress responses. here, we review the latest research progress on mrna and dna epigenetic modifications, including the detection, dynamics, distribution, functions, regulatory proteins, and evolution, with a focus on m6a, m5c, and 6ma. we also provide some perspectives on future research of the newly identified and unknown epigenetic modifications of mrna and dna in plants.”
Sun, Y., Chen, B. R., & Deshpande, A.. (2018). Epigenetic regulators in the development, maintenance, and therapeutic targeting of acute myeloid leukemia. Frontiers in Oncology
Plain numerical DOI: 10.3389/fonc.2018.00041
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“The importance of epigenetic dysregulation to acute myeloid leukemia (aml) pathophysiology has become increasingly apparent in recent years. epigenetic regulators, including readers, writers, and erasers, are recurrently dysregulated by way of chromosomal translocations, somatic mutations, or genomic amplification in aml and many of these alterations are directly implicated in aml pathogenesis. mutations in epigenetic regulators are often discovered in founder clones and persist after therapy, indicating that they may contribute to a premalignant state poised for the acquisition of cooperating mutations and frank malignancy. apart from the proto-oncogenic impact of these mutations, the aml epigenome is also shaped by other epigenetic factors that are not mutated but co-opted by aml oncogenes, presenting with actionable vulnerabilities in this disease. targeting the aml epigenome might also be important for eradicating aml leukemia stem cells, which can be critical for disease maintenance and resistance to therapy. in this review, we describe the importance of epigenetic regulators in aml. we also summarize evidence implicating specific epigenetic regulators in aml pathobiology and discuss emerging epigenome-based therapies for the treatment of aml in the clinic.”
Maury, E., & Hashizume, R.. (2017). Epigenetic modification in chromatin machinery and its deregulation in pediatric brain tumors: Insight into epigenetic therapies. Epigenetics
Plain numerical DOI: 10.1080/15592294.2016.1278095
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“Malignancies are characterized by the reprogramming of epigenetic patterns. this reprogramming includes gains or losses in dna methylation and disruption of normal patterns of covalent histone modifications, which are associated with changes in chromatin remodeling processes. this review will focus on the mechanisms underlying this reprogramming and, specifically, on the role of histone modification in chromatin machinery and the modifications in epigenetic processes occurring in brain cancer, with a specific focus on epigenetic therapies for pediatric brain tumors.”
Lee, Y. T., Tan, Y. J., Falasca, M., & Oon, C. E.. (2020). Cancer-associated fibroblasts: Epigenetic regulation and therapeutic intervention in breast cancer. Cancers
Plain numerical DOI: 10.3390/cancers12102949
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“Breast cancer is the leading cause of cancer-related mortality in women worldwide. cancer-associated fibroblasts (cafs) are a heterogeneous population of cells in the solid tumour microenvironment. these cells are positively linked to breast cancer progression. breast cafs can be categorised into distinct subtypes according to their roles in breast carcinogenesis. epigenetic modifications change gene expression patterns as a consequence of altered chromatin configuration and dna accessibility to transcriptional machinery, without affecting the primary structure of dna. epigenetic dysregulation in breast cafs may enhance breast cancer cell survival and ultimately lead to therapeutic resistance. a growing body of evidence has described epigenetic modulators that target histones, dna, and mirna as a promising approach to treat cancer. this review aims to summarise the current findings on the mechanisms involved in the epigenetic regulation in breast cafs and discusses the potential therapeutic strategies via targeting these factors.”
Bugler, J., Kinstrie, R., Scott, M. T., & Vetrie, D.. (2019). Epigenetic Reprogramming and Emerging Epigenetic Therapies in CML. Frontiers in Cell and Developmental Biology
Plain numerical DOI: 10.3389/fcell.2019.00136
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“Chronic myeloid leukemia (cml) is a hematopoietic stem cell disorder characterized by bcr-abl1, an oncogenic fusion gene arising from the philadelphia chromosome. the development of tyrosine kinase inhibitors (tkis) to overcome the constitutive tyrosine kinase activity of the bcr-abl protein has dramatically improved disease management and patient outcomes over the past 20 years. however, the majority of patients are not cured and developing novel therapeutic strategies that target epigenetic processes are a promising avenue to improve cure rates. a number of epigenetic mechanisms are altered or reprogrammed during the development and progression of cml, resulting in alterations in histone modifications, dna methylation and dysregulation of the transcriptional machinery. in this review these epigenetic alterations are examined and the potential of epigenetic therapies are discussed as a means of eradicating residual disease and offering a potential cure for cml in combination with current therapies.”
Liao, Y., & Xu, K.. (2019). Epigenetic regulation of prostate cancer: The theories and the clinical implications. Asian Journal of Andrology
Plain numerical DOI: 10.4103/aja.aja_53_18
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“Epigenetics is the main mechanism that controls transcription of specific genes with no changes in the underlying dna sequences. epigenetic alterations lead to abnormal gene expression patterns that contribute to carcinogenesis and persist throughout disease progression. because of the reversible nature, epigenetic modifications emerge as promising anticancer drug targets. several compounds have been developed to reverse the aberrant activities of enzymes involved in epigenetic regulation, and some of them show encouraging results in both preclinical and clinical studies. in this article, we comprehensively review the up-to-date roles of epigenetics in the development and progression of prostate cancer. we especially focus on three epigenetic mechanisms: dna methylation, histone modifications, and noncoding rnas. we elaborate on current models/theories that explain the necessity of these epigenetic programs in driving the malignant phenotypes of prostate cancer cells. in particular, we elucidate how certain epigenetic regulators crosstalk with critical biological pathways, such as androgen receptor (ar) signaling, and how the cooperation dynamically controls cancer-oriented transcriptional profiles. restoration of a ‘normal’ epigenetic landscape holds promise as a cure for prostate cancer, so we concluded by highlighting particular epigenetic modifications as diagnostic and prognostic biomarkers or new therapeutic targets for treatment of the disease.”
Wei, Y., Schatten, H., & Sun, Q. Y.. (2015). Environmental epigenetic inheritance through gametes and implications for human reproduction. Human Reproduction Update
Plain numerical DOI: 10.1093/humupd/dmu061
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“Background: traditional studies focused ondnaas the heritable information carrier that passes the phenotype fromparents to offspring. however, increasing evidence suggests that information, that is independent of thednasequence, termed epigenetic information, can be inherited between generations. recently, in our lab, we found that prediabetes in fathers increases the susceptibility to diabetes in offspring through gametic cytosine methylation changes. paternal prediabetes changed overall methylation patterns in sperm, and a large portion of differentially methylated loci can be transmitted to pancreatic islets of offspring up to the second generation. in this review, we survey the extensive examples of environmentally induced epigenetic inheritance in various species, ranging from caenorhabditis elegans to humans. we focus mainly on elucidating the molecular basis of environmental epigenetic inheritance through gametes, which is an emerging theme and has important implications for explaining the prevalence of obesity, type 2 diabetes and other chronic non-genetic diseases, which is also important for understanding the influence of environmental exposures on reproductive and overall health in offspring. methods: for this review, we included relevant data and information obtained through a pubmed database search for all english language articles published up to august 2014 which included the term ‘environmental epigenetic inheritance’ and ‘transgenerational epigenetic inheritance’. we focused on research papers using animal models including drosophila, c. elegans, mouse and rat. human data were also included. results: evidence fromanimal models suggests that environmental epigenetic inheritance through gametes exists in various species. extensive molecular evidence suggests that epigenetic information carriers including dna methylation, non-coding rnas and chromatin proteins in gametes play important roles in the transmission of phenotypes from parents to offspring. conclusions: given the large number of experimental evidence fromvarious organisms, it is clear that parental environmental alterations can affect the phenotypes of offspring through gametic epigenetic alterations. this more recent thinking based on new data may have implications in explaining the prevalence of obesity, type 2 diabetes and other chronic non-genetic diseases. this also implies that, in the near future, epigenetic factors which are heritable should be regarded important in dete…”
Dimauro, I., Paronetto, M. P., & Caporossi, D.. (2020). Exercise, redox homeostasis and the epigenetic landscape. Redox Biology
Plain numerical DOI: 10.1016/j.redox.2020.101477
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“Physical exercise represents one of the strongest physiological stimuli capable to induce functional and structural modifications in all biological systems. indeed, beside the traditional genetic mechanisms, physical exercise can modulate gene expression through epigenetic modifications, namely dna methylation, post-translational histone modification and non-coding rna transcripts. initially considered as merely damaging molecules, it is now well recognized that both reactive oxygen (ros) and nitrogen species (rns) produced under voluntary exercise play an important role as regulatory mediators in signaling processes. while robust scientific evidences highlight the role of exercise-associated redox modifications in modulating gene expression through the genetic machinery, the understanding of their specific impact on epigenomic profile is still at an early stage. this review will provide an overview of the role of ros and rns in modulating the epigenetic landscape in the context of exercise-related adaptations.”
Mills, J. A., Beach, S. R. H., Dogan, M., Simons, R. L., Gibbons, F. X., Long, J. D., & Philibert, R.. (2019). A direct comparison of the relationship of epigenetic aging and epigenetic substance consumption markers to mortality in the framingham heart study. Genes
Plain numerical DOI: 10.3390/genes10010051
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“A number of studies have examined the relationship of indices of epigenetic aging (ea) to key health outcomes. unfortunately, our understanding of the relationship of ea to mortality and substance use-related health variables is unclear. in order to clarify these interpretations, we analyzed the relationship of the levine ea index (lea), as well as established epigenetic indices of cigarette (cg05575921) and alcohol consumption (cg04987734), to all-cause mortality in the framingham heart study offspring cohort (n = 2256) cox proportional hazards regression. we found that cg05575921 and cg04987734 had an independent effect relative to lea and vice versa, with the model including all the predictors having better performance than models with either lea or cg05575921 and cg04987734 alone. after correction for multiple comparisons, 195 and 327, respectively, of the 513 markers in the lea index, as well as the overall index itself, were significantly associated with cg05575921 and cg04987734 methylation status. we conclude that the epigenetic indices of substance use have an independent effect over and above lea, and are slightly stronger predictors of mortality in head-to-head comparisons. we also conclude that the majority of the strength of association conveyed by the lea is secondary to smoking and drinking behaviors, and that efforts to promote healthy aging should continue to focus on addressing substance use.”
Cheng, Y. Y., Rath, E. M., Linton, A., Yuen, M. L., Takahashi, K., & Lee, K.. (2020). The current understanding of asbestos-induced epigenetic changes associated with lung cancer. Lung Cancer: Targets and Therapy
Plain numerical DOI: 10.2147/LCTT.S186843
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“Asbestos is a naturally occurring mineral consisting of extremely fine fibres that can become trapped in the lungs after inhalation. occupational and environmental exposures to asbestos are linked to development of lung cancer and malignant mesothelioma, a cancer of the lining surrounding the lung. this review discusses the factors that are making asbestos-induced lung cancer a continuing problem, including the extensive historic use of asbestos and decades long latency between exposure and disease development. genomic mutations of dna nucleotides and gene rearrangements driving lung cancer are well-studied, with biomarkers and targeted therapies already in clinical use for some of these mutations. the genes involved in these mutation biomarkers and targeted therapies are also involved in epigenetic mechanisms and are discussed in this review as it is hoped that identification of epigenetic aberrations in these genes will enable the same gene biomarkers and targeted therapies to be used. currently, understanding of how asbestos fibres trapped in the lungs leads to epigenetic changes and lung cancer is incomplete. it has been shown that oxidoreduction reactions on fibre surfaces generate reactive oxygen species (ros) which in turn damage dna, leading to genetic and epigenetic alterations that reduce the activity of tumour suppressor genes. epigenetic dna methylation changes associated with lung cancer are summarised in this review, and some of these changes will be due to asbestos exposure. so far, little research has been carried out to separate the asbestos driven epigenetic changes from those due to non-asbestos causes of lung cancer. asbestos-associated lung cancers exhibit less methylation variability than lung cancers in general, and in a large proportion of samples variability has been found to be restricted to promoter regions. epigenetic aberrations in cancer are proving to be promising biomarkers for diagnosing cancers. it is hoped that further understanding of epigenetic changes in lung cancer can result in useful asbestos-associated lung cancer biomarkers to guide treatment. research is ongoing into the detection of lung cancer epigenetic alterations using non-invasive samples of blood and sputum. these efforts hold the promise of non-invasive cancer diagnosis in the future. efforts to reverse epigenetic aberrations in lung cancer by epigenetic therapies are ongoing but have not yet yielded success.”
Oblak, L., van der Zaag, J., Higgins-Chen, A. T., Levine, M. E., & Boks, M. P.. (2021). A systematic review of biological, social and environmental factors associated with epigenetic clock acceleration. Ageing Research Reviews
Plain numerical DOI: 10.1016/j.arr.2021.101348
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“Aging involves a diverse set of biological changes accumulating over time that leads to increased risk of morbidity and mortality. epigenetic clocks are now widely used to quantify biological aging, in order to investigate determinants that modify the rate of aging and to predict age-related outcomes. numerous biological, social and environmental factors have been investigated for their relationship to epigenetic clock acceleration and deceleration. the aim of this review was to synthesize general trends concerning the associations between human epigenetic clocks and these investigated factors. we conducted a systematic review of all available literature and included 156 publications across 4 resource databases. we compiled a list of all presently existing blood-based epigenetic clocks. subsequently, we created an extensive dataset of over 1300 study findings in which epigenetic clocks were utilized in blood tissue of human subjects to assess the relationship between these clocks and numeral environmental exposures and human traits. statistical analysis was possible on 57 such relationships, measured across 4 different epigenetic clocks (hannum, horvath, levine and grimage). we found that the horvath, hannum, levine and grimage epigenetic clocks tend to agree in direction of effects, but vary in size. body mass index, hiv infection, and male sex were significantly associated with acceleration of one or more epigenetic clocks. acceleration of epigenetic clocks was also significantly related to mortality, cardiovascular disease, cancer and diabetes. our findings provide a graphical and numerical synopsis of the past decade of epigenetic age estimation research and indicate areas where further attention could be focused in the coming years.”
Nemtsova, M. V., Zaletaev, D. V., Bure, I. V., Mikhaylenko, D. S., Kuznetsova, E. B., Alekseeva, E. A., … Zamyatnin, A. A.. (2019). Epigenetic changes in the pathogenesis of rheumatoid arthritis. Frontiers in Genetics
Plain numerical DOI: 10.3389/fgene.2019.00570
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“Rheumatoid arthritis (ra) is a systemic autoimmune disease that affects about 1% of the world’s population. the etiology of ra remains unknown. it is considered to occur in the presence of genetic and environmental factors. an increasing body of evidence pinpoints that epigenetic modifications play an important role in the regulation of ra pathogenesis. epigenetics causes heritable phenotype changes that are not determined by changes in the dna sequence. the major epigenetic mechanisms include dna methylation, histone proteins modifications and changes in gene expression caused by micrornas and other non-coding rnas. these modifications are reversible and could be modulated by diet, drugs, and other environmental factors. specific changes in dna methylation, histone modifications and abnormal expression of non-coding rnas associated with ra have already been identified. this review focuses on the role of these multiple epigenetic factors in the pathogenesis and progression of the disease, not only in synovial fibroblasts, immune cells, but also in the peripheral blood of patients with ra, which clearly shows their high diagnostic potential and promising targets for therapy in the future.”
Saavedra, K., Molina-Márquez, A. M., Saavedra, N., Zambrano, T., & Salazar, L. A.. (2016). Epigenetic modifications of major depressive disorder. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms17081279
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“Major depressive disorder (mdd) is a chronic disease whose neurological basis and pathophysiology remain poorly understood. initially, it was proposed that genetic variations were responsible for the development of this disease. nevertheless, several studies within the last decade have provided evidence suggesting that environmental factors play an important role in mdd pathophysiology. alterations in epigenetics mechanism, such as dna methylation, histone modification and microrna expression could favor mdd advance in response to stressful experiences and environmental factors. the aim of this review is to describe genetic alterations, and particularly altered epigenetic mechanisms, that could be determinants for mdd progress, and how these alterations may arise as useful screening, diagnosis and treatment monitoring biomarkers of depressive disorders.”
Yao, B., Christian, K. M., He, C., Jin, P., Ming, G. L., & Song, H.. (2016). Epigenetic mechanisms in neurogenesis. Nature Reviews Neuroscience
Plain numerical DOI: 10.1038/nrn.2016.70
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“In the embryonic and adult brain, neural stem cells proliferate and give rise to neurons and glia through highly regulated processes. epigenetic mechanisms-including dna and histone modifications, as well as regulation by non-coding rnas-have pivotal roles in different stages of neurogenesis. aberrant epigenetic regulation also contributes to the pathogenesis of various brain disorders. here, we review recent advances in our understanding of epigenetic regulation in neurogenesis and its dysregulation in brain disorders, including discussion of newly identified dna cytosine modifications. we also briefly cover the emerging field of epitranscriptomics, which involves modifications of mrnas and long non-coding rnas.”
Zarzour, A., Kim, H. W., & Weintraub, N. L.. (2019). Epigenetic Regulation of Vascular Diseases. Arteriosclerosis, Thrombosis, and Vascular Biology
Plain numerical DOI: 10.1161/ATVBAHA.119.312193
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“Epigenetic regulatory mechanisms, encompassing diverse molecular processes including dna methylation, histone post-translational modifications, and noncoding rnas, are essential to numerous processes such as cell differentiation, growth and development, environmental adaptation, aging, and disease states. in many cases, epigenetic changes occur in response to environmental cues and lifestyle factors, resulting in persistent changes in gene expression that affect vascular disease risk during the lifetime of the individual. biological aging-a powerful cardiovascular risk factor-is partly genetically determined yet strongly influenced by traditional risk factors, reflecting epigenetic modulation. quantification of specific dna methylation patterns may serve as an accurate predictor of biological age-a concept known as the epigenetic clock, which could help to refine cardiovascular risk assessment. epigenetic reprogramming of monocytes rewires cellular immune signaling and induces a metabolic shift toward aerobic glycolysis, thereby increasing innate immune responses. this form of trained epigenetic memory can be maladaptive, thus augmenting vascular inflammation. somatic mutations in epigenetic regulatory enzymes lead to clonal hematopoiesis of indeterminate potential, a precursor of hematologic malignancies and a recently recognized cardiovascular risk factor; moreover, epigenetic regulators are increasingly being targeted in cancer therapeutics. thus, understanding epigenetic regulatory mechanisms lies at the intersection between cancer and cardiovascular disease and is of paramount importance to the burgeoning field of cardio-oncology (graphic abstract).”
Muka, T., Koromani, F., Portilla, E., O’Connor, A., Bramer, W. M., Troup, J., … Franco, O. H.. (2016). The role of epigenetic modifications in cardiovascular disease: A systematic review. International Journal of Cardiology
Plain numerical DOI: 10.1016/j.ijcard.2016.03.062
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“Background epigenetic modifications of the genome, such as dna methylation and histone modifications, have been reported to play a role in processes underlying cardiovascular disease (cvd), including atherosclerosis, inflammation, hypertension and diabetes. methods eleven databases were searched for studies investigating the association between epigenetic marks (either global, site-specific or genome-wide methylation of dna and histone modifications) and cvd. results of the 3459 searched references, 31 studies met our inclusion criteria (26 cross-sectional studies and 5 prospective studies). overall, 12,648 individuals were included, with total of 4037 cvd events. the global dna methylation assessed at long-interspersed nuclear element (line-1) was inversely associated with cvd, independent of established cardiovascular risk factors. conversely, a higher degree of global dna methylation measured at alu repeats or by the luma method was associated with the presence of cvd. the studies reported epigenetic regulation of 34 metabolic genes (involved in fetal growth, glucose and lipid metabolism, inflammation, atherosclerosis and oxidative stress) in blood cells to be related with cvd. among them, 5 loci were validated and methylation at f2rl3 was reported in two large prospective studies to predict cardiovascular disease beyond the traditional risk factors. conclusions current evidence supports an association between genomic dna methylation and cvd. however, this review highlights important gaps in the existing evidences including lack of large-scale epigenetic investigations, needed to reliably identify genomic loci where dna methylation is related to risk of cvd.”
Mehdipour, P., Marhon, S. A., Ettayebi, I., Chakravarthy, A., Hosseini, A., Wang, Y., … De Carvalho, D. D.. (2020). Epigenetic therapy induces transcription of inverted SINEs and ADAR1 dependency. Nature
Plain numerical DOI: 10.1038/s41586-020-2844-1
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“Cancer therapies that target epigenetic repressors can mediate their effects by activating retroelements within the human genome. retroelement transcripts can form double-stranded rna (dsrna) that activates the mda5 pattern recognition receptor1–6. this state of viral mimicry leads to loss of cancer cell fitness and stimulates innate and adaptive immune responses7,8. however, the clinical efficacy of epigenetic therapies has been limited. to find targets that would synergize with the viral mimicry response, we sought to identify the immunogenic retroelements that are activated by epigenetic therapies. here we show that intronic and intergenic sine elements, specifically inverted-repeat alus, are the major source of drug-induced immunogenic dsrna. these inverted-repeat alus are frequently located downstream of ‘orphan’ cpg islands9. in mammals, the adar1 enzyme targets and destabilizes inverted-repeat alu dsrna10, which prevents activation of the mda5 receptor11. we found that adar1 establishes a negative-feedback loop, restricting the viral mimicry response to epigenetic therapy. depletion of adar1 in patient-derived cancer cells potentiates the efficacy of epigenetic therapy, restraining tumour growth and reducing cancer initiation. therefore, epigenetic therapies trigger viral mimicry by inducing a subset of inverted-repeats alus, leading to an adar1 dependency. our findings suggest that combining epigenetic therapies with adar1 inhibitors represents a promising strategy for cancer treatment.”
Xavier, M. J., Roman, S. D., Aitken, R. J., & Nixon, B.. (2019). Transgenerational inheritance: How impacts to the epigenetic and genetic information of parents affect offspring health. Human Reproduction Update
Plain numerical DOI: 10.1093/humupd/dmz017
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“BACKGROUND: a defining feature of sexual reproduction is the transmission of genomic information from both parents to the offspring. there is now compelling evidence that the inheritance of such genetic information is accompanied by additional epigenetic marks, or stable heritable information that is not accounted for by variations in dna sequence. the reversible nature of epigenetic marks coupled with multiple rounds of epigenetic reprogramming that erase the majority of existing patterns have made the investigation of this phenomenon challenging. however, continual advances in molecular methods are allowing closer examination of the dynamic alterations to histone composition and dna methylation patterns that accompany development and, in particular, how these modifications can occur in an individual’s germline and be transmitted to the following generation. while the underlying mechanisms that permit this form of transgenerational inheritance remain unclear, it is increasingly apparent that a combination of genetic and epigenetic modifications plays major roles in determining the phenotypes of individuals and their offspring. objective and rationale: information pertaining to transgenerational inheritance was systematically reviewed focusing primarily on mammalian cells to the exclusion of inheritance in plants, due to inherent differences in the means by which information is transmitted between generations. the effects of environmental factors and biological processes on both epigenetic and genetic information were reviewed to determine their contribution to modulating inheritable phenotypes. search methods: articles indexed in pubmed were searched using keywords related to transgenerational inheritance, epigenetic modifications, paternal and maternal inheritable traits and environmental and biological factors influencing transgenerational modifications. we sought to clarify the role of epigenetic reprogramming events during the life cycle of mammals and provide a comprehensive review of how the genomic and epigenomic make-up of progenitors may determine the phenotype of its descendants. outcomes: we found strong evidence supporting the role of dna methylation patterns, histone modifications and even non-protein-coding rna in altering the epigenetic composition of individuals and producing stable epigenetic effects that were transmitted from parents to offspring, in both humans and rodent species. multiple genomic domains and several histone modifica…”
Yildirim, Z., Sahin, O. S., Yazar, S., & Bozok Cetintas, V.. (2021). Genetic and epigenetic factors associated with increased severity of Covid-19. Cell Biology International
Plain numerical DOI: 10.1002/cbin.11572
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“Since december 2019, a new form of severe acute respiratory syndrome (sars) from a novel strain of coronavirus (sars coronavirus 2 [sars-cov-2]) has been spreading worldwide. the disease caused by sars-cov-2 was named covid-19 and declared as a pandemic by the world health organization in march 2020. clinical symptoms of covid-19 range from common cold to more severe disease defined as pneumonia, hypoxia, and severe respiratory distress. in the next stage, disease can become more critical with respiratory failure, sepsis, septic shock, and/or multiorgan failure. outcomes of covid-19 indicate large gaps between the male–female and the young–elder groups. several theories have been proposed to explain variations, such as gender, age, comorbidity, and genetic factors. it is likely that mixture of genetic and nongenetic factors interplays between virus and host genetics and determines the severity of disease outcome. in this review, we aimed to summarize current literature in terms of potential host genetic and epigenetic factors that associated with increased severity of covid-19. several studies indicated that the genetic variants of the sars-cov-2 entry mechanism-related (angiotensin-converting enzymes, transmembrane serine protease-2, furin) and host innate immune response-related genes (interferons [ifns], interleukins, toll-like receptors), and human leukocyte antigen, abo, 3p21.31, and 9q34.2 loci are critical host determinants related to covid-19 severity. epigenetic mechanisms also affect covid-19 outcomes by regulating ifn signaling, angiotensin-converting enzyme-2, and immunity-related genes that particularly escape from x chromosome inactivation. enhanced understanding of host genetic and epigenetic factors and viral interactions of sars-cov-2 is critical for improved prognostic tools and innovative therapeutics.”
Hoshino, A., Horvath, S., Sridhar, A., Chitsazan, A., & Reh, T. A.. (2019). Synchrony and asynchrony between an epigenetic clock and developmental timing. Scientific Reports
Plain numerical DOI: 10.1038/s41598-019-39919-3
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“Epigenetic changes have been used to estimate chronological age across the lifespan, and some studies suggest that epigenetic ‘aging’ clocks may already operate in developing tissue. to better understand the relationship between developmental stage and epigenetic age, we utilized the highly regular sequence of development found in the mammalian neural retina and a well-established epigenetic aging clock based on dna methylation. our results demonstrate that the epigenetic age of fetal retina is highly correlated with chronological age. we further establish that epigenetic aging progresses normally in vitro, suggesting that epigenetic aging is a property of individual tissues. this correlation is also retained in stem cell-derived retinal organoids, but is accelerated in individuals with down syndrome, a progeroid-like condition. overall, our results suggest that epigenetic aging begins as early as a few weeks post-conception, in fetal tissues, and the mechanisms underlying the phenomenon of epigenetic aging might be studied in developing organs.”
Cui, M., Wang, Z., Bassel-Duby, R., & Olson, E. N.. (2018). Genetic and epigenetic regulation of cardiomyocytes in development, regeneration and disease. Development (Cambridge)
Plain numerical DOI: 10.1242/dev.171983
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“Embryonic and postnatal life depend on the uninterrupted function of cardiac muscle cells. these cells, termed cardiomyocytes, display many fascinating behaviors, including complex morphogenic movements, interactions with other cell types of the heart, persistent contractility and quiescence after birth. each of these behaviors depends on complex interactions between both cardiac-restricted and widely expressed transcription factors, as well as on epigenetic modifications. here, we review recent advances in our understanding of the genetic and epigenetic control of cardiomyocyte differentiation and proliferation during heart development, regeneration and disease. we focus on those regulators that are required for both heart development and disease, and highlight the regenerative principles that might be manipulated to restore function to the injured adult heart.”
Sanders, T. H., Weiss, J., Hogewood, L., Chen, L., Paton, C., McMahan, R. L., & Sweatt, J. D.. (2019). Cognition-enhancing vagus nerve stimulation alters the epigenetic landscape. Journal of Neuroscience
Plain numerical DOI: 10.1523/JNEUROSCI.2407-18.2019
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“Vagus nerve stimulation (vns) has been shown to enhance learning and memory, yet the mechanisms behind these enhancements are unknown. here, we present evidence that epigenetic modulation underlies vns-induced improvements in cognition. we show that vns enhances novelty preference (np); alters the hippocampal, cortical, and blood epigenetic transcriptomes; and epigenetically modulates neuronal plasticity and stress-response signaling genes in male sprague dawley rats. brain-behavior analysis revealed structure-specific relationships between np test performance (nptp) and epigenetic alterations. in the hippocampus, nptp correlated with decreased histone deacetylase 11 (hdac11), a transcriptional repressor enriched in ca1 cells important for memory consolidation. in the cortex, the immediate early gene (ieg) arc was increased in vns rats and correlated with transcription of plasticity genes and epigenetic regulators, including hdac3. for rats engaged in nptp, arc correlated with performance. interestingly, blood arc transcripts decreased in vns rats performing nptp, but increased in vns-only rats. because dna double-strand breaks (dsbs) facilitate transcription of iegs, we investigated phosphorylated h2a.x (γh2a.x), a histone modification known to colocalize with dsbs. in agreement with reduced cortical stress-response transcription factor nf-κb1, chromatin immunoprecipitation revealed reduced γh2a.x in the arc promoter. surprisingly, vns did not significantly reduce transcription of cortical or hippocampal proinflammatory cytokines. however, tnfrsf11b (osteoprotegerin) correlated with nptp as well as plasticity, stress-response signaling, and epigenetic regulation transcripts in both hippocampus and cortex. together, our findings provide the first evidence that vns induces widespread changes in the cognitive epigenetic landscape and specifically affects epigenetic modulators associated with nptp, stress-response signaling, memory consolidation, and cortical neural remodeling.”
Yoon, S. H., Choi, J., Lee, W. J., & Do, J. T.. (2020). Genetic and Epigenetic Etiology Underlying Autism Spectrum Disorder. Journal of Clinical Medicine
Plain numerical DOI: 10.3390/jcm9040966
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“Autism spectrum disorder (asd) is a pervasive neurodevelopmental disorder characterized by difficulties in social interaction, language development delays, repeated body movements, and markedly deteriorated activities and interests. environmental factors, such as viral infection, parental age, and zinc deficiency, can be plausible contributors to asd susceptibility. as asd is highly heritable, genetic risk factors involved in neurodevelopment, neural communication, and social interaction provide important clues in explaining the etiology of asd. accumulated evidence also shows an important role of epigenetic factors, such as dna methylation, histone modification, and noncoding rna, in asd etiology. in this review, we compiled the research published to date and described the genetic and epigenetic epidemiology together with environmental risk factors underlying the etiology of the different phenotypes of asd.”
Bagot, R. C., Labonté, B., Peña, C. J., & Nestler, E. J.. (2014). Epigenetic signaling in psychiatric disorders: Stress and depression. Dialogues in Clinical Neuroscience
Plain numerical DOI: 10.31887/dcns.2014.16.3/rbagot
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“Psychiatric disorders are complex multifactorial disorders involving chronic alterations in neural circuit structure and function. while genetic factors play a role in the etiology of disorders such as depression, addiction, and schizophrenia, relatively high rates of discordance among identical twins clearly point to the importance of additional factors. environmental factors, such as stress, play a major role in the psychiatric disorders by inducing stable changes in gene expression, neural circuit function, and ultimately behavior. insults at the developmental stage and in adulthood appear to induce distinct maladaptations. increasing evidence indicates that these sustained abnormalities are maintained by epigenetic modifications in specific brain regions. indeed, transcriptional dysregulation and associated aberrant epigenetic regulation is a unifying theme in psychiatric disorders. aspects of depression can be modeled in animals by inducing disease-like states through environmental manipulations, and these studies can provide a more general understanding of epigenetic mechanisms in psychiatric disorders. understanding how environmental factors recruit the epigenetic machinery in animal models is providing new insights into disease mechanisms in humans.”
Serrano-Gomez, S. J., Maziveyi, M., & Alahari, S. K.. (2016). Regulation of epithelial-mesenchymal transition through epigenetic and post-translational modifications. Molecular Cancer
Plain numerical DOI: 10.1186/s12943-016-0502-x
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“The epithelial to mesenchymal transition (emt) is a biological process in which a non-motile epithelial cell changes to a mesenchymal phenotype with invasive capacities. this phenomenon has been well documented in multiple biological processes including embryogenesis, fibrosis, tumor progression and metastasis. the hallmark of emt is the loss of epithelial surface markers, most notably e-cadherin, and the acquisition of mesenchymal markers including vimentin and n-cadherin. the downregulation of e-cadherin during emt can be mediated by its transcriptional repression through the binding of emt transcription factors (emt-tfs) such as snail, slug and twist to e-boxes present in the e-cadherin promoter. additionally, emt-tfs can also cooperate with several enzymes to repress the expression of e-cadherin and regulate emt at the epigenetic and post- translational level. in this review, we will focus on epigenetic and post- translational modifications that are important in emt. in addition, we will provide an overview of the various therapeutic approaches currently being investigated to undermine emt and hence, the metastatic progression of cancer as well.”
Baizabal, J. M., Mistry, M., García, M. T., Gómez, N., Olukoya, O., Tran, D., … Harwell, C. C.. (2018). The Epigenetic State of PRDM16-Regulated Enhancers in Radial Glia Controls Cortical Neuron Position. Neuron
Plain numerical DOI: 10.1016/j.neuron.2018.04.033
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“The epigenetic landscape is dynamically remodeled during neurogenesis. however, it is not understood how chromatin modifications in neural stem cells instruct the formation of complex structures in the brain. we report that the histone methyltransferase prdm16 is required in radial glia to regulate lineage-autonomous and stage-specific gene expression programs that control number and position of upper layer cortical projection neurons. prdm16 regulates the epigenetic state of transcriptional enhancers to activate genes involved in intermediate progenitor cell production and repress genes involved in cell migration. the histone methyltransferase domain of prdm16 is necessary in radial glia to promote cortical neuron migration through transcriptional silencing. we show that repression of the gene encoding the e3 ubiquitin ligase pdzrn3 by prdm16 determines the position of upper layer neurons. these findings provide insights into how epigenetic control of transcriptional enhancers in radial glial determines the organization of the mammalian cerebral cortex. baizabal et al. uncover an epigenetic mechanism that encodes the number and position of upper layer cortical neurons in the activity of transcriptional enhancers in neural stem cells.”
Sun, L., Fu, X., Ma, G., & Hutchins, A. P.. (2021). Chromatin and Epigenetic Rearrangements in Embryonic Stem Cell Fate Transitions. Frontiers in Cell and Developmental Biology
Plain numerical DOI: 10.3389/fcell.2021.637309
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“A major event in embryonic development is the rearrangement of epigenetic information as the somatic genome is reprogrammed for a new round of organismal development. epigenetic data are held in chemical modifications on dna and histones, and there are dramatic and dynamic changes in these marks during embryogenesis. however, the mechanisms behind this intricate process and how it is regulating and responding to embryonic development remain unclear. as embryos develop from totipotency to pluripotency, they pass through several distinct stages that can be captured permanently or transiently in vitro. pluripotent naïve cells resemble the early epiblast, primed cells resemble the late epiblast, and blastomere-like cells have been isolated, although fully totipotent cells remain elusive. experiments using these in vitro model systems have led to insights into chromatin changes in embryonic development, which has informed exploration of pre-implantation embryos. intriguingly, human and mouse cells rely on different signaling and epigenetic pathways, and it remains a mystery why this variation exists. in this review, we will summarize the chromatin rearrangements in early embryonic development, drawing from genomic data from in vitro cell lines, and human and mouse embryos.”
Esposito, M., & Sherr, G. L.. (2019). Epigenetic modifications in Alzheimer’s neuropathology and therapeutics. Frontiers in Neuroscience
Plain numerical DOI: 10.3389/fnins.2019.00476
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“Transcriptional activation is a highly synchronized process in eukaryotes that requires a series of cis- and trans-acting elements at promoter regions. epigenetic modifications, such as chromatin remodeling, histone acetylation/deacetylation, and methylation, have frequently been studied with regard to transcriptional regulation/dysregulation. recently however, it has been determined that implications in epigenetic modification seem to expand into various neurodegenerative disease mechanisms. impaired learning and memory deterioration are cognitive dysfunctions often associated with a plethora of neurodegenerative diseases, including alzheimer’s disease. through better understanding of the epigenetic mechanisms underlying these dysfunctions, new epigenomic therapeutic targets, such as histone deacetylases, are being explored. here we review the intricate packaging of dna in eukaryotic cells, and the various modifications in epigenetic mechanisms that are now linked to the neuropathology and the progression of alzheimer’s disease (ad), as well as potential therapeutic interventions.”
Budhavarapu, V. N., Chavez, M., & Tyler, J. K.. (2013). How is epigenetic information maintained through DNA replication?. Epigenetics and Chromatin
Plain numerical DOI: 10.1186/1756-8935-6-32
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“DNA replication is a highly conserved process that accurately copies the genetic information from one generation to the next. the processes of chromatin disassembly and reassembly during dna replication also have to be precisely regulated to ensure that the genetic material is compactly packaged to fit into the nucleus while also maintaining the epigenetic information that is carried by the histone proteins bound to the dna, through cell divisions. half of the histones that are deposited during replication are from the parental chromatin and carry the parental epigenetic information, while the other half of the histones are newly-synthesized. it has been of growing interest to understand how the parental pattern of epigenetic marks is re-established on the newly-synthesized histones, in a dna sequence-specific manner, in order to maintain the epigenetic information through cell divisions. in this review we will discuss how histone chaperone proteins precisely coordinate the chromatin assembly process during dna replication. we also discuss the recent evidence that histone-modifying enzymes, rather than the parental histones, are themselves epigenetic factors that remain associated with the dna through replication to re-establish the epigenetic information on the newly-assembled chromatin. © 2013budhavarapu et al.; licensee biomed central ltd.”
Zhang, P., & Zhang, M.. (2020). Epigenetic alterations and advancement of treatment in peripheral T-cell lymphoma. Clinical Epigenetics
Plain numerical DOI: 10.1186/s13148-020-00962-x
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“Peripheral t-cell lymphoma (ptcl) is a rare and heterogeneous group of clinically aggressive diseases associated with poor prognosis. except for alk + anaplastic large-cell lymphoma (alcl), most peripheral t-cell lymphomas are highly malignant and have an aggressive disease course and poor clinical outcomes, with a poor remission rate and frequent relapse after first-line treatment. aberrant epigenetic alterations play an important role in the pathogenesis and development of specific types of peripheral t-cell lymphoma, including the regulation of the expression of genes and signal transduction. the most common epigenetic alterations are dna methylation and histone modification. histone modification alters the level of gene expression by regulating the acetylation status of lysine residues on the promoter surrounding histones, often leading to the silencing of tumour suppressor genes or the overexpression of proto-oncogenes in lymphoma. dna methylation refers to cpg islands, generally leading to tumour suppressor gene transcriptional silencing. genetic studies have also shown that some recurrent mutations in genes involved in the epigenetic machinery, including tet2, idh2-r172, dnmt3a, rhoa, cd28, idh2, tet2, mll2, kmt2a, kdm6a, crebbp, and ep300, have been observed in cases of ptcl. the aberrant expression of mirnas has also gradually become a diagnostic biomarker. these provide a reasonable molecular mechanism for epigenetic modifying drugs in the treatment of ptcl. as epigenetic drugs implicated in lymphoma have been continually reported in recent years, many new ideas for the diagnosis, treatment, and prognosis of ptcl originate from epigenetics in recent years. novel epigenetic-targeted drugs have shown good tolerance and therapeutic effects in the treatment of peripheral t-cell lymphoma as monotherapy or combination therapy. nccn clinical practice guidelines also recommended epigenetic drugs for ptcl subtypes as second-line therapy. epigenetic mechanisms provide new directions and therapeutic strategies for the research and treatment of peripheral t-cell lymphoma. therefore, this paper mainly reviews the epigenetic changes in the pathogenesis of peripheral t-cell lymphoma and the advancement of epigenetic-targeted drugs in the treatment of peripheral t-cell lymphoma (ptcl).”
Zhuang, J., Huo, Q., Yang, F., & Xie, N.. (2020). Perspectives on the Role of Histone Modification in Breast Cancer Progression and the Advanced Technological Tools to Study Epigenetic Determinants of Metastasis. Frontiers in Genetics
Plain numerical DOI: 10.3389/fgene.2020.603552
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“Metastasis is a complex process that involved in various genetic and epigenetic alterations during the progression of breast cancer. recent evidences have indicated that the mutation in the genome sequence may not be the key factor for increasing metastatic potential. epigenetic changes were revealed to be important for metastatic phenotypes transition with the development in understanding the epigenetic basis of breast cancer. herein, we aim to present the potential epigenetic drivers that induce dysregulation of genes related to breast tumor growth and metastasis, with a particular focus on histone modification including histone acetylation and methylation. the pervasive role of major histone modification enzymes in cancer metastasis such as histone acetyltransferases (hat), histone deacetylases (hdacs), dna methyltransferases (dnmts), and so on are demonstrated and further discussed. in addition, we summarize the recent advances of next-generation sequencing technologies and microfluidic-based devices for enhancing the study of epigenomic landscapes of breast cancer. this feature also introduces several important biotechnologists for identifying robust epigenetic biomarkers and enabling the translation of epigenetic analyses to the clinic. in summary, a comprehensive understanding of epigenetic determinants in metastasis will offer new insights of breast cancer progression and can be achieved in the near future with the development of innovative epigenomic mapping tools.”
Segers, V. F. M., Gevaert, A. B., Boen, J. R. A., Van Craenenbroeck, E. M., & De Keulenaer, G. W.. (2019). Epigenetic regulation of intercellular communication in the heart. American Journal of Physiology – Heart and Circulatory Physiology
Plain numerical DOI: 10.1152/ajpheart.00038.2019
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“Epigenetic regulation of intercellular communication in the heart. am j physiol heart circ physiol 316: h1417–h1425, 2019. first published april 5, 2019; doi:10.1152/ajpheart.00038.2019.—the myocardium is a highly structured tissue consisting of different cell types including cardiomyocytes, endothelial cells, fibroblasts, smooth muscle cells, inflammatory cells, and stem cells. microvascular endothelial cells are the most abundant cell type in the myocardium and play crucial roles during cardiac development, in normal adult myocardium, and during myocardial diseases such as heart failure. in the last decade, epigenetic changes have been described regulating cellular function in almost every cell type in the organism. here, we review recent evidence on different epigenetic changes that regulate intercellular communication in normal myocardium and during myocardial diseases, including cardiac remodeling. epigenetic changes influence many intercellular communication signaling systems, including the nitric oxide, angiotensin, and endothelin signaling systems. in this review, we go beyond discussing classic endothelial function (for instance nitric oxide secretion) and will discuss epigenetic regulation of intercellular communication.”
Heerboth, S., Lapinska, K., Snyder, N., Leary, M., Rollinson, S., & Sarkar, S.. (2014). Use of epigenetic drugs in disease: An overview. Genetics and Epigenetics
Plain numerical DOI: 10.4137/GeG.s12270
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“Epigenetic changes such as dna methylation and histone methylation and acetylation alter gene expression at the level of transcription by upregulating, downregulating, or silencing genes completely. dysregulation of epigenetic events can be pathological, leading to cardiovascular disease, neurological disorders, metabolic disorders, and cancer development. therefore, identifying drugs that inhibit these epigenetic changes are of great clinical interest. in this review, we summarize the epigenetic events associated with different disorders and diseases including cardiovascular, neurological, and metabolic disorders, and cancer. knowledge of the specific epigenetic changes associated with these types of diseases facilitates the development of specific inhibitors, which can be used as epigenetic drugs. in this review, we discuss the major classes of epigenetic drugs currently in use, such as dna methylation inhibiting drugs, bromodomain inhibitors, histone acetyl transferase inhibitors, histone deacetylase inhibitors, protein methyltransferase inhibitors, and histone methylation inhibitors and their role in reversing epigenetic changes and treating disease. © the authors, publisher and licensee libertas academica limited.”
Hannan, A. J.. (2020). Epimimetics: Novel Therapeutics Targeting Epigenetic Mediators and Modulators. Trends in Pharmacological Sciences
Plain numerical DOI: 10.1016/j.tips.2020.01.005
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“Epigenetic alterations have been associated with a wide range of diseases. furthermore, many therapeutic interventions modelling environmental exposures appear to involve epigenetic mechanisms. recent progress has been made in developing drugs targeting specific epigenetic components. here, i propose developing ‘epimimetics’, novel drugs that mimic or enhance therapeutic effects of epigenetic modifications.”
Rugo, H. S., Jacobs, I., Sharma, S., Scappaticci, F., Paul, T. A., Jensen-Pergakes, K., & Malouf, G. G.. (2020). The Promise for Histone Methyltransferase Inhibitors for Epigenetic Therapy in Clinical Oncology: A Narrative Review. Advances in Therapy
Plain numerical DOI: 10.1007/s12325-020-01379-x
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“Epigenetic processes are essential for normal development and the maintenance of tissue-specific gene expression in mammals. changes in gene expression and malignant cellular transformation can result from disruption of epigenetic mechanisms, and global disruption in the epigenetic landscape is a key feature of cancer. the study of epigenetics in cancer has revealed that human cancer cells harbor both genetic alterations and epigenetic abnormalities that interplay at all stages of cancer development. unlike genetic mutations, epigenetic aberrations are potentially reversible through epigenetic therapy, providing a therapeutically relevant treatment option. histone methyltransferase inhibitors are emerging as an epigenetic therapy approach with great promise in the field of clinical oncology. the recent accelerated approval of the enhancer of zeste homolog 2 (ezh2; also known as histone-lysine n-methyltransferase ezh2) inhibitor tazemetostat for metastatic or locally advanced epithelioid sarcoma marks the first approval of such a compound for the treatment of cancer. many other histone methyltransferase inhibitors are currently in development, some of which are being tested in clinical studies. this review focuses on histone methyltransferase inhibitors, highlighting their potential in the treatment of cancer. we also discuss the role for such epigenetic drugs in overcoming epigenetically driven drug resistance mechanisms, and their value in combination with other therapeutic approaches such as immunotherapy.”
Greco, A., Goossens, R., van Engelen, B., & van der Maarel, S. M.. (2020). Consequences of epigenetic derepression in facioscapulohumeral muscular dystrophy. Clinical Genetics
Plain numerical DOI: 10.1111/cge.13726
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“Facioscapulohumeral muscular dystrophy (fshd), a common hereditary myopathy, is caused either by the contraction of the d4z4 macrosatellite repeat at the distal end of chromosome 4q to a size of 1 to 10 repeat units (fshd1) or by mutations in d4z4 chromatin modifiers such as structural maintenance of chromosomes hinge domain containing 1 (fshd2). these two genotypes share a phenotype characterized by progressive and often asymmetric muscle weakening and atrophy, and common epigenetic alterations of the d4z4 repeat. all together, these epigenetic changes converge the two genetic forms into one disease and explain the derepression of the dux4 gene, which is otherwise kept epigenetically silent in skeletal muscle. dux4 is consistently transcriptionally upregulated in fshd1 and fshd2 skeletal muscle cells where it is believed to exercise a toxic effect. here we provide a review of the recent literature describing the progress in understanding the complex genetic and epigenetic architecture of fshd, with a focus on one of the consequences that these epigenetic changes inflict, the dux4-induced immune deregulation cascade. moreover, we review the latest therapeutic strategies, with particular attention to the potential of epigenetic correction of the fshd locus.”
Cortijo, S., Wardenaar, R., Colomé-Tatché, M., Gilly, A., Etcheverry, M., Labadie, K., … Johannes, F.. (2014). Mapping the epigenetic basis of complex traits. Science
Plain numerical DOI: 10.1126/science.1248127
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“Quantifying the impact of heritable epigenetic variation on complex traits is an emerging challenge in population genetics. here, we analyze a population of isogenic arabidopsis lines that segregate experimentally induced dna methylation changes at hundreds of regions across the genome. we demonstrate that several of these differentially methylated regions (dmrs) act as bona fide epigenetic quantitative trait loci (qtlepi), accounting for 60 to 90% of the heritability for two complex traits, flowering time and primary root length. these qtlepi are reproducible and can be subjected to artificial selection. many of the experimentally induced dmrs are also variable in natural populations of this species and may thus provide an epigenetic basis for darwinian evolution independently of dna sequence changes.”
Ledezma, D. K., Balakrishnan, P. B., Cano-Mejia, J., Sweeney, E. E., Hadley, M., Bollard, C. M., … Fernandes, R.. (2020). Indocyanine green-nexturastat A-PLGA nanoparticles combine photothermal and epigenetic therapy for melanoma. Nanomaterials
Plain numerical DOI: 10.3390/nano10010161
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“In this study, we describe poly (lactic-co-glycolic) acid (plga)-based nanoparticles that combine photothermal therapy (ptt) with epigenetic therapy for melanoma. specifically, we co-encapsulated indocyanine green (icg), a ptt agent, and nexturastat a (nexta), an epigenetic drug within plga nanoparticles (icg-nexta-plga; inaps). we hypothesized that combining ptt with epigenetic therapy elicits favorable cytotoxic and immunomodulatory responses that result in improved survival in melanoma-bearing mice. we utilized a nanoemulsion synthesis scheme to co-encapsulate icg and nexta within stable and monodispersed inaps. the inaps exhibited concentration-dependent and near-infrared (nir) laser power-dependent photothermal heating characteristics, and functioned as effective single-use agents for ptt of melanoma cells in vitro. the inaps functioned as e_ective epigenetic therapy agents by inhibiting the expression of pan-histone deacetylase (hdac) and hdac6-specific activity in melanoma cells in vitro. when used for both ptt and epigenetic therapy in vitro, the inaps increased the expression of co-stimulatory molecules and major histocompatibility complex (mhc) class i in melanoma cells relative to controls. these advantages persisted in vivo in a syngeneic murine model of melanoma, where the combination therapy slowed tumor progression and improved median survival. these findings demonstrate the potential of inaps as agents of ptt and epigenetic therapy for melanoma.”
Lu, Y., Brommer, B., Tian, X., Krishnan, A., Meer, M., Wang, C., … Sinclair, D. A.. (2020). Reprogramming to recover youthful epigenetic information and restore vision. Nature
Plain numerical DOI: 10.1038/s41586-020-2975-4
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“Ageing is a degenerative process that leads to tissue dysfunction and death. a proposed cause of ageing is the accumulation of epigenetic noise that disrupts gene expression patterns, leading to decreases in tissue function and regenerative capacity1–3. changes to dna methylation patterns over time form the basis of ageing clocks4, but whether older individuals retain the information needed to restore these patterns—and, if so, whether this could improve tissue function—is not known. over time, the central nervous system (cns) loses function and regenerative capacity5–7. using the eye as a model cns tissue, here we show that ectopic expression of oct4 (also known as pou5f1), sox2 and klf4 genes (osk) in mouse retinal ganglion cells restores youthful dna methylation patterns and transcriptomes, promotes axon regeneration after injury, and reverses vision loss in a mouse model of glaucoma and in aged mice. the beneficial effects of osk-induced reprogramming in axon regeneration and vision require the dna demethylases tet1 and tet2. these data indicate that mammalian tissues retain a record of youthful epigenetic information—encoded in part by dna methylation—that can be accessed to improve tissue function and promote regeneration in vivo.”
Deutschmeyer, V. E., & Richter, A. M.. (2020). The ZAR1 protein in cancer; from epigenetic silencing to functional characterisation and epigenetic therapy of tumour suppressors. Biochimica et Biophysica Acta – Reviews on Cancer
Plain numerical DOI: 10.1016/j.bbcan.2020.188417
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“ZAR1, zygote arrest 1, is a zinc finger protein (c-terminus), which was initially identified in mouse oocytes. later it was found that its expression is present in various human tissues e.g. lung and kidney. interestingly, it was observed that in various tumour types the zar1 transcript is missing due to hypermethylation of its cpg island promoter, but not zar2. since methylation of the zar1 promoter is described as a frequent event in tumourigenesis, zar1 could serve as a useful diagnostic marker in cancer screens. zar1 was described as a useful prognostic/diagnostic cancer marker for lung cancer, kidney cancer, melanoma and possibly liver carcinoma. furthermore, zar1 was reactivated as a tumour suppressor by epigenetic therapy using crispr-dcas9 method. this method holds the potential to precisely target not only zar1 and reactivate tumour suppressors in a tailored cancer therapy. zar1 is highly conserved amongst vertebrates, especially its zinc finger, which is the relevant domain for its protein and rna binding ability. zar1 is implicated in various cellular mechanisms including regulation of oocyte/embryo development, cell cycle control and mrna binding, though little was known about the underlying mechanisms. zar1 was reported to regulate and activate translation through the binding to tcs translation control sequences in the 3’Utrs of its target mrna the kinase wee1. zar1 has a tumour suppressing function by inhibiting cell cycle progression. here we review the current literature on zar1 focusing on structural, functional and epigenetic aspects. characterising the cellular mechanisms that regulate the signalling pathways zar1 is involved in, could lead to a deeper understanding of tumour development and, furthermore, to new strategies in cancer treatment.”
Portela, A., & Esteller, M.. (2010). Epigenetic modifications and human disease. Nature Biotechnology
Plain numerical DOI: 10.1038/nbt.1685
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“Epigenetics is one of the most rapidly expanding fields in biology. the recent characterization of a human dna methylome at single nucleotide resolution, the discovery of the cpg island shores, the finding of new histone variants and modifications, and the unveiling of genome-wide nucleosome positioning maps highlight the accelerating speed of discovery over the past two years. increasing interest in epigenetics has been accompanied by technological breakthroughs that now make it possible to undertake large-scale epigenomic studies. these allow the mapping of epigenetic marks, such as dna methylation, histone modifications and nucleosome positioning, which are critical for regulating gene and noncoding rna expression. in turn, we are learning how aberrant placement of these epigenetic marks and mutations in the epigenetic machinery is involved in disease. thus, a comprehensive understanding of epigenetic mechanisms, their interactions and alterations in health and disease, has become a priority in biomedical research. © 2010 nature america, inc. all rights reserved.”
Sen, R., Garbati, M., Bryant, K., & Lu, Y.. (2021). Epigenetic mechanisms influencing COVID-19. Genome
Plain numerical DOI: 10.1139/gen-2020-0135
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“The covid-19 pandemic is one of the most significant public health threats in recent history and has impacted the lives of almost everyone worldwide. epigenetic mechanisms contribute to many aspects of the sars-cov-2 replication cycle, including expression levels of viral receptor ace2, expression of cytokine genes as part of the host immune response, and the implication of various histone modifications in several aspects of covid-19. sars-cov-2 proteins physically associate with many different host proteins over the course of infection, and notably there are several interactions between viral proteins and epigenetic enzymes such as hdacs and bromodomain-containing proteins as shown by correlation-based studies. the many contributions of epigenetic mechanisms to the viral life cycle and the host immune response to infection have resulted in epigenetic factors being identified as emerging biomarkers for covid-19, and project epigenetic modifiers as promising therapeutic targets to combat covid-19. this review article highlights the major epigenetic pathways at play during covid-19 disease and discusses ongoing clinical trials that will hopefully contribute to slowing the spread of sars-cov-2.”
Zhuo, C., Yao, Y., Xu, Y., Liu, C., Chen, M., Ji, F., … Chen, C.. (2019). Schizophrenia and gut-flora related epigenetic factors. Progress in Neuro-Psychopharmacology and Biological Psychiatry
Plain numerical DOI: 10.1016/j.pnpbp.2018.11.005
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“Background: schizophrenia (sz) is a complex psychiatric disorder and the exact mechanisms that underpin sz remain poorly understood despite decades of research. genetic, epigenetic, and environmental factors are all considered to play a role. the importance of gut flora and its influence on the central nervous system has been recognized in recent years. we hypothesize that gut flora may be a converging point where environmental factors interact with epigenetic factors and contribute to sz pathogenesis. aim: to summarize the current understanding of genetic and epigenetic factors and the possible involvement of gut flora in the pathogenesis of schizophrenia. results: we searched pubmed and medline with a combination of the key words schizophrenia, microbiome, epigenetic factors to identify studies of genetic and epigenetic factors in the pathogenesis of schizophrenia. numerous genes that encode key proteins in neuronal signaling pathways have been linked to sz. epigenetic modifications, particularly, methylation and acetylation profiles, have been found to differ in individuals that present with sz from those that don’t. gut flora may affect epigenetic modifications by regulation of key metabolic pathway molecules, including methionine, florate, biotin, and metabolites that are acetyl group donors. despite a lack of direct studies on the subject, it is possible that gut flora may influence genetic and epigenetic expression and thereby contribute to the pathogenesis of sz. conclusion: gut flora is sensitive to both internal and environmental stimuli and the synthesis of some key molecules that participate in the epigenetic modulation of gene expression. therefore, it is possible that gut flora is a converging point where environmental factors interact with genetic and epigenetic factors in the pathogenesis of sz.”
Segers, V. F. M., Gevaert, A. B., Boen, J. R. A., Van Craenenbroeck, E. M., & De Keulenaer, G. W.. (2019). Epigenetic regulation of intercellular communication in the heart. American Journal of Physiology – Heart and Circulatory Physiology
Plain numerical DOI: 10.1152/ajpheart.00038.2019
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“Epigenetic regulation of intercellular communication in the heart. am j physiol heart circ physiol 316: h1417–h1425, 2019. first published april 5, 2019; doi:10.1152/ajpheart.00038.2019.—the myocardium is a highly structured tissue consisting of different cell types including cardiomyocytes, endothelial cells, fibroblasts, smooth muscle cells, inflammatory cells, and stem cells. microvascular endothelial cells are the most abundant cell type in the myocardium and play crucial roles during cardiac development, in normal adult myocardium, and during myocardial diseases such as heart failure. in the last decade, epigenetic changes have been described regulating cellular function in almost every cell type in the organism. here, we review recent evidence on different epigenetic changes that regulate intercellular communication in normal myocardium and during myocardial diseases, including cardiac remodeling. epigenetic changes influence many intercellular communication signaling systems, including the nitric oxide, angiotensin, and endothelin signaling systems. in this review, we go beyond discussing classic endothelial function (for instance nitric oxide secretion) and will discuss epigenetic regulation of intercellular communication.”
Serrano-Gomez, S. J., Maziveyi, M., & Alahari, S. K.. (2016). Regulation of epithelial-mesenchymal transition through epigenetic and post-translational modifications. Molecular Cancer
Plain numerical DOI: 10.1186/s12943-016-0502-x
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“The epithelial to mesenchymal transition (emt) is a biological process in which a non-motile epithelial cell changes to a mesenchymal phenotype with invasive capacities. this phenomenon has been well documented in multiple biological processes including embryogenesis, fibrosis, tumor progression and metastasis. the hallmark of emt is the loss of epithelial surface markers, most notably e-cadherin, and the acquisition of mesenchymal markers including vimentin and n-cadherin. the downregulation of e-cadherin during emt can be mediated by its transcriptional repression through the binding of emt transcription factors (emt-tfs) such as snail, slug and twist to e-boxes present in the e-cadherin promoter. additionally, emt-tfs can also cooperate with several enzymes to repress the expression of e-cadherin and regulate emt at the epigenetic and post- translational level. in this review, we will focus on epigenetic and post- translational modifications that are important in emt. in addition, we will provide an overview of the various therapeutic approaches currently being investigated to undermine emt and hence, the metastatic progression of cancer as well.”
Bagot, R. C., Labonté, B., Peña, C. J., & Nestler, E. J.. (2014). Epigenetic signaling in psychiatric disorders: Stress and depression. Dialogues in Clinical Neuroscience
Plain numerical DOI: 10.31887/dcns.2014.16.3/rbagot
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“Psychiatric disorders are complex multifactorial disorders involving chronic alterations in neural circuit structure and function. while genetic factors play a role in the etiology of disorders such as depression, addiction, and schizophrenia, relatively high rates of discordance among identical twins clearly point to the importance of additional factors. environmental factors, such as stress, play a major role in the psychiatric disorders by inducing stable changes in gene expression, neural circuit function, and ultimately behavior. insults at the developmental stage and in adulthood appear to induce distinct maladaptations. increasing evidence indicates that these sustained abnormalities are maintained by epigenetic modifications in specific brain regions. indeed, transcriptional dysregulation and associated aberrant epigenetic regulation is a unifying theme in psychiatric disorders. aspects of depression can be modeled in animals by inducing disease-like states through environmental manipulations, and these studies can provide a more general understanding of epigenetic mechanisms in psychiatric disorders. understanding how environmental factors recruit the epigenetic machinery in animal models is providing new insights into disease mechanisms in humans.”
Zhang, P., & Zhang, M.. (2020). Epigenetic alterations and advancement of treatment in peripheral T-cell lymphoma. Clinical Epigenetics
Plain numerical DOI: 10.1186/s13148-020-00962-x
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“Peripheral t-cell lymphoma (ptcl) is a rare and heterogeneous group of clinically aggressive diseases associated with poor prognosis. except for alk + anaplastic large-cell lymphoma (alcl), most peripheral t-cell lymphomas are highly malignant and have an aggressive disease course and poor clinical outcomes, with a poor remission rate and frequent relapse after first-line treatment. aberrant epigenetic alterations play an important role in the pathogenesis and development of specific types of peripheral t-cell lymphoma, including the regulation of the expression of genes and signal transduction. the most common epigenetic alterations are dna methylation and histone modification. histone modification alters the level of gene expression by regulating the acetylation status of lysine residues on the promoter surrounding histones, often leading to the silencing of tumour suppressor genes or the overexpression of proto-oncogenes in lymphoma. dna methylation refers to cpg islands, generally leading to tumour suppressor gene transcriptional silencing. genetic studies have also shown that some recurrent mutations in genes involved in the epigenetic machinery, including tet2, idh2-r172, dnmt3a, rhoa, cd28, idh2, tet2, mll2, kmt2a, kdm6a, crebbp, and ep300, have been observed in cases of ptcl. the aberrant expression of mirnas has also gradually become a diagnostic biomarker. these provide a reasonable molecular mechanism for epigenetic modifying drugs in the treatment of ptcl. as epigenetic drugs implicated in lymphoma have been continually reported in recent years, many new ideas for the diagnosis, treatment, and prognosis of ptcl originate from epigenetics in recent years. novel epigenetic-targeted drugs have shown good tolerance and therapeutic effects in the treatment of peripheral t-cell lymphoma as monotherapy or combination therapy. nccn clinical practice guidelines also recommended epigenetic drugs for ptcl subtypes as second-line therapy. epigenetic mechanisms provide new directions and therapeutic strategies for the research and treatment of peripheral t-cell lymphoma. therefore, this paper mainly reviews the epigenetic changes in the pathogenesis of peripheral t-cell lymphoma and the advancement of epigenetic-targeted drugs in the treatment of peripheral t-cell lymphoma (ptcl).”
Wang, C., Wang, L., Ding, Y., Lu, X., Zhang, G., Yang, J., … Xu, L.. (2017). LncRNA structural characteristics in epigenetic regulation. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms18122659
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“The rapid development of new generation sequencing technology has deepened the understanding of genomes and functional products. rna-sequencing studies in mammals show that approximately 85% of the dna sequences have rna products, for which the length greater than 200 nucleotides (nt) is called long non-coding rnas (lncrna). lncrnas now have been shown to play important epigenetic regulatory roles in key molecular processes, such as gene expression, genetic imprinting, histone modification, chromatin dynamics, and other activities by forming specific structures and interacting with all kinds of molecules. this paper mainly discusses the correlation between the structure and function of lncrnas with the recent progress in epigenetic regulation, which is important to the understanding of the mechanism of lncrnas in physiological and pathological processes.”
Wagner, K. E., McCormick, J. B., Barns, S., Carney, M., Middleton, F. A., & Hicks, S. D.. (2020). Parent Perspectives Towards Genetic and Epigenetic Testing for Autism Spectrum Disorder. Journal of Autism and Developmental Disorders
Plain numerical DOI: 10.1007/s10803-019-03990-6
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“Examining community views on genetic/epigenetic research allows collaborative technology development. parent perspectives toward genetic/epigenetic testing for autism spectrum disorder (asd) are not well-studied. parents of children with asd (n = 131), non-asd developmental delay (n = 39), and typical development (n = 74) completed surveys assessing genetic/epigenetic knowledge, genetic/epigenetic concerns, motives for research participation, and attitudes/preferences toward asd testing. most parents (96%) were interested in saliva-based molecular testing for asd. some had concerns about privacy (14%) and insurance-status (10%). none (0%) doubted scientific evidence behind genetic/epigenetic testing. most reported familiarity with genetics (88%), but few understood differences from epigenetics (19%). child developmental status impacted insurance concerns (p = 0.01). there is broad parent interest in a genetic/epigenetic test for asd. it will be crucial to carefully consider and address bioethical issues surrounding this sensitive topic while developing such technology.”
Portela, A., & Esteller, M.. (2010). Epigenetic modifications and human disease. Nature Biotechnology
Plain numerical DOI: 10.1038/nbt.1685
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“Epigenetics is one of the most rapidly expanding fields in biology. the recent characterization of a human dna methylome at single nucleotide resolution, the discovery of the cpg island shores, the finding of new histone variants and modifications, and the unveiling of genome-wide nucleosome positioning maps highlight the accelerating speed of discovery over the past two years. increasing interest in epigenetics has been accompanied by technological breakthroughs that now make it possible to undertake large-scale epigenomic studies. these allow the mapping of epigenetic marks, such as dna methylation, histone modifications and nucleosome positioning, which are critical for regulating gene and noncoding rna expression. in turn, we are learning how aberrant placement of these epigenetic marks and mutations in the epigenetic machinery is involved in disease. thus, a comprehensive understanding of epigenetic mechanisms, their interactions and alterations in health and disease, has become a priority in biomedical research. © 2010 nature america, inc. all rights reserved.”
Baizabal, J. M., Mistry, M., García, M. T., Gómez, N., Olukoya, O., Tran, D., … Harwell, C. C.. (2018). The Epigenetic State of PRDM16-Regulated Enhancers in Radial Glia Controls Cortical Neuron Position. Neuron
Plain numerical DOI: 10.1016/j.neuron.2018.04.033
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“The epigenetic landscape is dynamically remodeled during neurogenesis. however, it is not understood how chromatin modifications in neural stem cells instruct the formation of complex structures in the brain. we report that the histone methyltransferase prdm16 is required in radial glia to regulate lineage-autonomous and stage-specific gene expression programs that control number and position of upper layer cortical projection neurons. prdm16 regulates the epigenetic state of transcriptional enhancers to activate genes involved in intermediate progenitor cell production and repress genes involved in cell migration. the histone methyltransferase domain of prdm16 is necessary in radial glia to promote cortical neuron migration through transcriptional silencing. we show that repression of the gene encoding the e3 ubiquitin ligase pdzrn3 by prdm16 determines the position of upper layer neurons. these findings provide insights into how epigenetic control of transcriptional enhancers in radial glial determines the organization of the mammalian cerebral cortex. baizabal et al. uncover an epigenetic mechanism that encodes the number and position of upper layer cortical neurons in the activity of transcriptional enhancers in neural stem cells.”
Yoon, S. H., Choi, J., Lee, W. J., & Do, J. T.. (2020). Genetic and Epigenetic Etiology Underlying Autism Spectrum Disorder. Journal of Clinical Medicine
Plain numerical DOI: 10.3390/jcm9040966
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“Autism spectrum disorder (asd) is a pervasive neurodevelopmental disorder characterized by difficulties in social interaction, language development delays, repeated body movements, and markedly deteriorated activities and interests. environmental factors, such as viral infection, parental age, and zinc deficiency, can be plausible contributors to asd susceptibility. as asd is highly heritable, genetic risk factors involved in neurodevelopment, neural communication, and social interaction provide important clues in explaining the etiology of asd. accumulated evidence also shows an important role of epigenetic factors, such as dna methylation, histone modification, and noncoding rna, in asd etiology. in this review, we compiled the research published to date and described the genetic and epigenetic epidemiology together with environmental risk factors underlying the etiology of the different phenotypes of asd.”
Xavier, P. L. P., Müller, S., & Fukumasu, H.. (2020). Epigenetic Mechanisms in Canine Cancer. Frontiers in Oncology
Plain numerical DOI: 10.3389/fonc.2020.591843
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“A plethora of data has highlighted the role of epigenetics in the development of cancer. initiation and progression of different cancer types are associated with a variety of changes of epigenetic mechanisms, including aberrant dna methylation, histone modifications, and mirna expression. at the same time, advances in the available epigenetic tools allow to investigate and reverse these epigenetic changes and form the basis for the development of anticancer drugs in human oncology. although human and canine cancer shares several common features, only recently that studies emerged investigating the epigenetic landscape in canine cancer and applying epigenetic modulators to canine cancer. this review focuses on the existing studies involving epigenetic changes in different types of canine cancer and the use of small-molecule inhibitors in canine cancer cells.”
Alashkar Alhamwe, B., Miethe, S., Pogge von Strandmann, E., Potaczek, D. P., & Garn, H.. (2020). Epigenetic Regulation of Airway Epithelium Immune Functions in Asthma. Frontiers in Immunology
Plain numerical DOI: 10.3389/fimmu.2020.01747
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“Asthma is a chronic inflammatory disease of the respiratory tract characterized by recurrent breathing problems resulting from airway obstruction and hyperresponsiveness. human airway epithelium plays an important role in the initiation and control of the immune responses to different types of environmental factors contributing to asthma pathogenesis. using pattern recognition receptors airway epithelium senses external stimuli, such as allergens, microbes, or pollutants, and subsequently secretes endogenous danger signaling molecules alarming and activating dendritic cells. hence, airway epithelial cells not only mediate innate immune responses but also bridge them with adaptive immune responses involving t and b cells that play a crucial role in the pathogenesis of asthma. the effects of environmental factors on the development of asthma are mediated, at least in part, by epigenetic mechanisms. those comprise classical epigenetics including dna methylation and histone modifications affecting transcription, as well as micrornas influencing translation. the common feature of such mechanisms is that they regulate gene expression without affecting the nucleotide sequence of the genomic dna. epigenetic mechanisms play a pivotal role in the regulation of different cell populations involved in asthma pathogenesis, with the remarkable example of t cells. recently, however, there is increasing evidence that epigenetic mechanisms are also crucial for the regulation of airway epithelial cells, especially in the context of epigenetic transfer of environmental effects contributing to asthma pathogenesis. in this review, we summarize the accumulating evidence for this very important aspect of airway epithelial cell pathobiology.”
Ciccarone, F., Zampieri, M., & Caiafa, P.. (2017). PARP1 orchestrates epigenetic events setting up chromatin domains. Seminars in Cell and Developmental Biology
Plain numerical DOI: 10.1016/j.semcdb.2016.11.010
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“Epigenetic events include reversible modifications of dna and histone tails driving chromatin organization and thus transcription. the epigenetic regulation is a highly integrated process underlying the plasticity of the genomic information both in the context of complex physiological and pathological processes. the global regulatory aspects of epigenetic events are largely unknown. parylation and parp1 are recently emerging as multi-level regulatory effectors that modulate the topology of chromatin by orchestrating very different processes. this review focuses in particular on the role of parp1 in epigenetics, trying to build a comprehensive perspective of its involvement in the regulation of epigenetic modifications of histones and dna, contextualizing it in the global organization of chromatin domains in the nucleus.”
Esposito, M., & Sherr, G. L.. (2019). Epigenetic modifications in Alzheimer’s neuropathology and therapeutics. Frontiers in Neuroscience
Plain numerical DOI: 10.3389/fnins.2019.00476
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“Transcriptional activation is a highly synchronized process in eukaryotes that requires a series of cis- and trans-acting elements at promoter regions. epigenetic modifications, such as chromatin remodeling, histone acetylation/deacetylation, and methylation, have frequently been studied with regard to transcriptional regulation/dysregulation. recently however, it has been determined that implications in epigenetic modification seem to expand into various neurodegenerative disease mechanisms. impaired learning and memory deterioration are cognitive dysfunctions often associated with a plethora of neurodegenerative diseases, including alzheimer’s disease. through better understanding of the epigenetic mechanisms underlying these dysfunctions, new epigenomic therapeutic targets, such as histone deacetylases, are being explored. here we review the intricate packaging of dna in eukaryotic cells, and the various modifications in epigenetic mechanisms that are now linked to the neuropathology and the progression of alzheimer’s disease (ad), as well as potential therapeutic interventions.”
Mac, M., & Moody, C. A.. (2020). Epigenetic regulation of the human papillomavirus life cycle. Pathogens
Plain numerical DOI: 10.3390/pathogens9060483
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“Persistent infection with certain types of human papillomaviruses (hpvs), termed high risk, presents a public health burden due to their association with multiple human cancers, including cervical cancer and an increasing number of head and neck cancers. despite the development of prophylactic vaccines, the incidence of hpv-associated cancers remains high. in addition, no vaccine has yet been licensed for therapeutic use against pre-existing hpv infections and hpv-associated diseases. although persistent hpv infection is the major risk factor for cancer development, additional genetic and epigenetic alterations are required for progression to the malignant phenotype. unlike genetic mutations, the reversibility of epigenetic modifications makes epigenetic regulators ideal therapeutic targets for cancer therapy. this review article will highlight the recent advances in the understanding of epigenetic modifications associated with hpv infections, with a particular focus on the role of these epigenetic changes during different stages of the hpv life cycle that are closely associated with activation of dna damage response pathways.”
Lu, Y., Brommer, B., Tian, X., Krishnan, A., Meer, M., Wang, C., … Sinclair, D. A.. (2020). Reprogramming to recover youthful epigenetic information and restore vision. Nature
Plain numerical DOI: 10.1038/s41586-020-2975-4
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“Ageing is a degenerative process that leads to tissue dysfunction and death. a proposed cause of ageing is the accumulation of epigenetic noise that disrupts gene expression patterns, leading to decreases in tissue function and regenerative capacity1–3. changes to dna methylation patterns over time form the basis of ageing clocks4, but whether older individuals retain the information needed to restore these patterns—and, if so, whether this could improve tissue function—is not known. over time, the central nervous system (cns) loses function and regenerative capacity5–7. using the eye as a model cns tissue, here we show that ectopic expression of oct4 (also known as pou5f1), sox2 and klf4 genes (osk) in mouse retinal ganglion cells restores youthful dna methylation patterns and transcriptomes, promotes axon regeneration after injury, and reverses vision loss in a mouse model of glaucoma and in aged mice. the beneficial effects of osk-induced reprogramming in axon regeneration and vision require the dna demethylases tet1 and tet2. these data indicate that mammalian tissues retain a record of youthful epigenetic information—encoded in part by dna methylation—that can be accessed to improve tissue function and promote regeneration in vivo.”
Berson, A., Nativio, R., Berger, S. L., & Bonini, N. M.. (2018). Epigenetic Regulation in Neurodegenerative Diseases. Trends in Neurosciences
Plain numerical DOI: 10.1016/j.tins.2018.05.005
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“Mechanisms of epigenetic regulation, including dna methylation, chromatin remodeling, and histone post-translational modifications, are involved in multiple aspects of neuronal function and development. recent discoveries have shed light on critical functions of chromatin in the aging brain, with an emerging realization that the maintenance of a healthy brain relies heavily on epigenetic mechanisms. here, we present recent advances, with a focus on histone modifications and the implications for several neurodegenerative diseases including alzheimer’s disease (ad), huntington’s disease (hd), and amyotrophic lateral sclerosis (als). we highlight common and unique epigenetic mechanisms among these situations and point to emerging therapeutic approaches.”
Grimaldi, V., De Pascale, M. R., Zullo, A., Soricelli, A., Infante, T., Mancini, F. P., & Napoli, C.. (2017). Evidence of epigenetic tags in cardiac fibrosis. Journal of Cardiology
Plain numerical DOI: 10.1016/j.jjcc.2016.10.004
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“In cardiac fibrosis, following an injury or a stress, non-functional fibrotic tissue substitutes normal myocardium, thus leading to progressive heart failure. activated fibroblasts are principal determinants of cardiac fibrosis by producing excessive fibrotic extracellular matrix and causing hypertrophy of cardiomyocytes. epigenetic changes, such as dna methylation, histone modifications, and mirnas have been involved in these mechanisms. therefore, there is a strong interest in reverting such epigenetic transformations in order to arrest myocardial fibrotic degeneration. demethylating agents, such as 5-aza-2′-deoxycytidine, 5-azacytidine, some selective histone deacetylase inhibitors, including mocetinostat, trichostatin a, and mpt0e014, have a direct action on important inducers of cardiac fibrosis. also dietary compounds, such as resveratrol, can suppress the differentiation of fibroblasts to myofibroblasts. although in vivo and in vitro studies suggest specific epigenetic therapies to treat cardiac fibrosis, the related clinical trials are still lacking. a better understanding of the epigenetic effects of dietary compounds (e.g. curcumin and green tea catechins) on the onset and progression of cardiac fibrosis, will allow the identification of protective dietary patterns and/or the generation of novel potential epidrugs.”
Yamamuro, C., Zhu, J. K., & Yang, Z.. (2016). Epigenetic Modifications and Plant Hormone Action. Molecular Plant
Plain numerical DOI: 10.1016/j.molp.2015.10.008
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“The action of phytohormones in plants requires the spatiotemporal regulation of their accumulation and responses at various levels. recent studies reveal an emerging relationship between the function of phytohormones and epigenetic modifications. in particular, evidence suggests that auxin biosynthesis, transport, and signal transduction is modulated by micrornas and epigenetic factors such as histone modification, chromatin remodeling, and dna methylation. furthermore, some phytohormones have been shown to affect epigenetic modifications. these findings are shedding light on the mode of action of phytohormones and are opening up a new avenue of research on phytohormones as well as on the mechanisms regulating epigenetic modifications.”
Faleiro, I., Leão, R., Binnie, A., de Mello, R. A., Maia, A. T., & Castelo-Branco, P.. (2017). Epigenetic therapy in urologic cancers: An update on clinical trials. Oncotarget
Plain numerical DOI: 10.18632/oncotarget.14226
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“Epigenetic dysregulation is one of many factors that contribute to cancer development and progression. numerous epigenetic alterations have been identified in urologic cancers including histone modifications, dna methylation changes, and microrna expression. since these changes are reversible, efforts are being made to develop epigenetic drugs that restore the normal epigenetic patterns of cells, and many clinical trials are already underway to test their clinical potential. in this review we analyze multiple clinical trials (n=51) that test the efficacy of these drugs in patients with urologic cancers. the most frequently used epigenetic drugs were histone deacetylase inhibitors followed by antisense oligonucleotides, dna methyltransferase inhibitors and histone demethylase inhibitors, the last of which are only being tested in prostate cancer. in more than 50% of the clinical trials considered, epigenetic drugs were used as part of combination therapy, which achieved the best results. the epigenetic regulation of some cancers is still matter of research but will undoubtedly open a window to new therapeutic approaches in the era of personalized medicine. the future of therapy for urological malignancies is likely to include multidrug regimens in which epigenetic modifying drugs will play an important role.”
Cortijo, S., Wardenaar, R., Colomé-Tatché, M., Gilly, A., Etcheverry, M., Labadie, K., … Johannes, F.. (2014). Mapping the epigenetic basis of complex traits. Science
Plain numerical DOI: 10.1126/science.1248127
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“Quantifying the impact of heritable epigenetic variation on complex traits is an emerging challenge in population genetics. here, we analyze a population of isogenic arabidopsis lines that segregate experimentally induced dna methylation changes at hundreds of regions across the genome. we demonstrate that several of these differentially methylated regions (dmrs) act as bona fide epigenetic quantitative trait loci (qtlepi), accounting for 60 to 90% of the heritability for two complex traits, flowering time and primary root length. these qtlepi are reproducible and can be subjected to artificial selection. many of the experimentally induced dmrs are also variable in natural populations of this species and may thus provide an epigenetic basis for darwinian evolution independently of dna sequence changes.”
Marioni, R. E., Shah, S., McRae, A. F., Ritchie, S. J., Muniz-Terrera, G., Harris, S. E., … Deary, I. J.. (2015). The epigenetic clock is correlated with physical and cognitive fitness in the Lothian Birth Cohort 1936. International Journal of Epidemiology
Plain numerical DOI: 10.1093/ije/dyu277
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“Background: the dna methylation-based ‘epigenetic clock’ correlates strongly with chronological age, but it is currently unclear what drives individual differences. we examine cross-sectional and longitudinal associations between the epigenetic clock and four mortality-linked markers of physical and mental fitness: lung function, walking speed, grip strength and cognitive ability. methods: dna methylation-based age acceleration (residuals of the epigenetic clock estimate regressed on chronological age) were estimated in the lothian birth cohort 1936 at ages 70 (n=920), 73 (n=299) and 76 (n=273) years. general cognitive ability, walking speed, lung function and grip strength were measured concurrently. cross-sectional correlations between age acceleration and the fitness variables were calculated. longitudinal change in the epigenetic clock estimates and the fitness variables were assessed via linear mixed models and latent growth curves. epigenetic age acceleration at age 70 was used as a predictor of longitudinal change in fitness. epigenome-wide association studies (ewass) were conducted on the four fitness measures. results: cross-sectional correlations were significant between greater age acceleration and poorer performance on the lung function, cognition and grip strength measures (r range: -0.07 to -0.05, p range: 9.7 x 10-3 to 0.024). all of the fitness variables declined over time but age acceleration did not correlate with subsequent change over 6 years. there were no ewas hits for the fitness traits. conclusions: markers of physical and mental fitness are associated with the epigenetic clock (lower abilities associated with age acceleration). however, age acceleration does not associate with decline in these measures, at least over a relatively short follow-up.”
Zhuang, J., Huo, Q., Yang, F., & Xie, N.. (2020). Perspectives on the Role of Histone Modification in Breast Cancer Progression and the Advanced Technological Tools to Study Epigenetic Determinants of Metastasis. Frontiers in Genetics
Plain numerical DOI: 10.3389/fgene.2020.603552
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“Metastasis is a complex process that involved in various genetic and epigenetic alterations during the progression of breast cancer. recent evidences have indicated that the mutation in the genome sequence may not be the key factor for increasing metastatic potential. epigenetic changes were revealed to be important for metastatic phenotypes transition with the development in understanding the epigenetic basis of breast cancer. herein, we aim to present the potential epigenetic drivers that induce dysregulation of genes related to breast tumor growth and metastasis, with a particular focus on histone modification including histone acetylation and methylation. the pervasive role of major histone modification enzymes in cancer metastasis such as histone acetyltransferases (hat), histone deacetylases (hdacs), dna methyltransferases (dnmts), and so on are demonstrated and further discussed. in addition, we summarize the recent advances of next-generation sequencing technologies and microfluidic-based devices for enhancing the study of epigenomic landscapes of breast cancer. this feature also introduces several important biotechnologists for identifying robust epigenetic biomarkers and enabling the translation of epigenetic analyses to the clinic. in summary, a comprehensive understanding of epigenetic determinants in metastasis will offer new insights of breast cancer progression and can be achieved in the near future with the development of innovative epigenomic mapping tools.”
Oh, G., Ebrahimi, S., Wang, S. C., Cortese, R., Kaminsky, Z. A., Gottesman, I. I., … Petronis, A.. (2016). Epigenetic assimilation in the aging human brain. Genome Biology
Plain numerical DOI: 10.1186/s13059-016-0946-8
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“Background: epigenetic drift progressively increases variation in dna modification profiles of aging cells, but the finale of such divergence remains elusive. in this study, we explored the dynamics of dna modification and transcription in the later stages of human life. results: we find that brain tissues of older individuals (>75 years) become more similar to each other, both epigenetically and transcriptionally, compared with younger individuals. inter-individual epigenetic assimilation is concurrent with increasing similarity between the cerebral cortex and the cerebellum, which points to potential brain cell dedifferentiation. dna modification analysis of twins affected with alzheimer’s disease reveals a potential for accelerated epigenetic assimilation in neurodegenerative disease. we also observe loss of boundaries and merging of neighboring dna modification and transcriptomic domains over time. conclusions: age-dependent epigenetic divergence, paradoxically, changes to convergence in the later stages of life. the newly described phenomena of epigenetic assimilation and tissue dedifferentiation may help us better understand the molecular mechanisms of aging and the origins of diseases for which age is a risk factor.”
Pastore, A., Gaiti, F., Lu, S. X., Brand, R. M., Kulm, S., Chaligne, R., … Landau, D. A.. (2019). Corrupted coordination of epigenetic modifications leads to diverging chromatin states and transcriptional heterogeneity in CLL. Nature Communications
Plain numerical DOI: 10.1038/s41467-019-09645-5
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“Cancer evolution is fueled by epigenetic as well as genetic diversity. in chronic lymphocytic leukemia (cll), intra-tumoral dna methylation (dname) heterogeneity empowers evolution. here, to comprehensively study the epigenetic dimension of cancer evolution, we integrate dname analysis with histone modification mapping and single cell analyses of rna expression and dname in 22 primary cll and 13 healthy donor b lymphocyte samples. our data reveal corrupted coherence across different layers of the cll epigenome. this manifests in decreased mutual information across epigenetic modifications and gene expression attributed to cell-to-cell heterogeneity. disrupted epigenetic-transcriptional coordination in cll is also reflected in the dysregulation of the transcriptional output as a function of the combinatorial chromatin states, including incomplete polycomb-mediated gene silencing. notably, we observe unexpected co-mapping of typically mutually exclusive activating and repressing histone modifications, suggestive of intra-tumoral epigenetic diversity. thus, cll epigenetic diversification leads to decreased coordination across layers of epigenetic information, likely reflecting an admixture of cells with diverging cellular identities.”
Degerman, S., Josefsson, M., Nordin Adolfsson, A., Wennstedt, S., Landfors, M., Haider, Z., … Adolfsson, R.. (2017). Maintained memory in aging is associated with young epigenetic age. Neurobiology of Aging
Plain numerical DOI: 10.1016/j.neurobiolaging.2017.02.009
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“Epigenetic alterations during aging have been proposed to contribute to decline in physical and cognitive functions, and accelerated epigenetic aging has been associated with disease and all-cause mortality later in life. in this study, we estimated epigenetic age dynamics in groups with different memory trajectories (maintained high performance, average decline, and accelerated decline) over a 15-year period. epigenetic (dna-methylation [dnam]) age was assessed, and delta age (dnam age − chronological age) was calculated in blood samples at baseline (age: 55–65 years) and 15 years later in 52 age- and gender-matched individuals from the betula study in sweden. a lower delta dnam age was observed for those with maintained memory functions compared with those with average (p = 0.035) or accelerated decline (p = 0.037). moreover, separate analyses revealed that dnam age at follow-up, but not chronologic age, was a significant predictor of dementia (p = 0.019). our findings suggest that young epigenetic age contributes to maintained memory in aging.”
Bégin, P., & Nadeau, K. C.. (2014). Epigenetic regulation of asthma and allergic disease. Allergy, Asthma and Clinical Immunology
Plain numerical DOI: 10.1186/1710-1492-10-27
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“Epigenetics of asthma and allergic disease is a field that has expanded greatly in the last decade. previously thought only in terms of cell differentiation, it is now evident the epigenetics regulate many processes. with t cell activation, commitment toward an allergic phenotype is tightly regulated by dna methylation and histone modifications at the th2 locus control region. when normal epigenetic control is disturbed, either experimentally or by environmental exposures, th1/th2 balance can be affected. epigenetic marks are not only transferred to daughter cells with cell replication but they can also be inherited through generations. in animal models, with constant environmental pressure, epigenetically determined phenotypes are amplified through generations and can last up to 2 generations after the environment is back to normal. in this review on the epigenetic regulation of asthma and allergic diseases we review basic epigenetic mechanisms and discuss the epigenetic control of th2 cells. we then cover the transgenerational inheritance model of epigenetic traits and discuss how this could relate the amplification of asthma and allergic disease prevalence and severity through the last decades. finally, we discuss recent epigenetic association studies for allergic phenotypes and related environmental risk factors as well as potential underlying mechanisms for these associations. © 2014 bégin and nadeau; licensee biomed central ltd.”
Rugo, H. S., Jacobs, I., Sharma, S., Scappaticci, F., Paul, T. A., Jensen-Pergakes, K., & Malouf, G. G.. (2020). The Promise for Histone Methyltransferase Inhibitors for Epigenetic Therapy in Clinical Oncology: A Narrative Review. Advances in Therapy
Plain numerical DOI: 10.1007/s12325-020-01379-x
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“Epigenetic processes are essential for normal development and the maintenance of tissue-specific gene expression in mammals. changes in gene expression and malignant cellular transformation can result from disruption of epigenetic mechanisms, and global disruption in the epigenetic landscape is a key feature of cancer. the study of epigenetics in cancer has revealed that human cancer cells harbor both genetic alterations and epigenetic abnormalities that interplay at all stages of cancer development. unlike genetic mutations, epigenetic aberrations are potentially reversible through epigenetic therapy, providing a therapeutically relevant treatment option. histone methyltransferase inhibitors are emerging as an epigenetic therapy approach with great promise in the field of clinical oncology. the recent accelerated approval of the enhancer of zeste homolog 2 (ezh2; also known as histone-lysine n-methyltransferase ezh2) inhibitor tazemetostat for metastatic or locally advanced epithelioid sarcoma marks the first approval of such a compound for the treatment of cancer. many other histone methyltransferase inhibitors are currently in development, some of which are being tested in clinical studies. this review focuses on histone methyltransferase inhibitors, highlighting their potential in the treatment of cancer. we also discuss the role for such epigenetic drugs in overcoming epigenetically driven drug resistance mechanisms, and their value in combination with other therapeutic approaches such as immunotherapy.”
Cheng, Z., Zheng, L., & Almeida, F. A.. (2018). Epigenetic reprogramming in metabolic disorders: nutritional factors and beyond. Journal of Nutritional Biochemistry
Plain numerical DOI: 10.1016/j.jnutbio.2017.10.004
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“Environmental factors (e.g., malnutrition and physical inactivity) contribute largely to metabolic disorders including obesity, type 2 diabetes, cardiometabolic disease and nonalcoholic fatty liver diseases. the abnormalities in metabolic activity and pathways have been increasingly associated with altered dna methylation, histone modification and noncoding rnas, whereas lifestyle interventions targeting diet and physical activity can reverse the epigenetic and metabolic changes. here we review recent evidence primarily from human studies that links dna methylation reprogramming to metabolic derangements or improvements, with a focus on cross-tissue (e.g., the liver, skeletal muscle, pancreas, adipose tissue and blood samples) epigenetic markers, mechanistic mediators of the epigenetic reprogramming, and the potential of using epigenetic traits to predict disease risk and intervention response. the challenges in epigenetic studies addressing the mechanisms of metabolic diseases and future directions are also discussed and prospected.”
Kuznetsova, T., Prange, K. H. M., Glass, C. K., & de Winther, M. P. J.. (2020). Transcriptional and epigenetic regulation of macrophages in atherosclerosis. Nature Reviews Cardiology
Plain numerical DOI: 10.1038/s41569-019-0265-3
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“Monocytes and macrophages provide defence against pathogens and danger signals. these cells respond to stimulation in a fast and stimulus-specific manner by utilizing complex cascaded activation by lineage-determining and signal-dependent transcription factors. the complexity of the functional response is determined by interactions between triggered transcription factors and depends on the microenvironment and interdependent signalling cascades. dysregulation of macrophage phenotypes is a major driver of various diseases such as atherosclerosis, rheumatoid arthritis and type 2 diabetes mellitus. furthermore, exposure of monocytes, which are macrophage precursor cells, to certain stimuli can lead to a hypo-inflammatory tolerized phenotype or a hyper-inflammatory trained phenotype in a macrophage. in atherosclerosis, macrophages and monocytes are exposed to inflammatory cytokines, oxidized lipids, cholesterol crystals and other factors. all these stimuli induce not only a specific transcriptional response but also interact extensively, leading to transcriptional and epigenetic heterogeneity of macrophages in atherosclerotic plaques. targeting the epigenetic landscape of plaque macrophages can be a powerful therapeutic tool to modulate pro-atherogenic phenotypes and reduce the rate of plaque formation. in this review, we discuss the emerging role of transcription factors and epigenetic remodelling in macrophages in the context of atherosclerosis and inflammation, and provide a comprehensive overview of epigenetic enzymes and transcription factors that are involved in macrophage activation.”
Ewe, C. K., Torres Cleuren, Y. N., Flowers, S. E., Alok, G., Snell, R. G., & Rothman, J. H.. (2020). Natural cryptic variation in epigenetic modulation of an embryonic gene regulatory network. Proceedings of the National Academy of Sciences of the United States of America
Plain numerical DOI: 10.1073/pnas.1920343117
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“Gene regulatory networks (grns) that direct animal embryogenesis must respond to varying environmental and physiological conditions to ensure robust construction of organ systems. while grns are evolutionarily modified by natural genomic variation, the roles of epigenetic processes in shaping plasticity of grn architecture are not well understood. the endoderm grn in caenorhabditis elegans is initiated by the maternally supplied skn-1/nrf2 bzip transcription factor; however, the requirement for skn-1 in endoderm specification varies widely among distinct c. elegans wild isotypes, owing to rapid developmental system drift driven by accumulation of cryptic genetic variants. we report here that heritable epigenetic factors that are stimulated by transient developmental diapause also underlie cryptic variation in the requirement for skn-1 in endoderm development. this epigenetic memory is inherited from the maternal germline, apparently through a nuclear, rather than cytoplasmic, signal, resulting in a parent-of-origin effect (poe), in which the phenotype of the progeny resembles that of the maternal founder. the occurrence and persistence of poe varies between different parental pairs, perduring for at least 10 generations in one pair. this long-perduring poe requires piwi-interacting rna (pirna) function and the germline nuclear rna interference (rnai) pathway, as well as met-2 and set-32, which direct histone h3k9 trimethylation and drive heritable epigenetic modification. such nongenetic cryptic variation may provide a resource of additional phenotypic diversity through which adaptation may facilitate evolutionary changes and shape developmental regulatory systems.”
de Laval, B., Maurizio, J., Kandalla, P. K., Brisou, G., Simonnet, L., Huber, C., … Sieweke, M. H.. (2020). C/EBPβ-Dependent Epigenetic Memory Induces Trained Immunity in Hematopoietic Stem Cells. Cell Stem Cell
Plain numerical DOI: 10.1016/j.stem.2020.01.017
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“Hematopoietic stem cells (hscs) maintain life-long production of immune cells and can directly respond to infection, but sustained effects on the immune response remain unclear. we show that acute immune stimulation with lipopolysaccharide (lps) induced only transient changes in hsc abundance, composition, progeny, and gene expression, but persistent alterations in accessibility of specific myeloid lineage enhancers occurred, which increased responsiveness of associated immune genes to secondary stimulation. functionally, this was associated with increased myelopoiesis of pre-exposed hscs and improved innate immunity against the gram-negative bacterium p. aeruginosa. the accessible myeloid enhancers were enriched for c/ebpβ targets, and c/ebpβ deletion erased the long-term inscription of lps-induced epigenetic marks and gene expression. thus, short-term immune signaling can induce c/ebpβ-dependent chromatin accessibility, resulting in hsc-trained immunity, during secondary infection. this establishes a mechanism for how infection history can be epigenetically inscribed in hscs as an integral memory function of innate immunity.”
Morel, D., Almouzni, G., Soria, J. C., & Postel-Vinay, S.. (2017). Targeting chromatin defects in selected solid tumors based on oncogene addiction, synthetic lethality and epigenetic antagonism. Annals of Oncology
Plain numerical DOI: 10.1093/annonc/mdw552
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“Background: although the role of epigenetic abnormalities has been studied for several years in cancer genesis and development, epigenetic-targeting drugs have historically failed to demonstrate efficacy in solid malignancies. however, successful targeting of chromatin remodeling deficiencies, histone writers and histone reader alterations has been achieved very recently using biomarker-driven and mechanism-based approaches. epigenetic targeting is now one of the most active areas in drug development and could represent novel therapeutic opportunity for up to 25% of all solid tumors. material and methods: we reviewed preclinical and clinical studies that described epigenetic oncogenic addictions, synthetic lethal relationships or epigenetic antagonisms in chromatin regulators. experimental approaches, their clinical relevance and applicability, as well as corresponding on-going studies are described. results: the most successful approaches that have been clinically validated so far include the targeting of the brd4-nut fusion transcript in nut-midline carcinoma by bet (bromodomain extra-terminal) inhibitors, and the use of ezh2 (enhancer of zest homolog 2) inhibitors in smarcb1-deficient malignant rhabdoid tumors and smarca4-deficient ovarian small cell carcinomas. clinical validation is still required for other synthetic lethal relationships or epigenetic antagonisms, including those described between ezh2 inhibitors and deficiencies in components of the polycomb or swi/snf chromatin-remodeling complexes (including bap1, arid1a and pbrm1 subunits), as well as between the crebbp and ep300 histone acetylases. further, interplays between epigenetic modifiers and non-epigenetic cellular processes might be therapeutically exploited, and combinatorial strategies could be envisioned to overcome resistance or to sensitize cells to already approved drugs. conclusion: epigenetic-targeting drugs have historically failed proving efficacy in solid malignancies when used broadly, but novel mechanism-based approaches in molecularly selected patient populations have facilitated recent successes in proof-ofconcept studies in solid tumors. appropriate clinical trial design and molecular patient selection will be key for the success of epigenetic modifiers in solid tumours.”
Horvath, S., Langfelder, P., Kwak, S., Aaronson, J., Rosinski, J., Vogt, T. F., … Yang, X. W.. (2016). Huntington’s disease accelerates epigenetic aging of human brain and disrupts DNA methylation levels. Aging
Plain numerical DOI: 10.18632/aging.101005
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“Age of huntington’s disease (hd) motoric onset is strongly related to the number of cag trinucleotide repeats in the huntingtin gene, suggesting that biological tissue age plays an important role in disease etiology. recently, a dna methylation based biomarker of tissue age has been advanced as an epigenetic aging clock. we sought to inquire if hd is associated with an accelerated epigenetic age. dna methylation data was generated for 475 brain samples from various brain regions of 26 hd cases and 39 controls. overall, brain regions from hd cases exhibit a significant epigenetic age acceleration effect (p=0.0012). a multivariate model analysis suggests that hd status increases biological age by 3.2 years. accelerated epigenetic age can be observed in specific brain regions (frontal lobe, parietal lobe, and cingulate gyrus). after excluding controls, we observe a negative correlation (r=-0.41, p=5.5×10-8) between hd gene cag repeat length and the epigenetic age of hd brain samples. using correlation network analysis, we identify 11 co-methylation modules with a significant association with hd status across 3 broad cortical regions. in conclusion, hd is associated with an accelerated epigenetic age of specific brain regions and more broadly with substantial changes in brain methylation levels.”
Van Otterdijk, S. D., & Michels, K. B.. (2016). Transgenerational epigenetic inheritance in mammals: How good is the evidence?. FASEB Journal
Plain numerical DOI: 10.1096/fj.201500083
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“Epigenetics plays an important role in orchestrating key biologic processes. epigenetic marks, including dna methylation, histones, chromatin structure, and noncoding rnas, are modified throughout life in response to environmental and behavioral influences. with each new generation, dna methylation patterns are erased in gametes and reset after fertilization, probably to prevent these epigenetic marks from being transferred from parents to their offspring. however, some recent animal studies suggest an apparent resistance to complete erasure of epigenetic marks during early development, enabling transgenerational epigenetic inheritance. whether there are similar mechanisms in humans remains unclear, with the exception of epigenetic imprinting. nevertheless, a distinctly different mechanism-namely, intrauterine exposure to environmental stressors that may affect establishment of the newly composing epigenetic patterns after fertilization-is often confused with transgenerational epigenetic inheritance. in this review, we delineate the definition of and requirement for transgenerational epigenetic inheritance, differentiate it from the consequences of intrauterine exposure, and discuss the available evidence in both animal models and humans.”
Ghasemi, S.. (2020). Cancer’s epigenetic drugs: where are they in the cancer medicines?. Pharmacogenomics Journal
Plain numerical DOI: 10.1038/s41397-019-0138-5
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“Epigenetic modulation can affect the characteristics of cancers. because it is likely to manipulate epigenetic genes, they can be considered as potential targets for cancer treatment. in this comprehensive study, epigenetic drugs are categorized according to anticancer mechanisms and phase of therapy. the relevant articles or databases were searched for epigenetic approaches to cancer therapy. epigenetic drugs are divided according to their mechanisms and clinical phases that have been approved by the fda or are undergoing evaluation phases. dna methylation agents, chromatin remodelers specially hdacs, and noncoding rnas especially micrornas are the main epi-drugs for cancer. despite many challenges, combination therapy using epi-drugs and routine therapies such as chemotherapy in various approaches have exhibited beneficial effects compared with each treatment alone. cancer stem cell targeting and epigenetic editing have been confirmed as definitive pathways for cancer treatment. this paper reviewed the available epigenetic approaches to cancer therapy.”
Medrano, M., Alonso, C., Bazaga, P., López, E., & Herrera, C. M.. (2021). Comparative genetic and epigenetic diversity in pairs of sympatric, closely related plants with contrasting distribution ranges in south-eastern Iberian mountains. AoB PLANTS
Plain numerical DOI: 10.1093/AOBPLA/PLAA013
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“Genetic diversity defines the evolutionary potential of a species, yet mounting evidence suggests that epigenetic diversity could also contribute to adaptation. elucidating the complex interplay between genetic and epigenetic variation in wild populations remains a challenge for evolutionary biologists, and the intriguing possibility that epigenetic diversity could compensate for the loss of genetic diversity is one aspect that remains basically unexplored in wild plants. this hypothesis is addressed in this paper by comparing the extent and patterns of genetic and epigenetic diversity of phylogenetically closely related but ecologically disparate species. seven pairs of congeneric species from cazorla mountains in south-eastern spain were studied, each pair consisting of one endemic, restricted-range species associated to stressful environments, and one widespread species occupying more favourable habitats. the prediction was tested that endemic species should have lower genetic diversity due to population fragmentation, and higher epigenetic diversity induced by environmental stress, than their widespread congeners. genetic (dna sequence variants) and epigenetic (dna cytosine methylation variants) diversities and their possible co-variation were assessed in three populations of each focal species using amplified fragment length polymorphism (aflp) and methylation-sensitive aflp (msap). all species and populations exhibited moderate to high levels of genetic polymorphism irrespective of their ecological characteristics. epigenetic diversity was greater than genetic diversity in all cases. only in endemic species were the two variables positively related, but the difference between epigenetic and genetic diversity was greater at populations with low genetic polymorphism. results revealed that the relationship between genetic and epigenetic diversity can be more complex than envisaged by the simple hypothesis addressed in this study, and highlight the need of additional research on the actual role of epigenetic variation as a source of phenotypic diversity before a realistic understanding of the evolutionary relevance of epigenetic phenomena in plant adaptation can be achieved.”
Zhang, W., Song, M., Qu, J., & Liu, G. H.. (2018). Epigenetic modifications in cardiovascular aging and diseases. Circulation Research
Plain numerical DOI: 10.1161/CIRCRESAHA.118.312497
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“Aging is associated with a progressive decline in cardiovascular structure and function. accumulating evidence links cardiovascular aging to epigenetic alterations encompassing a complex interplay of dna methylation, histone posttranslational modifications, and dynamic nucleosome occupancy governed by numerous epigenetic factors. advances in genomics technology have led to a profound understanding of chromatin reorganization in both cardiovascular aging and diseases. this review summarizes recent discoveries in epigenetic mechanisms involved in cardiovascular aging and diseases and discusses potential therapeutic strategies to retard cardiovascular aging and conquer related diseases through the rejuvenation of epigenetic signatures to a young state.”
Ge, S. Q., Lin, S. L., Zhao, Z. H., & Sun, Q. Y.. (2017). Epigenetic dynamics and interplay during spermatogenesis and embryogenesis: Implications for male fertility and offspring health. Oncotarget
Plain numerical DOI: 10.18632/oncotarget.17479
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“Mapping epigenetic modifications and identifying their roles in the regulation of spermatogenesis and embryogenesis are essential for gaining fundamental medical understandings and for clinical applications. more and more evidence has shown that specific epigenetic modifications are established during spermatogenesis, which will be transferred into oocyte via fertilisation, and play an important role in the early embryo development. defects in epigenetic patterns may increase the risk of abnormal spermatogenesis, fertilisation failure, early embryogenesis abnormality and several other complications during pregnancy. this review mainly discusses the relationship between altered epigenetic profiles and reproductive diseases, highlighting how epigenetic defects affect the quality of sperm and embryo.”
Miao, Z., Wang, Y., & Sun, Z.. (2020). The relationships between stress, mental disorders, and epigenetic regulation of bdnf. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms21041375
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“Brain-derived neurotrophic factor (bdnf), a critical member of the neurotrophic family, plays an important role in multiple stress-related mental disorders. although alterations in bdnf in multiple brain regions of individuals experiencing stress have been demonstrated in previous studies, it appears that a set of elements are involved in the complex regulation. in this review, we summarize the specific brain regions with altered bdnf expression during stress exposure. how various environmental factors, including both physical and psychological stress, affect the expression of bdnf in specific brain regions are further summarized. moreover, epigenetic regulation of bdnf, including dna methylation, histone modification, and noncoding rna, in response to diverse types of stress, as well as sex differences in the sensitivity of bdnf to the stress response, is also summarized. clarification of the underlying role of bdnf in the stress process will promote our understanding of the pathology of stress-linked mental disorders and provide a potent target for the future treatment of stress-related illness.”
Arney, K. L., & Fisher, A. G.. (2004). Epigenetic aspects of differentiation. Journal of Cell Science
Plain numerical DOI: 10.1242/jcs.01390
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“A major challenge in biology is to understand how genetic information is interpreted to direct the formation of specialized tissues within a multicellular organism. during differentiation, changes in chromatin structure and nuclear organization establish heritable patterns of gene expression in response to signals. epigenetic states can be broadly divided into three categories: euchromatin, constitutive heterochromatin and facultative hetereochromatin. although the static epigenetic profiles of expressed and silent loci are relatively well characterized, less is known about the transition between active and repressed states. furthermore, it is important to expand on localized models of chromatin structure at specific genetic addresses to examine the entire nucleus. changes in nuclear organization, replication timing and global chromatin modifications should be integrated when attempting to describe the epigenetic signature of a given cell type. it is also crucial to examine the temporal aspect of these changes. in this context, the capacity for cellular differentiation reflects both the repertoire of available transcription factors and the accessibility of cis-regulatory elements, which is governed by chromatin structure. understanding this interplay between epigenetics and transcription will help us to understand differentiation pathways and, ultimately, to manipulate or reverse them.”
Han, L. K. M., Aghajani, M., Clark, S. L., Chan, R. F., Hattab, M. W., Shabalin, A. A., … Penninx, B. W. J. H.. (2018). Epigenetic aging in major depressive disorder. American Journal of Psychiatry
Plain numerical DOI: 10.1176/appi.ajp.2018.17060595
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“Objective: major depressive disorder is associated with an increased risk of mortality and aging-related diseases. the authors examined whether major depression is associated with higher epigenetic aging in blood as measured by dna methylation (dnam) patterns, whether clinical characteristics of major depression have a further impact on these patterns, and whether the findings replicate in brain tissue. method: dnam age was estimated using all methylation sites in blood of 811 depressed patients and 319 control subjects with no lifetime psychiatric disorders and low depressive symptoms from the netherlands study of depression and anxiety. the residuals of the dnam age estimates regressed on chronological age were calculated to indicate epigenetic aging. major depression diagnosis and clinical characteristics were assessed with questionnaires and psychiatric interviews. analyses were adjusted for sociodemographic characteristics, lifestyle, and health status. postmortem brain samples of 74 depressed patients and 64 control subjects were used for replication. pathway enrichment analysis was conducted using consensuspathdb to gain insight into the biological processes underlying epigenetic aging in blood and brain. results: significantly higher epigenetic aging was observed in patients with major depression compared with control subjects (cohen’s d=0.18), with a significant dose effect with increasing symptom severity in the overall sample. in the depression group, epigenetic aging was positively and significantly associated with childhood trauma score. the case-control difference was replicated in an independent data set of postmortem brain samples. the top significantly enriched gene ontology terms included neuronal processes. conclusions: as compared with control subjects, patients with major depression exhibited higher epigenetic aging in blood and brain tissue, suggesting that they are biologically older than their corresponding chronological age. this effect was even more profound in the presence of childhood trauma.”
Samanta, S., Rajasingh, S., Cao, T., Dawn, B., & Rajasingh, J.. (2017). Epigenetic dysfunctional diseases and therapy for infection and inflammation. Biochimica et Biophysica Acta – Molecular Basis of Disease
Plain numerical DOI: 10.1016/j.bbadis.2016.11.030
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“Even though the discovery of the term ‘epigenetics’ was in the 1940s, it has recently become one of the most promising and expanding fields to unravel the gene expression pattern in several diseases. the most well studied example is cancer, but other diseases like metabolic disorders, autism, or inflammation-associated diseases such as lung injury, autoimmune disease, asthma, and type-2 diabetes display aberrant gene expression and epigenetic regulation during their occurrence. the change in the epigenetic pattern of a gene may also alter gene function because of a change in the dna status. constant environmental pressure, lifestyle, as well as food habits are the other important parameters responsible for transgenerational inheritance of epigenetic traits. discovery of epigenetic modifiers targeting dna methylation and histone deacetylation enzymes could be an alternative source to treat or manipulate the pathogenesis of diseases. particularly, the combination of epigenetic drugs such as 5-aza-2-deoxycytidine (aza) and trichostatin a (tsa) are well studied to reduce inflammation in an acute lung injury model. it is important to understand the epigenetic machinery and the function of its components in specific diseases to develop targeted epigenetic therapy. moreover, it is equally critical to know the specific inhibitors other than the widely used pan inhibitors in clinical trials and explore their roles in regulating specific genes in a more defined way during infection.”
Dong, B., Qiu, Z., & Wu, Y.. (2020). Tackle Epithelial-Mesenchymal Transition With Epigenetic Drugs in Cancer. Frontiers in Pharmacology
Plain numerical DOI: 10.3389/fphar.2020.596239
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“Epithelial-mesenchymal transition (emt) is a de-differentiation process in which epithelial cells lose their epithelial properties to acquire mesenchymal features. emt is essential for embryogenesis and wound healing but is aberrantly activated in pathological conditions like fibrosis and cancer. tumor-associated emt contributes to cancer cell initiation, invasion, metastasis, drug resistance and recurrence. this dynamic and reversible event is governed by emt-transcription factors (emt-tfs) with epigenetic complexes. in this review, we discuss recent advances regarding the mechanisms that modulate emt in the context of epigenetic regulation, with emphasis on epigenetic drugs, such as dna demethylating reagents, inhibitors of histone modifiers and non-coding rna medication. therapeutic contributions that improve epigenetic regulation of emt will translate the clinical manifestation as treating cancer progression more efficiently.”
Sun, L., Fu, X., Ma, G., & Hutchins, A. P.. (2021). Chromatin and Epigenetic Rearrangements in Embryonic Stem Cell Fate Transitions. Frontiers in Cell and Developmental Biology
Plain numerical DOI: 10.3389/fcell.2021.637309
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“A major event in embryonic development is the rearrangement of epigenetic information as the somatic genome is reprogrammed for a new round of organismal development. epigenetic data are held in chemical modifications on dna and histones, and there are dramatic and dynamic changes in these marks during embryogenesis. however, the mechanisms behind this intricate process and how it is regulating and responding to embryonic development remain unclear. as embryos develop from totipotency to pluripotency, they pass through several distinct stages that can be captured permanently or transiently in vitro. pluripotent naïve cells resemble the early epiblast, primed cells resemble the late epiblast, and blastomere-like cells have been isolated, although fully totipotent cells remain elusive. experiments using these in vitro model systems have led to insights into chromatin changes in embryonic development, which has informed exploration of pre-implantation embryos. intriguingly, human and mouse cells rely on different signaling and epigenetic pathways, and it remains a mystery why this variation exists. in this review, we will summarize the chromatin rearrangements in early embryonic development, drawing from genomic data from in vitro cell lines, and human and mouse embryos.”
Yu, X., Ma, R., Wu, Y., Zha, Y., & Li, S.. (2018). Reciprocal regulation of metabolic reprogramming and epigenetic modifications in cancer. Frontiers in Genetics
Plain numerical DOI: 10.3389/fgene.2018.00394
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“Cancer cells reprogram their metabolism to meet their demands for survival and proliferation. the metabolic plasticity of tumor cells help them adjust to changes in the availability and utilization of nutrients in the microenvironment. recent studies revealed that many metabolites and metabolic enzymes have non-metabolic functions contributing to tumorigenesis. one major function is regulating epigenetic modifications to facilitate appropriate responses to environmental cues. accumulating evidence showed that epigenetic modifications could in turn alter metabolism in tumors. although a comprehensive understanding of the reciprocal connection between metabolic and epigenetic rewiring in cancer is lacking, some conceptual advances have been made. understanding the link between metabolism and epigenetic modifications in cancer cells will shed lights on the development of more effective cancer therapies.”
Ozkan, H., Tuzun, F., Taheri, S., Korhan, P., Akokay, P., Yılmaz, O., … Özkul, Y.. (2020). Epigenetic Programming Through Breast Milk and Its Impact on Milk-Siblings Mating. Frontiers in Genetics
Plain numerical DOI: 10.3389/fgene.2020.569232
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“Background: the epigenetic effects of transmission of certain regulatory molecules, such as mirnas, through maternal milk on future generations, are still unknown and have not been fully understood yet. we hypothesized that breastfeeding regularly by adoptive-mother may cause transmission of mirnas as epigenetic regulating factors to the infant, and the marriage of milk-siblings may cause various pathologies in the future generations. results: a cross-fostering model using a/a and avy/a mice had been established. f2 milk-sibling and f2 control groups were obtained from mating of milk-siblings or unrelated mice. randomized selected animals in the both f2 groups were sacrificed for mirna expression studies and the remainings were followed for phenotypic changes (coat color, obesity, hyperglycemia, liver pathology, and life span). the lifespan in the f2 milk-sibling group was shorter than the control group (387 vs 590 days, p = 0.011) and they were more obese during the aging period. histopathological examination of liver tissues revealed abnormal findings in f2 milk-sibling group. in order to understand the epigenetic mechanisms leading to these phenotypic changes, we analyzed mirna expression differences between offspring of milk-sibling and control matings and focused on the signaling pathways regulating lifespan and metabolism. bioinformatic analysis demonstrated that differentially expressed mirnas were associated with pathways regulating metabolism, survival, and cancer development such as the pi3k-akt, erbb, mtor, and mapk, insulin signaling pathways. we further analyzed the expression patterns of mir-186-5p, mir-141-3p, mir-345-5p, and mir-34c-5p and their candidate target genes mapk8, gsk3b, and ppargc1a in ovarian and liver tissues. conclusion: our findings support for the first time that the factors modifying the epigenetic mechanisms may be transmitted by breast milk and these epigenetic interactions may be transferred transgenerationally. results also suggested hereditary epigenetic effects of cross-fostering on future generations and the impact of mother-infant dyad on epigenetic programming.”
Thompson, M. J., von Holdt, B., Horvath, S., & Pellegrini, M.. (2017). An epigenetic aging clock for dogs and wolves. Aging
Plain numerical DOI: 10.18632/aging.101211
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“Several articles describe highly accurate age estimation methods based on human dna-methylation data. it is not yet known whether similar epigenetic aging clocks can be developed based on blood methylation data from canids. using reduced representation bisulfite sequencing, we assessed blood dna-methylation data from 46 domesticated dogs (canis familiaris) and 62 wild gray wolves (c. lupus). by regressing chronological dog age on the resulting cpgs, we defined highly accurate multivariate age estimators for dogs (based on 41 cpgs), wolves (67 cpgs), and both combined (115 cpgs). age related dna methylation changes in canids implicate similar gene ontology categories as those observed in humans suggesting an evolutionarily conserved mechanism underlying age-related dna methylation in mammals.”
Bin, L., & Leung, D. Y. M.. (2016). Genetic and epigenetic studies of atopic dermatitis. Allergy, Asthma and Clinical Immunology
Plain numerical DOI: 10.1186/s13223-016-0158-5
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“Background: atopic dermatitis (ad) is a chronic inflammatory disease caused by the complex interaction of genetic, immune and environmental factors. there have many recent discoveries involving the genetic and epigenetic studies of ad. methods: a retrospective pubmed search was carried out from june 2009 to june 2016 using the terms ‘atopic dermatitis’, ‘association’, ‘eczema’, ‘gene’, ‘polymorphism’, ‘mutation’, ‘variant’, ‘genome wide association study’, ‘microarray’ ‘gene profiling’, ‘rna sequencing’, ‘epigenetics’ and ‘microrna’. a total of 132 publications in english were identified. results: to elucidate the genetic factors for ad pathogenesis, candidate gene association studies, genome-wide association studies (gwas) and transcriptomic profiling assays have been performed in this period. epigenetic mechanisms for ad development, including genomic dna modification and microrna posttranscriptional regulation, have been explored. to date, candidate gene association studies indicate that filaggrin (flg) null gene mutations are the most significant known risk factor for ad, and genes in the type 2 t helper lymphocyte (th2) signaling pathways are the second replicated genetic risk factor for ad. gwas studies identified 34 risk loci for ad, these loci also suggest that genes in immune responses and epidermal skin barrier functions are associated with ad. additionally, gene profiling assays demonstrated ad is associated with decreased gene expression of epidermal differentiation complex genes and elevated th2 and th17 genes. hypomethylation of tslp and fcer1g in ad were reported; and mir-155, which target the immune suppressor ctla-4, was found to be significantly over-expressed in infiltrating t cells in ad skin lesions. conclusions: the results suggest that two major biologic pathways are responsible for ad etiology: skin epithelial function and innate/adaptive immune responses. the dysfunctional epidermal barrier and immune responses reciprocally affect each other, and thereby drive development of ad.”
He, Y., & Li, Z.. (2018). Epigenetic Environmental Memories in Plants: Establishment, Maintenance, and Reprogramming. Trends in Genetics
Plain numerical DOI: 10.1016/j.tig.2018.07.006
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“Plants are immobile and must respond to or endure fluctuating surroundings and diverse environmental challenges. environmental inputs often induce chromatin modifications at various responsive genes and consequent changes in their expression. environment-induced chromatin marks at certain loci are transmittable through cell divisions after relief from the original external signals, leading to acquired ‘memorization’ of environmental experiences in plants, namely epigenetic environmental memories, which enable plants to adapt to environmental changes or to perform better when events recur. here, we review recent progress in epigenetic or chromatin-mediated environmental memories in plants, including defense priming, stress memories, and ‘epigenetic memory of winter cold’ or vernalization. various advances in epigenetic mechanisms underlying plant–environment interactions highlight that plant environmental epigenetics is emerging as an important area in plant biology.”
Schlichting, C. D., & Wund, M. A.. (2014). Phenotypic plasticity and epigenetic marking: An assessment of evidence for genetic accommodation. Evolution
Plain numerical DOI: 10.1111/evo.12348
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“The relationship between genotype (which is inherited) and phenotype (the target of selection) is mediated by environmental inputs on gene expression, trait development, and phenotypic integration. phenotypic plasticity or epigenetic modification might influence evolution in two general ways: (1) by stimulating evolutionary responses to environmental change via population persistence or by revealing cryptic genetic variation to selection, and (2) through the process of genetic accommodation, whereby natural selection acts to improve the form, regulation, and phenotypic integration of novel phenotypic variants. we provide an overview of models and mechanisms for how such evolutionary influences may be manifested both for plasticity and epigenetic marking. we point to promising avenues of research, identifying systems that can best be used to address the role of plasticity in evolution, as well as the need to apply our expanding knowledge of genetic and epigenetic mechanisms to our understanding of how genetic accommodation occurs in nature. our review of a wide variety of studies finds widespread evidence for evolution by genetic accommodation. © 2014 the society for the study of evolution.”
Thompson, R. P., Nilsson, E., & Skinner, M. K.. (2020). Environmental epigenetics and epigenetic inheritance in domestic farm animals. Animal Reproduction Science
Plain numerical DOI: 10.1016/j.anireprosci.2020.106316
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“Epigenetics refers to molecular factors and processes around dna that can affect genome activity and gene expression independent of dna sequence. epigenetic mechanisms drive developmental processes and have also been shown to be tied to disease development. many epigenetic studies have been done using plants, rodent, and human models, but fewer have focused on domestic livestock species. the goal of this review is to present current epigenetic findings in livestock species (cattle, pigs, sheep and poultry). much of this research examined epigenetic effects following exposure to toxicants, nutritional changes or infectious disease in those animals directly exposed, or in the offspring they produced. a limited number of studies in domestic animals have examined epigenetic transgenerational inheritance in the absence of continued exposures. one example used a porcine model to investigate the effect that feeding males a diet supplemented with micronutrients had on liver dna methylation and muscle mass in grand-offspring (the transgenerational f2 generation). further research into how epigenetic mechanisms affect the health and production traits of domestic livestock and their offspring is important to elucidate.”
Irvin, M. R., Aslibekyan, S., Do, A., Zhi, D., Hidalgo, B., Claas, S. A., … Arnett, D. K.. (2018). Metabolic and inflammatory biomarkers are associated with epigenetic aging acceleration estimates in the GOLDN study. Clinical Epigenetics
Plain numerical DOI: 10.1186/s13148-018-0481-4
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“Background: recently, epigenetic age acceleration-or older epigenetic age in comparison to chronological age-has been robustly associated with mortality and various morbidities. however, accelerated epigenetic aging has not been widely investigated in relation to inflammatory or metabolic markers, including postprandial lipids. methods: we estimated measures of epigenetic age acceleration in 830 caucasian participants from the genetics of lipid lowering drugs and diet network (goldn) considering two epigenetic age calculations based on differing sets of 5’-cytosine-phosphate-guanine-3’ genomic site, derived from the horvath and hannum dna methylation age calculators, respectively. goldn participants underwent a standardized high-fat meal challenge after fasting for at least 8 h followed by timed blood draws, the last being 6 h postmeal. we used adjusted linear mixed models to examine the association of the epigenetic age acceleration estimate with fasting and postprandial (0- and 6-h time points) low-density lipoprotein (ldl), high-density lipoprotein (hdl), and triglyceride (tg) levels as well as five fasting inflammatory markers plus adiponectin. results: both dna methylation age estimates were highly correlated with chronological age (r > 0.90). we found that the horvath and hannum measures of epigenetic age acceleration were moderately correlated (r = 0.50). the regression models revealed that the horvath age acceleration measure exhibited marginal associations with increased postprandial hdl (p = 0.05), increased postprandial total cholesterol (p = 0.06), and decreased soluble interleukin 2 receptor subunit alpha (il2srα, p = 0.02). the hannum measure of epigenetic age acceleration was inversely associated with fasting hdl (p = 0.02) and positively associated with postprandial tg (p = 0.02), interleukin-6 (il6, p = 0.007), c-reactive protein (c-reactive protein, p = 0.0001), and tumor necrosis factor alpha (tnfα, p = 0.0001). overall, the observed effect sizes were small and the association of the hannum residual with inflammatory markers was attenuated by adjustment for estimated t cell type percentages. conclusions: our study demonstrates that epigenetic age acceleration in blood relates to inflammatory biomarkers and certain lipid classes in caucasian individuals of the goldn study. future studies should consider epigenetic age acceleration in other tissues and extend the analysis to other ethnic groups.”
Bludau, A., Royer, M., Meister, G., Neumann, I. D., & Menon, R.. (2019). Epigenetic Regulation of the Social Brain. Trends in Neurosciences
Plain numerical DOI: 10.1016/j.tins.2019.04.001
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“Social behavior, a highly adaptive and crucial component of mammalian life, is regulated by particularly sensitive regulatory brain mechanisms. substantial evidence implicates classical epigenetic mechanisms including histone modifications, dna methylation, and nucleosome remodeling as well as nonclassical mechanisms mediated by noncoding rna in the regulation of social behavior. these mechanisms collectively form the ‘epigenetic network’ that orchestrates genomic integration of salient and transient social experiences. consequently, its dysregulation has been linked to behavioral deficits and psychopathologies. this review focuses on the role of the epigenetic network in regulating the enduring effects of social experiences during early-life, adolescence, and adulthood. we discuss research in animal models, primarily rodents, and associations between dysregulation of epigenetic mechanisms and human psychopathologies, specifically autism spectrum disorder (asd) and schizophrenia.”
Deblois, G., Tonekaboni, S. A. M., Grillo, G., Martinez, C., Kao, Y. I., Tai, F., … Lupien, M.. (2020). Epigenetic switch–induced viral mimicry evasion in chemotherapy-resistant breast cancer. Cancer Discovery
Plain numerical DOI: 10.1158/2159-8290.CD-19-1493
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“Tumor progression upon treatment arises from preexisting resistant cancer cells and/or adaptation of persister cancer cells committing to an expansion phase. here, we show that evasion from viral mimicry response allows the growth of taxane-resistant triple-negative breast cancer (tnbc). this is enabled by an epigenetic state adapted to taxane-induced metabolic stress, where dna hypomethylation over loci enriched in transposable elements (te) is compensated by large chromatin domains of h3k27me3 to warrant te repression. this epigenetic state creates a vulnerability to epigenetic therapy against ezh2, the h3k27me3 methyltransferase, which alleviates te repression in taxane-resistant tnbc, leading to double-stranded rna production and growth inhibition through viral mimicry response. collectively, our results illustrate how epigenetic states over tes promote cancer progression under treatment and can inform about vulnerabilities to epigenetic therapy. significance: drug-resistant cancer cells represent a major barrier to remission for patients with cancer. here we show that drug-induced metabolic perturbation and epigenetic states enable evasion from the viral mimicry response induced by chemotherapy in tnbc. these epigenetic states define a vulnerability to epigenetic therapy using ezh2 inhibitors in taxane-resistant tnbc.”
Jasiulionis, M. G.. (2018). Abnormal epigenetic regulation of immune system during aging. Frontiers in Immunology
Plain numerical DOI: 10.3389/fimmu.2018.00197
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“Epigenetics refers to the study of mechanisms controlling the chromatin structure, which has fundamental role in the regulation of gene expression and genome stability. epigenetic marks, such as dna methylation and histone modifications, are established during embryonic development and epigenetic profiles are stably inherited during mitosis, ensuring cell differentiation and fate. under the effect of intrinsic and extrinsic factors, such as metabolic profile, hormones, nutrition, drugs, smoke, and stress, epigenetic marks are actively modulated. in this sense, the lifestyle may affect significantly the epigenome, and as a result, the gene expression profile and cell function. epigenetic alterations are a hallmark of aging and diseases, such as cancer. among biological systems compromised with aging is the decline of immune response. different regulators of immune response have their promoters and enhancers susceptible to the modulation by epigenetic marks, which is fundamental to the differentiation and function of immune cells. consistent evidence has showed the regulation of innate immune cells, and t and b lymphocytes by epigenetic mechanisms. therefore, age-dependent alterations in epigenetic marks may result in the decline of immune function and this might contribute to the increased incidence of diseases in old people. in order to maintain health, we need to better understand how to avoid epigenetic alterations related to immune aging. in this review, the contribution of epigenetic mechanisms to the loss of immune function during aging will be discussed, and the promise of new means of disease prevention and management will be pointed.”
Haws, S. A., Yu, D., Ye, C., Wille, C. K., Nguyen, L. C., Krautkramer, K. A., … Denu, J. M.. (2020). Methyl-Metabolite Depletion Elicits Adaptive Responses to Support Heterochromatin Stability and Epigenetic Persistence. Molecular Cell
Plain numerical DOI: 10.1016/j.molcel.2020.03.004
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“S-adenosylmethionine (sam) is the methyl-donor substrate for dna and histone methyltransferases that regulate epigenetic states and subsequent gene expression. this metabolism-epigenome link sensitizes chromatin methylation to altered sam abundance, yet the mechanisms that allow organisms to adapt and protect epigenetic information during life-experienced fluctuations in sam availability are unknown. we identified a robust response to sam depletion that is highlighted by preferential cytoplasmic and nuclear mono-methylation of h3 lys 9 (h3k9) at the expense of broad losses in histone di- and tri-methylation. under sam-depleted conditions, h3k9 mono-methylation preserves heterochromatin stability and supports global epigenetic persistence upon metabolic recovery. this unique chromatin response was robust across the mouse lifespan and correlated with improved metabolic health, supporting a significant role for epigenetic adaptation to sam depletion in vivo. together, these studies provide evidence for an adaptive response that enables epigenetic persistence to metabolic stress.”
Moufarrij, S., Dandapani, M., Arthofer, E., Gomez, S., Srivastava, A., Lopez-Acevedo, M., … Chiappinelli, K. B.. (2019). Epigenetic therapy for ovarian cancer: Promise and progress. Clinical Epigenetics
Plain numerical DOI: 10.1186/s13148-018-0602-0
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“Ovarian cancer is the deadliest gynecologic malignancy, with a 5-year survival rate of approximately 47%, a number that has remained constant over the past two decades. early diagnosis improves survival, but unfortunately only 15% of ovarian cancers are diagnosed at an early or localized stage. most ovarian cancers are epithelial in origin and treatment prioritizes surgery and cytoreduction followed by cytotoxic platinum and taxane chemotherapy. while most tumors will initially respond to this treatment, recurrence is likely to occur within a median of 16 months for patients who present with advanced stage disease. new treatment options separate from traditional chemotherapy that take advantage of advances in understanding of the pathophysiology of ovarian cancer are needed to improve outcomes. recent work has shown that mutations in genes encoding epigenetic regulators are mutated in ovarian cancer, driving tumorigenesis and resistance to treatment. several of these epigenetic modifiers have emerged as promising drug targets for ovarian cancer therapy. in this article, we delineate epigenetic abnormalities in ovarian cancer, discuss key scientific advances using epigenetic therapies in preclinical ovarian cancer models, and review ongoing clinical trials utilizing epigenetic therapies in ovarian cancer.”
Kane, A. E., & Sinclair, D. A.. (2019). Epigenetic changes during aging and their reprogramming potential. Critical Reviews in Biochemistry and Molecular Biology
Plain numerical DOI: 10.1080/10409238.2019.1570075
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“The aging process results in significant epigenetic changes at all levels of chromatin and dna organization. these include reduced global heterochromatin, nucleosome remodeling and loss, changes in histone marks, global dna hypomethylation with cpg island hypermethylation, and the relocalization of chromatin modifying factors. exactly how and why these changes occur is not fully understood, but evidence that these epigenetic changes affect longevity and may cause aging, is growing. excitingly, new studies show that age-related epigenetic changes can be reversed with interventions such as cyclic expression of the yamanaka reprogramming factors. this review presents a summary of epigenetic changes that occur in aging, highlights studies indicating that epigenetic changes may contribute to the aging process and outlines the current state of research into interventions to reprogram age-related epigenetic changes.”
Li, C. chen, Wang, Z. yue, Wang, L. juan, & Zhang, C. yang. (2019). Biosensors for epigenetic biomarkers detection: A review. Biosensors and Bioelectronics
Plain numerical DOI: 10.1016/j.bios.2019.111695
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“Epigenetic inheritance is a heritable change in gene function independent of alterations in nucleotide sequence. it regulates the normal cellular activities of the organisms by affecting gene expression and transcription, and its abnormal expression may lead to the developmental disorder, senile dementia, and carcinogenesis progression. thus, epigenetic inheritance is recognized as an important biomarker, and the accurate quantification of epigenetic inheritance is crucial to clinical diagnosis, drug development and cancer treatment. noncoding rna, dna methylation and histone modification are the most common epigenetic biomarkers. the conventional biosensors (e.g., northern blotting, radiometric, mass spectrometry and immunosorbent biosensors) for epigenetic biomarkers assay usually suffer from hazardous radiation, complicated manipulation, and time-consuming procedures. to facilitate the practical applications, some new biosensors including colorimetric, luminescent, raman scattering spectroscopy, electrochemical and fluorescent biosensors have been developed for the detection of epigenetic biomarkers with simplicity, rapidity, high throughput and high sensitivity. in this review, we summarize the recent advances in epigenetic biomarkers assay. we classify the biosensors into the direct amplification-free and the nucleotide amplification-assisted ones, and describe the principles of various biosensors, and further compare their performance for epigenetic biomarkers detection. moreover, we discuss the emerging trends and challenges in the future development of epigenetic biomarkers biosensors.”
Soler-Botija, C., Forcales, S. V., & Bayés Genís, A.. (2020). Spotlight on epigenetic reprogramming in cardiac regeneration. Seminars in Cell and Developmental Biology
Plain numerical DOI: 10.1016/j.semcdb.2019.04.009
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“Heart failure of ischemic origin is caused by the presence of a large scar resulting from an acute myocardial infarction. acute myocardial infarction generally occurs when blood supply to the heart is blocked. regenerative strategies that limit infarct injury would be able to prevent adverse post-ischemic remodelling and maintain the structural support necessary for effective cardiomyocyte contraction. our understanding of endogenous cardiac regeneration and its biology has exposed a variety of targets for therapeutic approaches, such as non-coding rnas, dna methylation, histone modifications, direct cardiac reprogramming, cell transplantation, stimulation of resident cardiomyocytes, proliferation, and inhibition of cardiomyocyte death. in this review, we address the epigenetic mechanisms underlying these strategies and the use of therapeutic epigenetic molecules or epidrugs.”
Sen, R., & Barnes, C.. (2021). Do transgenerational epigenetic inheritance and immune system development share common epigenetic processes?. Journal of Developmental Biology
Plain numerical DOI: 10.3390/jdb9020020
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“Epigenetic modifications regulate gene expression for development, immune response, disease, and other processes. a major role of epigenetics is to control the dynamics of chromatin structure, i.e., the condensed packaging of dna around histone proteins in eukaryotic nuclei. key epigenetic factors include enzymes for histone modifications and dna methylation, non-coding rnas, and prions. epigenetic modifications are heritable but during embryonic development, most parental epigenetic marks are erased and reset. interestingly, some epigenetic modifications, that may be resulting from immune response to stimuli, can escape remodeling and transmit to subsequent generations who are not exposed to those stimuli. this phenomenon is called transgenerational epigenetic inheritance if the epigenetic phenotype persists beyond the third generation in female germlines and second generation in male germlines. although its primary function is likely immune response for survival, its role in the development and functioning of the immune system is not extensively explored, despite studies reporting transgenerational inheritance of stress-induced epigenetic modifications resulting in immune disorders. hence, this review draws from studies on transgenerational epigenetic inheritance, immune system development and function, high-throughput epigenetics tools to study those phenomena, and relevant clinical trials, to focus on their significance and deeper understanding for future research, therapeutic developments, and various applications.”
Fernandes, G. F. S., Silva, G. D. B., Pavan, A. R., Chiba, D. E., Chin, C. M., & Dos Santos, J. L.. (2017). Epigenetic regulatory mechanisms induced by resveratrol. Nutrients
Plain numerical DOI: 10.3390/nu9111201
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“Resveratrol (rvt) is one of the main natural compounds studied worldwide due to its potential therapeutic use in the treatment of many diseases, including cancer, diabetes, cardiovascular diseases, neurodegenerative diseases and metabolic disorders. nevertheless, the mechanism of action of rvt in all of these conditions is not completely understood, as it can modify not only biochemical pathways but also epigenetic mechanisms. in this paper, we analyze the biological activities exhibited by rvt with a focus on the epigenetic mechanisms, especially those related to dna methyltransferase (dnmt), histone deacetylase (hdac) and lysine-specific demethylase-1 (lsd1).”
Vora, S., Tuttle, M., Cheng, J., & Church, G.. (2016). Next stop for the CRISPR revolution: RNA-guided epigenetic regulators. FEBS Journal
Plain numerical DOI: 10.1111/febs.13768
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“Clustered regularly interspaced short palindromic repeats (crisprs) and crispr-associated (cas) proteins offer a breakthrough platform for cheap, programmable, and effective sequence-specific dna targeting. the crispr-cas system is naturally equipped for targeted dna cutting through its native nuclease activity. as such, groups researching a broad spectrum of biological organisms have quickly adopted the technology with groundbreaking applications to genomic sequence editing in over 20 different species. however, the biological code of life is not only encoded in genetics but also in epigenetics as well. while genetic sequence editing is a powerful ability, we must also be able to edit and regulate transcriptional and epigenetic code. taking inspiration from work on earlier sequence-specific targeting technologies such as zinc fingers (zfs) and transcription activator-like effectors (tales), researchers quickly expanded the crispr-cas toolbox to include transcriptional activation, repression, and epigenetic modification. in this review, we highlight advances that extend the crispr-cas toolkit for transcriptional and epigenetic regulation, as well as best practice guidelines for these tools, and a perspective on future applications.”
Mehdipour, P., Santoro, F., & Minucci, S.. (2015). Epigenetic alterations in acute myeloid leukemias. FEBS Journal
Plain numerical DOI: 10.1111/febs.13142
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“Acute myeloid leukemia (aml) is a heterogeneous disease for which the standard treatment with cytotoxic chemotherapy has remained largely unchanged for over four decades, with unfavorable clinical results. epigenetic alterations have been described in several amls, and in some cases their origin has been studied in detail mechanistically (such as in acute promyelocytic leukemia, caused by the promyelocytic leukemia-retinoic acid receptor-α fusion protein). recently, the advent of massive parallel sequencing has revealed that > 70% of aml cases have mutations in dna methylation-related genes or mutations in histone modifiers, showing that epigenetic alterations are key players in the development of most, if not all, amls, and pointing to the exploitation of new molecular targets for more efficacious therapies. this review provides a brief overview of the latest findings on the characterization of the epigenetic landscape of aml and discusses the rationale for the optimization of epigenetic therapy of aml. acute myeloid leukemia (aml) is the most common form of acute leukemia in adults. mutations in epigenetic modifiers are emerging as a large class of mutations critical for aml development. this review gives a brief overview on the latest findings on the characterization of the epigenetic landscape in aml and the rational for the optimization of epigenetic therapy.”
D’Addario, C., Di Francesco, A., Pucci, M., Finazzi Agrò, A., & MacCarrone, M.. (2013). Epigenetic mechanisms and endocannabinoid signalling. FEBS Journal
Plain numerical DOI: 10.1111/febs.12125
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“The endocannabinoid system, composed of endogenous lipids, their target receptors and metabolic enzymes, has been implicated in multiple biological functions in health and disease, both in the central nervous system and in peripheral organs. despite the exponential growth of experimental evidence on the key role of endocannabinoid signalling in basic cellular processes, and on its potential exploitation for therapeutic interventions, much remains to be clarified about the respective regulatory mechanisms. epigenetics refers to a set of post-translational modifications that regulate gene expression without causing variation in dna sequence, endowed with a major impact on signal transduction pathways. the epigenetic machinery includes dna methylation, histone modifications, nucleosome positioning and non-coding rnas. due to the reversibility of epigenetic changes, an emerging field of interest is the possibility of an ‘epigenetic therapy’ that could possibly be applied also to endocannabinoids. here, we review current knowledge of epigenetic regulation of endocannabinoid system components under both physiological and pathological conditions, as well as the epigenetic changes induced by endocannabinoid signalling. © 2013 febs.”
Salameh, Y., Bejaoui, Y., & El Hajj, N.. (2020). DNA Methylation Biomarkers in Aging and Age-Related Diseases. Frontiers in Genetics
Plain numerical DOI: 10.3389/fgene.2020.00171
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“Recent research efforts provided compelling evidence of genome-wide dna methylation alterations in aging and age-related disease. it is currently well established that dna methylation biomarkers can determine biological age of any tissue across the entire human lifespan, even during development. there is growing evidence suggesting epigenetic age acceleration to be strongly linked to common diseases or occurring in response to various environmental factors. dna methylation based clocks are proposed as biomarkers of early disease risk as well as predictors of life expectancy and mortality. in this review, we will summarize key advances in epigenetic clocks and their potential application in precision health. we will also provide an overview of progresses in epigenetic biomarker discovery in alzheimer’s, type 2 diabetes, and cardiovascular disease. furthermore, we will highlight the importance of prospective study designs to identify and confirm epigenetic biomarkers of disease.”
Hanna, C. W., Demond, H., & Kelsey, G.. (2018). Epigenetic regulation in development: Is the mouse a good model for the human?. Human Reproduction Update
Plain numerical DOI: 10.1093/humupd/dmy021
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“BACKGROUND: over the past few years, advances in molecular technologies have allowed unprecedented mapping of epigenetic modifications in gametes and during early embryonic development. this work is allowing a detailed genomic analysis, which for the first time can answer long-standing questions about epigenetic regulation and reprogramming, and highlights differences between mouse and human, the implications of which are only beginning to be explored. objective and rationale: in this review, we summarise new low-cell molecular methods enabling the interrogation of epigenetic information in gametes and early embryos, the mechanistic insights these have provided, and contrast the findings in mouse and human. search methods: relevant studies were identified by pubmed search. outcomes: we discuss the levels of epigenetic regulation, from dna modifications to chromatin organisation, during mouse gametogenesis, fertilisation and pre-and post-implantation development. the recently characterised features of the oocyte epigenome highlight its exceptionally unique regulatory landscape. the chromatin organisation and epigenetic landscape of both gametic genomes are rapidly reprogrammed after fertilisation. this extensive epigenetic remodelling is necessary for zygotic genome activation, but the mechanistic link remains unclear. while the vast majority of epigenetic information from the gametes is erased in pre-implantation development, new insights suggest that repressive histone modifications from the oocyte may mediate a novel mechanism of imprinting. to date, the characterisation of epigenetics in human development has been almost exclusively limited to dna methylation profiling; these data reinforce that the global dynamics are conserved between mouse and human. however, as we look closer, it is becoming apparent that the mechanisms regulating these dynamics are distinct. these early findings emphasise the importance of investigations of fundamental epigenetic mechanisms in both mouse and humans. wider implications: failures in epigenetic regulation have been implicated in human disease and infertility. with increasing maternal age and use of reproductive technologies in countries all over the world, it is becoming ever more important to understand the necessary processes required to establish a developmentally competent embryo. furthermore, it is essential to evaluate the extent to which these epigenetic patterns are sensitive to such technologies and other …”
Costantino, S., Mohammed, S. A., Ambrosini, S., & Paneni, F.. (2019). Epigenetic processing in cardiometabolic disease. Atherosclerosis
Plain numerical DOI: 10.1016/j.atherosclerosis.2018.09.029
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“Albeit a consistent body of evidence supports the notion that genes influence cardiometabolic features and outcomes, the ‘non-genetic regulation’ of this process is gaining increasing attention. plastic chemical changes of dna/histone complexes – known as epigenetic changes – critically determine gene activity by rapidly modifying chromatin accessibility to transcription factors. in this review, we describe the emerging role of chromatin modifications as fine tuners of gene transcription in adipogenesis, insulin resistance, macrophage polarization, immuno-metabolism, endothelial dysfunction and metabolic cardiomyopathy. epigenetic processing participates in the dynamic interplay among different organs in the cardiometabolic patient. dna methylation and post-translational histone modifications in both visceral and subcutaneous adipose tissue enable the transcription of genes implicated in lipo- and adipogenesis, inflammation and insulin resistance. along the same line, complex networks of chromatin modifying enzymes are responsible for impaired nitric oxide bioavailability and defective insulin signalling in the vasculature, thus leading to reduced capillary recruitment and insulin delivery in the liver, skeletal muscle and adipose tissue. furthermore, changes in methylation status of il-4, ifnγ and forkhead box p3 (foxp3) gene loci are crucial for the polarization of immune cells, thus leading to adipose tissue inflammation and atherosclerosis. cell-specific epigenetic information could advance our understanding of cardiometabolic processes, thus leading to individualized risk assessment and personalized therapeutic approaches in patients with cardiometabolic disturbances. the development of new chromatin modifying drugs indicates that targeting epigenetic changes is a promising approach to reduce the burden of cardiovascular disease in this setting.”
Fransquet, P. D., Wrigglesworth, J., Woods, R. L., Ernst, M. E., & Ryan, J.. (2019). The epigenetic clock as a predictor of disease and mortality risk: A systematic review and meta-analysis. Clinical Epigenetics
Plain numerical DOI: 10.1186/s13148-019-0656-7
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“Background: ageing is one of the principal risk factors for many chronic diseases. however, there is considerable between-person variation in the rate of ageing and individual differences in their susceptibility to disease and death. epigenetic mechanisms may play a role in human ageing, and dna methylation age biomarkers may be good predictors of age-related diseases and mortality risk. the aims of this systematic review were to identify and synthesise the evidence for an association between peripherally measured dna methylation age and longevity, age-related disease, and mortality risk. methods: a systematic search was conducted in line with the preferred reporting items for systematic reviews and meta-analyses (prisma) guidelines. using relevant search terms, medline, embase, cochrane central register of controlled trials, and psychinfo databases were searched to identify articles meeting the inclusion criteria. studies were assessed for bias using joanna briggs institute critical appraisal checklists. data was extracted from studies measuring age acceleration as a predictor of age-related diseases, mortality or longevity, and the findings for similar outcomes compared. using review manager 5.3 software, two meta-analyses (one per epigenetic clock) were conducted on studies measuring all-cause mortality. results: twenty-three relevant articles were identified, including a total of 41,607 participants. four studies focused on ageing and longevity, 11 on age-related disease (cancer, cardiovascular disease, and dementia), and 11 on mortality. there was some, although inconsistent, evidence for an association between increased dna methylation age and risk of disease. meta-analyses indicated that each 5-year increase in dna methylation age was associated an 8 to 15% increased risk of mortality. conclusion: due to the small number of studies and heterogeneity in study design and outcomes, the association between dna methylation age and age-related disease and longevity is inconclusive. increased epigenetic age was associated with mortality risk, but positive publication bias needs to be considered. further research is needed to determine the extent to which dna methylation age can be used as a clinical biomarker.”
Zhu, L., Zhang, B., Dai, Y., Li, H., & Xu, W.. (2017). A review: Epigenetic mechanism in ochratoxin a toxicity studies. Toxins
Plain numerical DOI: 10.3390/toxins9040113
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“Ochratoxin a (ota) is a natural contaminant that has displayed nephrotoxicity and hepatotoxicity in mammals. it contaminates a great variety of foodstuffs and threatens people’s lives. the molecular mechanism of ota-induced toxicity has been studied since 1965. moreover, epigenetic mechanisms are also studied in ota-induced toxicity. additionally, the mode of ota epigenetic research has been advanced in research hotspots. however, there is still no epigenetic study of ota-induced toxicity. in this review, we discuss the relationship between these epigenetic mechanisms and ota-induced toxicity. we found that studies on the epigenetic mechanisms of ota-induced toxicity all chose the whole kidney or liver as the model, which cannot reveal the real change in dna methylation or mirnas or histone in the target sites of ota. our recommendations are as follows: (1) the specific target site of ota should be detected by advanced technologies; and (2) competing endogenous rnas (cerna) should be explored with ota.”
Hokello, J., Sharma, A. L., & Tyagi, M.. (2021). Combinatorial use of both epigenetic and non-epigenetic mechanisms to efficiently reactivate hiv latency. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms22073697
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“The persistence of latent hiv provirus pools in different resting cd4+ cell subsets remains the greatest obstacle in the current efforts to treat and cure hiv infection. recent efforts to purge out latently infected memory cd4+ t-cells using latency-reversing agents have failed in clinical trials. this review discusses the epigenetic and non-epigenetic mechanisms of hiv latency control, major limitations of the current approaches of using latency-reversing agents to reactivate hiv latency in resting cd4+ t-cells, and potential solutions to these limitations.”
Levine, M. E., Lu, A. T., Chen, B. H., Hernandez, D. G., Singleton, A. B., Ferrucci, L., … Horvath, S.. (2016). Menopause accelerates biological aging. Proceedings of the National Academy of Sciences of the United States of America
Plain numerical DOI: 10.1073/pnas.1604558113
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“Although epigenetic processes have been linked to aging and disease in other systems, it is not yet known whether they relate to reproductive aging. recently, we developed a highly accurate epigenetic biomarker of age (known as the ‘epigenetic clock’), which is based on dna methylation levels. here we carry out an epigenetic clock analysis of blood, saliva, and buccal epithelium using data from four large studies: the women’s health initiative (n = 1,864); invecchiare nel chianti (n = 200); parkinson’s disease, environment, and genes (n = 256); and the united kingdom medical research council national survey of health and development (n = 790). we find that increased epigenetic age acceleration in blood is significantly associated with earlier menopause (p = 0.00091), bilateral oophorectomy (p = 0.0018), and a longer time since menopause (p = 0.017). conversely, epigenetic age acceleration in buccal epithelium and saliva do not relate to age at menopause; however, a higher epigenetic age in saliva is exhibited in women who undergo bilateral oophorectomy (p = 0.0079), while a lower epigenetic age in buccal epithelium was found for womenwho underwentmenopausal hormone therapy (p = 0.00078). using genetic data, we find evidence of coheritability between age at menopause and epigenetic age acceleration in blood. using mendelian randomization analysis, we find that two snps that are highly associated with age at menopause exhibit a significant association with epigenetic age acceleration. overall, our mendelian randomization approach and other lines of evidence suggest that menopause accelerates epigenetic aging of blood, but mechanistic studieswill be needed to dissect cause-and-effect relationships further.”
Surani, M. A., Hayashi, K., & Hajkova, P.. (2007). Genetic and Epigenetic Regulators of Pluripotency. Cell
Plain numerical DOI: 10.1016/j.cell.2007.02.010
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“Genetic and epigenetic mechanisms regulate the transition from the totipotent zygote to pluripotent primitive ectoderm cells in the inner cell mass of mouse blastocysts. these pluripotent cells can be propagated indefinitely in vitro, underpinned by a unique epigenetic state. following implantation of the blastocyst, diverse epigenetic modifiers control differentiation of pluripotent epiblast cells into somatic cells, while specification of germ cells requires repression of the somatic program. regenerating totipotency during development of germ cells entails re-expression of pluripotency-specific genes and extensive erasure of epigenetic modifications. increasing knowledge of key underlying mechanisms heightens prospects for creating pluripotent cells directly from adult somatic cells. © 2007 elsevier inc. all rights reserved.”
Ostrowska-Mazurek, A., Kasprzak, P., Kubala, S., Zaborowska, M., & Sobieszczuk-Nowicka, E.. (2020). Epigenetic landmarks of leaf senescence and crop improvement. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms21145125
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“This review synthesizes knowledge on epigenetic regulation of leaf senescence and discusses the possibility of using this knowledge to improve crop quality. this control level is implemented by different but interacting epigenetic mechanisms, including dna methylation, covalent histone modifications, and non-covalent chromatin remodeling. the genetic and epigenetic changes may act alone or together and regulate the gene expression, which may result in heritable (stress memory) changes and may lead to crop survival. in the review, the question also arises whether the mitotically stable epigenetic information can be used for crop improvement. the barley crop model for early and late events of dark-induced leaf senescence (dils), where the point of no return was defined, revealed differences in dna and rna modifications active in dils compared to developmental leaf senescence. this suggests the possibility of a yet-to-be-discovered epigenetic-based switch between cell survival and cell death. conclusions from the analyzed research contributed to the hypothesis that chromatin-remodeling mechanisms play a role in the control of induced leaf senescence. understanding this mechanism in crops might provide a tool for further exploitation toward sustainable agriculture: so-called epibreeding.”
Jones, P. A., Ohtani, H., Chakravarthy, A., & De Carvalho, D. D.. (2019). Epigenetic therapy in immune-oncology. Nature Reviews Cancer
Plain numerical DOI: 10.1038/s41568-019-0109-9
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“DNA methylation inhibitors have become the mainstay for treatment of certain haematological malignancies. in addition to their abilities to reactivate genes, including tumour suppressors, that have acquired dna methylation during carcinogenesis, they induce the expression of thousands of transposable elements including endogenous retroviruses and latent cancer testis antigens normally silenced by dna methylation in most somatic cells. this results in a state of viral mimicry in which treated cells mount an innate immune response by turning on viral defence genes and potentially expressing neoantigens. furthermore, these changes mediated by dna methylation inhibitors can also alter the function of immune cells relevant to acquired immunity. additionally, other inhibitors of epigenetic processes, such as histone deacetylases, methylases and demethylases, can elicit similar effects either individually or in combinations with dna methylation inhibitors. these findings together with rapid development of immunotherapies open new avenues for cancer treatment.”
Deblois, G., Tonekaboni, S. A. M., Grillo, G., Martinez, C., Kao, Y. I., Tai, F., … Lupien, M.. (2020). Epigenetic switch–induced viral mimicry evasion in chemotherapy-resistant breast cancer. Cancer Discovery
Plain numerical DOI: 10.1158/2159-8290.CD-19-1493
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“Tumor progression upon treatment arises from preexisting resistant cancer cells and/or adaptation of persister cancer cells committing to an expansion phase. here, we show that evasion from viral mimicry response allows the growth of taxane-resistant triple-negative breast cancer (tnbc). this is enabled by an epigenetic state adapted to taxane-induced metabolic stress, where dna hypomethylation over loci enriched in transposable elements (te) is compensated by large chromatin domains of h3k27me3 to warrant te repression. this epigenetic state creates a vulnerability to epigenetic therapy against ezh2, the h3k27me3 methyltransferase, which alleviates te repression in taxane-resistant tnbc, leading to double-stranded rna production and growth inhibition through viral mimicry response. collectively, our results illustrate how epigenetic states over tes promote cancer progression under treatment and can inform about vulnerabilities to epigenetic therapy. significance: drug-resistant cancer cells represent a major barrier to remission for patients with cancer. here we show that drug-induced metabolic perturbation and epigenetic states enable evasion from the viral mimicry response induced by chemotherapy in tnbc. these epigenetic states define a vulnerability to epigenetic therapy using ezh2 inhibitors in taxane-resistant tnbc.”
Irvin, M. R., Aslibekyan, S., Do, A., Zhi, D., Hidalgo, B., Claas, S. A., … Arnett, D. K.. (2018). Metabolic and inflammatory biomarkers are associated with epigenetic aging acceleration estimates in the GOLDN study. Clinical Epigenetics
Plain numerical DOI: 10.1186/s13148-018-0481-4
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“Background: recently, epigenetic age acceleration-or older epigenetic age in comparison to chronological age-has been robustly associated with mortality and various morbidities. however, accelerated epigenetic aging has not been widely investigated in relation to inflammatory or metabolic markers, including postprandial lipids. methods: we estimated measures of epigenetic age acceleration in 830 caucasian participants from the genetics of lipid lowering drugs and diet network (goldn) considering two epigenetic age calculations based on differing sets of 5’-cytosine-phosphate-guanine-3’ genomic site, derived from the horvath and hannum dna methylation age calculators, respectively. goldn participants underwent a standardized high-fat meal challenge after fasting for at least 8 h followed by timed blood draws, the last being 6 h postmeal. we used adjusted linear mixed models to examine the association of the epigenetic age acceleration estimate with fasting and postprandial (0- and 6-h time points) low-density lipoprotein (ldl), high-density lipoprotein (hdl), and triglyceride (tg) levels as well as five fasting inflammatory markers plus adiponectin. results: both dna methylation age estimates were highly correlated with chronological age (r > 0.90). we found that the horvath and hannum measures of epigenetic age acceleration were moderately correlated (r = 0.50). the regression models revealed that the horvath age acceleration measure exhibited marginal associations with increased postprandial hdl (p = 0.05), increased postprandial total cholesterol (p = 0.06), and decreased soluble interleukin 2 receptor subunit alpha (il2srα, p = 0.02). the hannum measure of epigenetic age acceleration was inversely associated with fasting hdl (p = 0.02) and positively associated with postprandial tg (p = 0.02), interleukin-6 (il6, p = 0.007), c-reactive protein (c-reactive protein, p = 0.0001), and tumor necrosis factor alpha (tnfα, p = 0.0001). overall, the observed effect sizes were small and the association of the hannum residual with inflammatory markers was attenuated by adjustment for estimated t cell type percentages. conclusions: our study demonstrates that epigenetic age acceleration in blood relates to inflammatory biomarkers and certain lipid classes in caucasian individuals of the goldn study. future studies should consider epigenetic age acceleration in other tissues and extend the analysis to other ethnic groups.”
Declerck, K., & Vanden Berghe, W.. (2018). Back to the future: Epigenetic clock plasticity towards healthy aging. Mechanisms of Ageing and Development
Plain numerical DOI: 10.1016/j.mad.2018.01.002
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“Aging is the most important risk factor for major human lifestyle diseases, including cancer, neurological and cardiometabolic disorders. due to the complex interplay between genetics, lifestyle and environmental factors, some individuals seem to age faster than others, whereas centenarians seem to have a slower aging process. therefore, a biochemical biomarker reflecting the relative biological age would be helpful to predict an individual’s health status and aging disease risk. although it is already known for years that cumulative epigenetic changes occur upon aging, dna methylation patterns were only recently used to construct an epigenetic clock predictor for biological age, which is a measure of how well your body functions compared to your chronological age. moreover, the epigenetic dna methylation clock signature is increasingly applied as a biomarker to estimate aging disease susceptibility and mortality risk. finally, the epigenetic clock signature could be used as a lifestyle management tool to monitor healthy aging, to evaluate preventive interventions against chronic aging disorders and to extend healthy lifespan. dissecting the mechanism of the epigenetic aging clock will yield valuable insights into the aging process and how it can be manipulated to improve health span.”
Luo, X., & He, Y.. (2020). Experiencing winter for spring flowering: A molecular epigenetic perspective on vernalization. Journal of Integrative Plant Biology
Plain numerical DOI: 10.1111/jipb.12896
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“Many over-wintering plants, through vernalization, overcome a block to flowering and thus acquire competence to flower in the following spring after experiencing prolonged cold exposure or winter cold. the vernalization pathways in different angiosperm lineages appear to have convergently evolved to adapt to temperate climates. molecular and epigenetic mechanisms for vernalization regulation have been well studied in the crucifer model plant arabidopsis thaliana. here, we review recent progresses on the vernalization pathway in arabidopsis. in addition, we summarize current molecular and genetic understandings of vernalization regulation in temperate grasses including wheat and brachypodium, two monocots from pooideae, followed by a brief discussion on divergence of the vernalization pathways between brassicaceae and pooideae.”
Torroglosa, A., Villalba-Benito, L., Luzón-Toro, B., Fernández, R. M., Antiñolo, G., & Borrego, S.. (2019). Epigenetic mechanisms in hirschsprung disease. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms20133123
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“Hirschsprung disease (hscr, omim 142623) is due to a failure of enteric precursor cells derived from neural crest (epcs) to proliferate, migrate, survive or differentiate during enteric nervous system (ens) formation. this is a complex process which requires a strict regulation that results in an ens specific gene expression pattern. alterations at this level lead to the onset of neurocristopathies such as hscr. gene expression is regulated by different mechanisms, such as dna modifications (at the epigenetic level), transcriptional mechanisms (transcription factors, silencers, enhancers and repressors), postranscriptional mechanisms (3’utr and ncrna) and regulation of translation. all these mechanisms are finally implicated in cell signaling to determine the migration, proliferation, differentiation and survival processes for correct ens development. in this review, we have performed an overview on the role of epigenetic mechanisms at transcriptional and posttranscriptional levels on these cellular events in neural crest cells (nccs), ens development, as well as in hscr.”
Talarowska, M.. (2020). Epigenetic Mechanisms in the Neurodevelopmental Theory of Depression. Depression Research and Treatment
Plain numerical DOI: 10.1155/2020/6357873
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“The genome (genes), epigenome, and environment work together from the earliest stages of human life to produce a phenotype of human health or disease. epigenetic modifications, including among other things: dna methylation, modifications of histones and chromatin structure, as well as functions of noncoding rna, are coresponsible for specific patterns of gene expression. this refers also to mental disorders, including depressive disorders. early childhood experiences accompanied by severe stressors (considered a risk factor for depression in adult life) are linked with changes in gene expression. they include genes involved in a response to stress (hypothalamic-pituitary-adrenal axis, hpa), associated with autonomic nervous system hyperactivity and with cortical, and subcortical processes of neuroplasticity and neurodegeneration. these are, among others: gene encoding glucocorticoid receptor, fk506 binding protein 5 gene (fkbp5), gene encoding arginine vasopressin and oestrogen receptor alpha, 5-hydroxy-tryptamine transporter gene (slc6a4), and gene encoding brain-derived neurotrophic factor. how about personality? can the experiences unique to every human being, the history of his or her development and gene-environment interactions, through epigenetic mechanisms, shape the features of our personality? can we pass on these features to future generations? hence, is the risk of depression inherent in our biological nature? can we change our destiny?”
Surani, M. A., Hayashi, K., & Hajkova, P.. (2007). Genetic and Epigenetic Regulators of Pluripotency. Cell
Plain numerical DOI: 10.1016/j.cell.2007.02.010
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“Genetic and epigenetic mechanisms regulate the transition from the totipotent zygote to pluripotent primitive ectoderm cells in the inner cell mass of mouse blastocysts. these pluripotent cells can be propagated indefinitely in vitro, underpinned by a unique epigenetic state. following implantation of the blastocyst, diverse epigenetic modifiers control differentiation of pluripotent epiblast cells into somatic cells, while specification of germ cells requires repression of the somatic program. regenerating totipotency during development of germ cells entails re-expression of pluripotency-specific genes and extensive erasure of epigenetic modifications. increasing knowledge of key underlying mechanisms heightens prospects for creating pluripotent cells directly from adult somatic cells. © 2007 elsevier inc. all rights reserved.”
Eyler, C. E., Matsunaga, H., Hovestadt, V., Vantine, S. J., Van Galen, P., & Bernstein, B. E.. (2020). Single-cell lineage analysis reveals genetic and epigenetic interplay in glioblastoma drug resistance. Genome Biology
Plain numerical DOI: 10.1186/s13059-020-02085-1
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“Background: tumors can evolve and adapt to therapeutic pressure by acquiring genetic and epigenetic alterations that may be transient or stable. a precise understanding of how such events contribute to intratumoral heterogeneity, dynamic subpopulations, and overall tumor fitness will require experimental approaches to prospectively label, track, and characterize resistant or otherwise adaptive populations at the single-cell level. in glioblastoma, poor efficacy of receptor tyrosine kinase (rtk) therapies has been alternatively ascribed to genetic heterogeneity or to epigenetic transitions that circumvent signaling blockade. results: we combine cell lineage barcoding and single-cell transcriptomics to trace the emergence of drug resistance in stem-like glioblastoma cells treated with rtk inhibitors. whereas a broad variety of barcoded lineages adopt a notch-dependent persister phenotype that sustains them through early drug exposure, rare subclones acquire genetic changes that enable their rapid outgrowth over time. single-cell analyses reveal that these genetic subclones gain copy number amplifications of the insulin receptor substrate-1 and substrate-2 (irs1 or irs2) loci, which activate insulin and akt signaling programs. persister-like cells and genomic amplifications of irs2 and other loci are evident in primary glioblastomas and may underlie the inefficacy of targeted therapies in this disease. conclusions: a method for combined lineage tracing and scrna-seq reveals the interplay between complementary genetic and epigenetic mechanisms of resistance in a heterogeneous glioblastoma tumor model.”
Baulcombe, D. C., & Dean, C.. (2014). Epigenetic regulation in plant responses to the environment. Cold Spring Harbor Perspectives in Biology
Plain numerical DOI: 10.1101/cshperspect.a019471
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“In this article, we review environmentally mediated epigenetic regulation in plants using two case histories. one of these, vernalization, mediates adaptation of plants to different environments and it exemplifies processes that are reset in each generation. the other, virus-induced silencing, involves transgenerationally inherited epigenetic modifications. heritable epigenetic marks may result in heritable phenotypic variation, influencing fitness, and so be subject to natural selection. however, unlike genetic inheritance, the epigenetic modifications showinstabilityand are influenced by the environment. these two case histories are then compared with other phenomena in plant biology that are likely to represent epigenetic regulation in response to the environment. © 2014 cold spring harbor laboratory press; all rights reserved.”
Soler-Botija, C., Forcales, S. V., & Bayés Genís, A.. (2020). Spotlight on epigenetic reprogramming in cardiac regeneration. Seminars in Cell and Developmental Biology
Plain numerical DOI: 10.1016/j.semcdb.2019.04.009
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“Heart failure of ischemic origin is caused by the presence of a large scar resulting from an acute myocardial infarction. acute myocardial infarction generally occurs when blood supply to the heart is blocked. regenerative strategies that limit infarct injury would be able to prevent adverse post-ischemic remodelling and maintain the structural support necessary for effective cardiomyocyte contraction. our understanding of endogenous cardiac regeneration and its biology has exposed a variety of targets for therapeutic approaches, such as non-coding rnas, dna methylation, histone modifications, direct cardiac reprogramming, cell transplantation, stimulation of resident cardiomyocytes, proliferation, and inhibition of cardiomyocyte death. in this review, we address the epigenetic mechanisms underlying these strategies and the use of therapeutic epigenetic molecules or epidrugs.”
Santos, E. S. Dos, Rodrigues-Fernandes, C. I., Ramos, J. C., Fonseca, F. P., & Leme, A. F. P.. (2021). Epigenetic alterations in ameloblastomas: A literature review. Journal of Clinical and Experimental Dentistry
Plain numerical DOI: 10.4317/jced.56191
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“Background: ameloblastoma is a locally aggressive tumor, originated from odontogenic epithelium, and affects the jawbones with an elevated recurrence rate. the molecular mechanisms involved with the pathogenesis of this tumor remain undetermined. this review aimed to describe the current data regarding epigenetic alterations in ameloblastoma. material and methods: a systematized electronic search was performed in the english-language literature in three databases, combining the following keywords: ameloblastoma, epigenetic, methylation, noncoding rna, histone acetylation. results: according to the gathered results of 11 studies in this review, epigenetic alterations could induce the development and progression of ameloblastoma. dna methylation has been the most assessed mechanism in ameloblastomas. conclusions: current literature data indicate that epigenetic events can be involved in the etiopathogenesis of ameloblastomas.”
Mehdipour, P., Santoro, F., & Minucci, S.. (2015). Epigenetic alterations in acute myeloid leukemias. FEBS Journal
Plain numerical DOI: 10.1111/febs.13142
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“Acute myeloid leukemia (aml) is a heterogeneous disease for which the standard treatment with cytotoxic chemotherapy has remained largely unchanged for over four decades, with unfavorable clinical results. epigenetic alterations have been described in several amls, and in some cases their origin has been studied in detail mechanistically (such as in acute promyelocytic leukemia, caused by the promyelocytic leukemia-retinoic acid receptor-α fusion protein). recently, the advent of massive parallel sequencing has revealed that > 70% of aml cases have mutations in dna methylation-related genes or mutations in histone modifiers, showing that epigenetic alterations are key players in the development of most, if not all, amls, and pointing to the exploitation of new molecular targets for more efficacious therapies. this review provides a brief overview of the latest findings on the characterization of the epigenetic landscape of aml and discusses the rationale for the optimization of epigenetic therapy of aml. acute myeloid leukemia (aml) is the most common form of acute leukemia in adults. mutations in epigenetic modifiers are emerging as a large class of mutations critical for aml development. this review gives a brief overview on the latest findings on the characterization of the epigenetic landscape in aml and the rational for the optimization of epigenetic therapy.”
Angers, B., Perez, M., Menicucci, T., & Leung, C.. (2020). Sources of epigenetic variation and their applications in natural populations. Evolutionary Applications
Plain numerical DOI: 10.1111/eva.12946
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“Epigenetic processes manage gene expression and products in a real-time manner, allowing a single genome to display different phenotypes. in this paper, we discussed the relevance of assessing the different sources of epigenetic variation in natural populations. for a given genotype, the epigenetic variation could be environmentally induced or occur randomly. strategies developed by organisms to face environmental fluctuations such as phenotypic plasticity and diversified bet-hedging rely, respectively, on these different sources. random variation can also represent a proxy of developmental stability and can be used to assess how organisms deal with stressful environmental conditions. we then proposed the microbiome as an extension of the epigenotype of the host to assess the factors determining the establishment of the community of microorganisms. finally, we discussed these perspectives in the applied context of conservation.”
Westphal, M., Sant, P., Hauser, A. T., Jung, M., & Driever, W.. (2020). Chemical Genetics Screen Identifies Epigenetic Mechanisms Involved in Dopaminergic and Noradrenergic Neurogenesis in Zebrafish. Frontiers in Genetics
Plain numerical DOI: 10.3389/fgene.2020.00080
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“The cell type diversity and complexity of the nervous system is generated by a network of signaling events, transcription factors, and epigenetic regulators. signaling and transcriptional control have been easily amenable to forward genetic screens in model organisms like zebrafish. in contrast, epigenetic mechanisms have been somewhat elusive in genetic screens, likely caused by broad action in multiple developmental pathways that masks specific phenotypes, but also by genetic redundancies of epigenetic factors. here, we performed a screen using small molecule inhibitors of epigenetic mechanisms to reveal contributions to specific aspects of neurogenesis in zebrafish. we chose development of dopaminergic and noradrenergic neurons from neural progenitors as target of epigenetic regulation. we performed the screen in two phases: first, we tested a small molecule inhibitor library that targets a broad range of epigenetic protein classes and mechanisms, using expression of the dopaminergic and noradrenergic marker tyrosine hydroxylase as readout. we identified 10 compounds, including hdac, bromodomain and hat inhibitors, which interfered with dopaminergic and noradrenergic development in larval zebrafish. in the second screening phase, we aimed to identify neurogenesis stages affected by these 10 inhibitors. we analyzed treated embryos for effects on neural stem cells, growth progression of the retina, and apoptosis in neural tissues. in addition, we analyzed effects on islet1 expressing neuronal populations to determine potential selectivity of compounds for transmitter phenotypes. in summary, our targeted screen of epigenetic inhibitors identified specific compounds, which reveal chromatin regulator classes that contribute to dopaminergic and noradrenergic neurogenesis in vivo.”
Mazzone, R., Zwergel, C., Artico, M., Taurone, S., Ralli, M., Greco, A., & Mai, A.. (2019). The emerging role of epigenetics in human autoimmune disorders. Clinical Epigenetics
Plain numerical DOI: 10.1186/s13148-019-0632-2
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“Epigenetic pathways play a pivotal role in the development and function of the immune system. over the last decade, a growing body of studies has been published out seeking to explain a correlation between epigenetic modifications and the development of autoimmune disorders. epigenetic changes, such as dna methylation, histone modifications, and noncoding rnas, are involved in the pathogenesis of autoimmune diseases mainly by regulating gene expression. this paper reviews the importance of epigenetic alterations during the development of the most prevalent human autoimmune diseases, such as systemic lupus erythematosus (sle), rheumatoid arthritis (ra), systemic sclerosis (ssc), sjogren’s syndrome (ss), autoimmune thyroid diseases (aitd), and type 1 diabetes (t1d), aiming to provide new insights in the pathogenesis of autoimmune diseases and the possibility to develop novel therapeutic approaches targeting the epigenome.”
Lee, Y., Choufani, S., Weksberg, R., Wilson, S. L., Yuan, V., Burt, A., … Horvath, S.. (2019). Placental epigenetic clocks: Estimating gestational age using placental DNA methylation levels. Aging
Plain numerical DOI: 10.18632/aging.102049
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“The human pan-tissue epigenetic clock is widely used for estimating age across the entire lifespan, but it does not lend itself well to estimating gestational age (ga) based on placental dnam methylation (dnam) data. we replicate previous findings demonstrating a strong correlation between ga and genome-wide dnam changes. using substantially more dnam arrays (n=1,102 in the training set) than a previous study, we present three new placental epigenetic clocks: 1) a robust placental clock (rpc) which is unaffected by common pregnancy complications (e.g., gestational diabetes, preeclampsia), 2) a control placental clock (cpc) constructed using placental samples from pregnancies without known placental pathology, and 3) a refined rpc for uncomplicated term pregnancies. these placental clocks are highly accurate estimators of ga based on placental tissue; e.g., predicted ga based on rpc is highly correlated with actual ga (r > 0.95 in test data, median error less than one week). we show that epigenetic clocks derived from cord blood or other tissues do not accurately estimate ga in placental samples. while fundamentally different from horvath’s pan-tissue epigenetic clock, placental clocks closely track fetal age during development and may have interesting applications.”
Hanna, C. W., Demond, H., & Kelsey, G.. (2018). Epigenetic regulation in development: Is the mouse a good model for the human?. Human Reproduction Update
Plain numerical DOI: 10.1093/humupd/dmy021
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“BACKGROUND: over the past few years, advances in molecular technologies have allowed unprecedented mapping of epigenetic modifications in gametes and during early embryonic development. this work is allowing a detailed genomic analysis, which for the first time can answer long-standing questions about epigenetic regulation and reprogramming, and highlights differences between mouse and human, the implications of which are only beginning to be explored. objective and rationale: in this review, we summarise new low-cell molecular methods enabling the interrogation of epigenetic information in gametes and early embryos, the mechanistic insights these have provided, and contrast the findings in mouse and human. search methods: relevant studies were identified by pubmed search. outcomes: we discuss the levels of epigenetic regulation, from dna modifications to chromatin organisation, during mouse gametogenesis, fertilisation and pre-and post-implantation development. the recently characterised features of the oocyte epigenome highlight its exceptionally unique regulatory landscape. the chromatin organisation and epigenetic landscape of both gametic genomes are rapidly reprogrammed after fertilisation. this extensive epigenetic remodelling is necessary for zygotic genome activation, but the mechanistic link remains unclear. while the vast majority of epigenetic information from the gametes is erased in pre-implantation development, new insights suggest that repressive histone modifications from the oocyte may mediate a novel mechanism of imprinting. to date, the characterisation of epigenetics in human development has been almost exclusively limited to dna methylation profiling; these data reinforce that the global dynamics are conserved between mouse and human. however, as we look closer, it is becoming apparent that the mechanisms regulating these dynamics are distinct. these early findings emphasise the importance of investigations of fundamental epigenetic mechanisms in both mouse and humans. wider implications: failures in epigenetic regulation have been implicated in human disease and infertility. with increasing maternal age and use of reproductive technologies in countries all over the world, it is becoming ever more important to understand the necessary processes required to establish a developmentally competent embryo. furthermore, it is essential to evaluate the extent to which these epigenetic patterns are sensitive to such technologies and other …”
Tee, W. W., & Reinberg, D.. (2014). Chromatin features and the epigenetic regulation of pluripotency states in ESCs. Development (Cambridge)
Plain numerical DOI: 10.1242/dev.096982
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“In pluripotent stem cells, the interplay between signaling cues, epigenetic regulators and transcription factors orchestrates developmental potency. flexibility in gene expression control is imparted by molecular changes to the nucleosomes, the building block of chromatin. here, we review the current understanding of the role of chromatin as a plastic and integrative platform to direct gene expression changes in pluripotent stem cells, giving rise to distinct pluripotent states. we will further explore the concept of epigenetic asymmetry, focusing primarily on histone stoichiometry and their associated modifications, that is apparent at both the nucleosome and chromosome-wide levels, and discuss the emerging importance of these asymmetric chromatin configurations in diversifying epigenetic states and their implications for cell fate control. © 2014. published by the company of biologists ltd.”
Hillary, R. F., Stevenson, A. J., McCartney, D. L., Campbell, A., Walker, R. M., Howard, D. M., … Marioni, R. E.. (2020). Epigenetic measures of ageing predict the prevalence and incidence of leading causes of death and disease burden. Clinical Epigenetics
Plain numerical DOI: 10.1186/s13148-020-00905-6
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“Background: individuals of the same chronological age display different rates of biological ageing. a number of measures of biological age have been proposed which harness age-related changes in dna methylation profiles. these measures include five ‘epigenetic clocks’ which provide an index of how much an individual’s biological age differs from their chronological age at the time of measurement. the five clocks encompass methylation-based predictors of chronological age (horvathage, hannumage), all-cause mortality (dnam phenoage, dnam grimage) and telomere length (dnam telomere length). a sixth epigenetic measure of ageing differs from these clocks in that it acts as a speedometer providing a single time-point measurement of the pace of an individual’s biological ageing. this measure of ageing is termed dunedinpoam. in this study, we test the association between these six epigenetic measures of ageing and the prevalence and incidence of the leading causes of disease burden and mortality in high-income countries (n ≤ 9537, generation scotland: scottish family health study). results: dnam grimage predicted incidence of clinically diagnosed chronic obstructive pulmonary disease (copd), type 2 diabetes and ischemic heart disease after 13 years of follow-up (hazard ratios = 2.22, 1.52 and 1.41, respectively). dunedinpoam predicted the incidence of copd and lung cancer (hazard ratios = 2.02 and 1.45, respectively). dnam phenoage predicted incidence of type 2 diabetes (hazard ratio = 1.54). dnam telomere length associated with the incidence of ischemic heart disease (hazard ratio = 0.80). dnam grimage associated with all-cause mortality, the prevalence of copd and spirometry measures at the study baseline. these associations were present after adjusting for possible confounding risk factors including alcohol consumption, body mass index, deprivation, education and tobacco smoking and surpassed stringent bonferroni-corrected significance thresholds. conclusions: our data suggest that epigenetic measures of ageing may have utility in clinical settings to complement gold-standard methods for disease assessment and management.”
Kwon, M. J., Kim, S., Han, M. H., & Lee, S. B.. (2016). Epigenetic changes in neurodegenerative diseases. Molecules and Cells
Plain numerical DOI: 10.14348/molcells.2016.0233
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“Afflicted neurons in various neurodegenerative diseases generally display diverse and complex pathological features before catastrophic occurrence of massive neuronal loss at the late stages of the diseases. this complex nature of neuronal pathophysiology inevitably implicates systemwide changes in basic cellular activities such as transcriptional controls and signal cascades, and so on, as a cause. recently, as one of these systemwide cellular changes associated with neurodegenerative diseases, epigenetic changes caused by protein toxicity have begun to be highlighted. notably, recent advances in related techniques including next-generation sequencing (ngs) and mass spectrometry enable us to monitor changes in the post-translational modifications (ptms) of histone proteins and to link these changes in histone ptms to the specific transcriptional changes. indeed, epigenetic alterations and consequent changes in neuronal transcriptome are now begun to be extensively studied in neurodegenerative diseases including alzheimer’s disease (ad). in this review, we will discuss details of our current understandings on epigenetic changes associated with two representative neurodegenerative diseases [ad and polyglutamine (polyq) diseases] and further discuss possible future development of pharmaceutical treatment of the diseases through modulating these epigenetic changes.”
Fransquet, P. D., Wrigglesworth, J., Woods, R. L., Ernst, M. E., & Ryan, J.. (2019). The epigenetic clock as a predictor of disease and mortality risk: A systematic review and meta-analysis. Clinical Epigenetics
Plain numerical DOI: 10.1186/s13148-019-0656-7
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“Background: ageing is one of the principal risk factors for many chronic diseases. however, there is considerable between-person variation in the rate of ageing and individual differences in their susceptibility to disease and death. epigenetic mechanisms may play a role in human ageing, and dna methylation age biomarkers may be good predictors of age-related diseases and mortality risk. the aims of this systematic review were to identify and synthesise the evidence for an association between peripherally measured dna methylation age and longevity, age-related disease, and mortality risk. methods: a systematic search was conducted in line with the preferred reporting items for systematic reviews and meta-analyses (prisma) guidelines. using relevant search terms, medline, embase, cochrane central register of controlled trials, and psychinfo databases were searched to identify articles meeting the inclusion criteria. studies were assessed for bias using joanna briggs institute critical appraisal checklists. data was extracted from studies measuring age acceleration as a predictor of age-related diseases, mortality or longevity, and the findings for similar outcomes compared. using review manager 5.3 software, two meta-analyses (one per epigenetic clock) were conducted on studies measuring all-cause mortality. results: twenty-three relevant articles were identified, including a total of 41,607 participants. four studies focused on ageing and longevity, 11 on age-related disease (cancer, cardiovascular disease, and dementia), and 11 on mortality. there was some, although inconsistent, evidence for an association between increased dna methylation age and risk of disease. meta-analyses indicated that each 5-year increase in dna methylation age was associated an 8 to 15% increased risk of mortality. conclusion: due to the small number of studies and heterogeneity in study design and outcomes, the association between dna methylation age and age-related disease and longevity is inconclusive. increased epigenetic age was associated with mortality risk, but positive publication bias needs to be considered. further research is needed to determine the extent to which dna methylation age can be used as a clinical biomarker.”
Salameh, Y., Bejaoui, Y., & El Hajj, N.. (2020). DNA Methylation Biomarkers in Aging and Age-Related Diseases. Frontiers in Genetics
Plain numerical DOI: 10.3389/fgene.2020.00171
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“Recent research efforts provided compelling evidence of genome-wide dna methylation alterations in aging and age-related disease. it is currently well established that dna methylation biomarkers can determine biological age of any tissue across the entire human lifespan, even during development. there is growing evidence suggesting epigenetic age acceleration to be strongly linked to common diseases or occurring in response to various environmental factors. dna methylation based clocks are proposed as biomarkers of early disease risk as well as predictors of life expectancy and mortality. in this review, we will summarize key advances in epigenetic clocks and their potential application in precision health. we will also provide an overview of progresses in epigenetic biomarker discovery in alzheimer’s, type 2 diabetes, and cardiovascular disease. furthermore, we will highlight the importance of prospective study designs to identify and confirm epigenetic biomarkers of disease.”
Carroll, J. E., Irwin, M. R., Levine, M., Seeman, T. E., Absher, D., Assimes, T., & Horvath, S.. (2017). Epigenetic Aging and Immune Senescence in Women With Insomnia Symptoms: Findings From the Women’s Health Initiative Study. Biological Psychiatry
Plain numerical DOI: 10.1016/j.biopsych.2016.07.008
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“Background insomnia symptoms are associated with vulnerability to age-related morbidity and mortality. cross-sectional data suggest that accelerated biological aging may be a mechanism through which sleep influences risk. a novel method for determining age acceleration using epigenetic methylation to dna has demonstrated predictive utility as an epigenetic clock and prognostic of age-related morbidity and mortality. methods we examined the association of epigenetic age and immune cell aging with sleep in the women’s health initiative study (n = 2078; mean 64.5 ± 7.1 years of age) with assessment of insomnia symptoms (restlessness, difficulty falling asleep, waking at night, trouble getting back to sleep, and early awakenings), sleep duration (short sleep 5 hours or less; long sleep greater than 8 hours), epigenetic age, naive t cell (cd8+cd45ra+ccr7+), and late differentiated t cells (cd8+cd28–cd45ra–). results insomnia symptoms were related to advanced epigenetic age (β ± se = 1.02 ± 0.37, p =.005) after adjustments for covariates. insomnia symptoms were also associated with more late differentiated t cells (β ± se = 0.59 ± 0.21, p =.006), but not with naive t cells. self-reported short and long sleep duration were unrelated to epigenetic age. short sleep, but not long sleep, was associated with fewer naive t cells (p <.005) and neither was related to late differentiated t cells. conclusions symptoms of insomnia were associated with increased epigenetic age of blood tissue and were associated with higher counts of late differentiated cd8+ t cells. short sleep was unrelated to epigenetic age and late differentiated cell counts, but was related to a decline in naive t cells. in this large population-based study of women in the united states, insomnia symptoms are implicated in accelerated aging.”
Wang, M. Z., Li, H. L., Li, J. M., & Yu, F. H.. (2020). Correlations between genetic, epigenetic and phenotypic variation of an introduced clonal herb. Heredity
Plain numerical DOI: 10.1038/s41437-019-0261-8
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“Heritable epigenetic modifications may occur in response to environmental variation, further altering phenotypes through gene regulation, without genome sequence changes. however, epigenetic variation in wild plant populations and their correlations with genetic and phenotypic variation remain largely unknown, especially for clonal plants. we investigated genetic, epigenetic and phenotypic variation of ten populations of an introduced clonal herb hydrocotyle vulgaris in china. populations of h. vulgaris exhibited extremely low genetic diversity with one genotype exclusively dominant, but significantly higher epigenetic diversity. both intra- and inter-population epigenetic variation were related to genetic variation. but there was no correlation between intra-/inter-population genetic variation and phenotypic variation. when genetic variation was controlled, intra-population epigenetic diversity was related to petiole length, specific leaf area, and leaf area variation, while inter-population epigenetic distance was correlated with leaf area differentiation. our study provides empirical evidence that even though epigenetic variation is partly under genetic control, it could also independently play a role in shaping plant phenotypes, possibly serving as a pathway to accelerate evolution of clonal plant populations.”
Xie, N., Zhou, Y., Sun, Q., & Tang, B.. (2018). Novel epigenetic techniques provided by the CRISPR/Cas9 System. Stem Cells International
Plain numerical DOI: 10.1155/2018/7834175
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“Epigenetics classically refers to the inheritable changes of hereditary information without perturbing dna sequences. understanding mechanisms of how epigenetic factors contribute to inheritable phenotype changes and cell identity will pave the way for us to understand diverse biological processes. in recent years, the emergence of crispr/cas9 technology has provided us with new routes to the epigenetic field. in this review, novel epigenetic techniques utilizing the crispr/cas9 system are the main contents to be discussed, including epigenome editing, temporal and spatial control of epigenetic effectors, noncoding rna manipulation, chromatin in vivo imaging, and epigenetic element screening.”
Patel, S. A., & Vanharanta, S.. (2017). Epigenetic determinants of metastasis. Molecular Oncology
Plain numerical DOI: 10.1016/j.molonc.2016.09.008
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“Genetic analyses of cancer progression in patient samples and model systems have thus far failed to identify specific mutational drivers of metastasis. yet, at least in experimental systems, metastatic cancer clones display stable traits that can facilitate progression through the many steps of metastasis. how cancer cells establish and maintain the transcriptional programmes required for metastasis remains mostly unknown. emerging evidence suggests that metastatic traits may arise from epigenetically altered transcriptional output of the oncogenic signals that drive tumour initiation and early progression. molecular dissection of such mechanisms remains a central challenge for a comprehensive understanding of the origins of metastasis.”
Kwon, M. J., Kim, S., Han, M. H., & Lee, S. B.. (2016). Epigenetic changes in neurodegenerative diseases. Molecules and Cells
Plain numerical DOI: 10.14348/molcells.2016.0233
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“Afflicted neurons in various neurodegenerative diseases generally display diverse and complex pathological features before catastrophic occurrence of massive neuronal loss at the late stages of the diseases. this complex nature of neuronal pathophysiology inevitably implicates systemwide changes in basic cellular activities such as transcriptional controls and signal cascades, and so on, as a cause. recently, as one of these systemwide cellular changes associated with neurodegenerative diseases, epigenetic changes caused by protein toxicity have begun to be highlighted. notably, recent advances in related techniques including next-generation sequencing (ngs) and mass spectrometry enable us to monitor changes in the post-translational modifications (ptms) of histone proteins and to link these changes in histone ptms to the specific transcriptional changes. indeed, epigenetic alterations and consequent changes in neuronal transcriptome are now begun to be extensively studied in neurodegenerative diseases including alzheimer’s disease (ad). in this review, we will discuss details of our current understandings on epigenetic changes associated with two representative neurodegenerative diseases [ad and polyglutamine (polyq) diseases] and further discuss possible future development of pharmaceutical treatment of the diseases through modulating these epigenetic changes.”
Harvey, Z. H., Chen, Y., & Jarosz, D. F.. (2018). Protein-Based Inheritance: Epigenetics beyond the Chromosome. Molecular Cell
Plain numerical DOI: 10.1016/j.molcel.2017.10.030
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“Epigenetics refers to changes in phenotype that are not rooted in dna sequence. this phenomenon has largely been studied in the context of chromatin modification. yet many epigenetic traits are instead linked to self-perpetuating changes in the individual or collective activity of proteins. most such proteins are prions (e.g., [psi+], [ure3], [swi+], [mot3+], [mph1+], [lsb+], and [gar+]), which have the capacity to adopt at least one conformation that self-templates over long biological timescales. this allows them to serve as protein-based epigenetic elements that are readily broadcast through mitosis and meiosis. in some circumstances, self-templating can fuel disease, but it also permits access to multiple activity states from the same polypeptide and transmission of that information across generations. ensuing phenotypic changes allow genetically identical cells to express diverse and frequently adaptive phenotypes. although long thought to be rare, protein-based epigenetic inheritance has now been uncovered in all domains of life. although long thought to be the exclusive purview of chromatin modification, recent insights suggest that epigenetic inheritance driven by protein alone is also common. harvey et al. review molecular mechanisms driving this form of inheritance, and they highlight key discoveries regarding its diverse roles in stress responses, evolution, and gene regulation.”
Roussel, M. F., & Stripay, J. L.. (2018). Epigenetic Drivers in Pediatric Medulloblastoma. Cerebellum
Plain numerical DOI: 10.1007/s12311-017-0899-9
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“Epigenetics is the process by which gene expression is regulated by events other than alterations of the genome. this includes dna methylation, histone modifications, chromatin remodeling, micrornas, and long non-coding rnas. methylation of dna, chromatin remodeling, and histone modifications regulate the chromatin and access of transcription factors to dna and in turn gene transcription. alteration of chromatin is now recognized to be deregulated in many cancers. medulloblastoma is an embryonal tumor of the cerebellum and the most common malignant brain tumor in children, that occurs only rarely in adults. medulloblastoma is characterized by four major molecularly and histopathologically distinct groups, wingless (wnt), sonic hedgehog (shh), group 3 (g3), and group 4 (g4), that, except for wnt, are each now subdivided in several subgroups. gene expression array, next-generation sequencing, and methylation profiling of several hundred primary tumors by several consortia and independent groups revealed that medulloblastomas harbor a paucity of mutations most of which occur in epigenetic regulators, genetic alterations in oncogenes and tumor suppressors, in addition to copy number alterations and chromosome gains and losses. remarkably, some tumors have no reported mutations, suggesting that some genes required for oncogenesis might be regulated by epigenetic mechanisms which are still to be uncovered and validated. this review will highlight several epigenetic regulators focusing mainly on histone modifiers identified in medulloblastoma.”
Carroll, J. E., Irwin, M. R., Levine, M., Seeman, T. E., Absher, D., Assimes, T., & Horvath, S.. (2017). Epigenetic Aging and Immune Senescence in Women With Insomnia Symptoms: Findings From the Women’s Health Initiative Study. Biological Psychiatry
Plain numerical DOI: 10.1016/j.biopsych.2016.07.008
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“Background insomnia symptoms are associated with vulnerability to age-related morbidity and mortality. cross-sectional data suggest that accelerated biological aging may be a mechanism through which sleep influences risk. a novel method for determining age acceleration using epigenetic methylation to dna has demonstrated predictive utility as an epigenetic clock and prognostic of age-related morbidity and mortality. methods we examined the association of epigenetic age and immune cell aging with sleep in the women’s health initiative study (n = 2078; mean 64.5 ± 7.1 years of age) with assessment of insomnia symptoms (restlessness, difficulty falling asleep, waking at night, trouble getting back to sleep, and early awakenings), sleep duration (short sleep 5 hours or less; long sleep greater than 8 hours), epigenetic age, naive t cell (cd8+cd45ra+ccr7+), and late differentiated t cells (cd8+cd28–cd45ra–). results insomnia symptoms were related to advanced epigenetic age (β ± se = 1.02 ± 0.37, p =.005) after adjustments for covariates. insomnia symptoms were also associated with more late differentiated t cells (β ± se = 0.59 ± 0.21, p =.006), but not with naive t cells. self-reported short and long sleep duration were unrelated to epigenetic age. short sleep, but not long sleep, was associated with fewer naive t cells (p <.005) and neither was related to late differentiated t cells. conclusions symptoms of insomnia were associated with increased epigenetic age of blood tissue and were associated with higher counts of late differentiated cd8+ t cells. short sleep was unrelated to epigenetic age and late differentiated cell counts, but was related to a decline in naive t cells. in this large population-based study of women in the united states, insomnia symptoms are implicated in accelerated aging.”
Nono, M., Kishimoto, S., Sato-Carlton, A., Carlton, P. M., Nishida, E., & Uno, M.. (2020). Intestine-to-Germline Transmission of Epigenetic Information Intergenerationally Ensures Systemic Stress Resistance in C. elegans. Cell Reports
Plain numerical DOI: 10.1016/j.celrep.2020.02.050
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“Changes in epigenetic states affect organismal homeostasis, including stress resistance. however, the mechanisms coordinating epigenetic states and systemic stress resistance remain largely unknown. here, we identify the intestine-to-germline communication of epigenetic states, which intergenerationally enhances stress resistance in c. elegans. the alterations in epigenetic states by deficiency of the histone h3k4me3 modifier ash-2 in the intestine or germline increase organismal stress resistance, which is abrogated by knockdown of the h3k4 demethylase rbr-2. remarkably, the increase in stress resistance induced by ash-2 deficiency in the intestine is abrogated by rbr-2 knockdown in the germline, suggesting the intestine-to-germline transmission of epigenetic information. this communication from intestine to germline in the parental generation increases stress resistance in the next generation. moreover, the intertissue communication is mediated partly by transcriptional regulation of f08f1.3. these results reveal that intertissue communication of epigenetic information provides mechanisms for intergenerational regulation of systemic stress resistance.”
Dusinska, M., Tulinska, J., El Yamani, N., Kuricova, M., Liskova, A., Rollerova, E., … Smolkova, B.. (2017). Immunotoxicity, genotoxicity and epigenetic toxicity of nanomaterials: New strategies for toxicity testing?. Food and Chemical Toxicology
Plain numerical DOI: 10.1016/j.fct.2017.08.030
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“The unique properties of nanomaterials (nms) are beneficial in numerous industrial and medical applications. however, they could also induce unintended effects. thus, a proper strategy for toxicity testing is essential in human hazard and risk assessment. toxicity can be tested in vivo and in vitro; in compliance with the 3rs, alternative strategies for in vitro testing should be further developed for nms. robust, standardized methods are of great importance in nanotoxicology, with comprehensive material characterization and uptake as an integral part of the testing strategy. oxidative stress has been shown to be an underlying mechanism of possible toxicity of nms, causing both immunotoxicity and genotoxicity. for testing nms in vitro, a battery of tests should be performed on cells of human origin, either cell lines or primary cells, in conditions as close as possible to an in vivo situation. novel toxicity pathways, particularly epigenetic modification, should be assessed along with conventional toxicity testing methods. however, to initiate epigenetic toxicity screens for nm exposure, there is a need to better understand their adverse effects on the epigenome, to identify robust and reproducible causal links between exposure, epigenetic changes and adverse phenotypic endpoints, and to develop improved assays to monitor epigenetic toxicity.”
Jones, P. A., Ohtani, H., Chakravarthy, A., & De Carvalho, D. D.. (2019). Epigenetic therapy in immune-oncology. Nature Reviews Cancer
Plain numerical DOI: 10.1038/s41568-019-0109-9
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“DNA methylation inhibitors have become the mainstay for treatment of certain haematological malignancies. in addition to their abilities to reactivate genes, including tumour suppressors, that have acquired dna methylation during carcinogenesis, they induce the expression of thousands of transposable elements including endogenous retroviruses and latent cancer testis antigens normally silenced by dna methylation in most somatic cells. this results in a state of viral mimicry in which treated cells mount an innate immune response by turning on viral defence genes and potentially expressing neoantigens. furthermore, these changes mediated by dna methylation inhibitors can also alter the function of immune cells relevant to acquired immunity. additionally, other inhibitors of epigenetic processes, such as histone deacetylases, methylases and demethylases, can elicit similar effects either individually or in combinations with dna methylation inhibitors. these findings together with rapid development of immunotherapies open new avenues for cancer treatment.”
Lee, Y., Choufani, S., Weksberg, R., Wilson, S. L., Yuan, V., Burt, A., … Horvath, S.. (2019). Placental epigenetic clocks: Estimating gestational age using placental DNA methylation levels. Aging
Plain numerical DOI: 10.18632/aging.102049
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“The human pan-tissue epigenetic clock is widely used for estimating age across the entire lifespan, but it does not lend itself well to estimating gestational age (ga) based on placental dnam methylation (dnam) data. we replicate previous findings demonstrating a strong correlation between ga and genome-wide dnam changes. using substantially more dnam arrays (n=1,102 in the training set) than a previous study, we present three new placental epigenetic clocks: 1) a robust placental clock (rpc) which is unaffected by common pregnancy complications (e.g., gestational diabetes, preeclampsia), 2) a control placental clock (cpc) constructed using placental samples from pregnancies without known placental pathology, and 3) a refined rpc for uncomplicated term pregnancies. these placental clocks are highly accurate estimators of ga based on placental tissue; e.g., predicted ga based on rpc is highly correlated with actual ga (r > 0.95 in test data, median error less than one week). we show that epigenetic clocks derived from cord blood or other tissues do not accurately estimate ga in placental samples. while fundamentally different from horvath’s pan-tissue epigenetic clock, placental clocks closely track fetal age during development and may have interesting applications.”
Korfi, K., Ali, S., Heward, J. A., & Fitzgibbon, J.. (2017). Follicular lymphoma, a B cell malignancy addicted to epigenetic mutations. Epigenetics
Plain numerical DOI: 10.1080/15592294.2017.1282587
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“While follicular lymphoma (fl) is exquisitely responsive to immuno-chemotherapy, many patients follow a relapsing remitting clinical course driven in part by a common precursor cell (cpc) population. advances in next generation sequencing have provided valuable insights into the genetic landscape of fl and its clonal evolution in response to therapy, implicating perturbations of epigenetic regulators as a hallmark of the disease. recurrent mutations of histone modifiers kmt2d, crebbp, ep300, ezh2, aridia, and linker histones are likely early events arising in the cpc pool, rendering epigenetic based therapies conceptually attractive for treatment of indolent and transformed fl. this review provides a synopsis of the main epigenetic aberrations and the current efforts in development and testing of epigenetic therapies in this b cell malignancy.”
Luo, X., & He, Y.. (2020). Experiencing winter for spring flowering: A molecular epigenetic perspective on vernalization. Journal of Integrative Plant Biology
Plain numerical DOI: 10.1111/jipb.12896
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“Many over-wintering plants, through vernalization, overcome a block to flowering and thus acquire competence to flower in the following spring after experiencing prolonged cold exposure or winter cold. the vernalization pathways in different angiosperm lineages appear to have convergently evolved to adapt to temperate climates. molecular and epigenetic mechanisms for vernalization regulation have been well studied in the crucifer model plant arabidopsis thaliana. here, we review recent progresses on the vernalization pathway in arabidopsis. in addition, we summarize current molecular and genetic understandings of vernalization regulation in temperate grasses including wheat and brachypodium, two monocots from pooideae, followed by a brief discussion on divergence of the vernalization pathways between brassicaceae and pooideae.”
Peedicayil, J.. (2016). Preclinical epigenetic models for screening epigenetic drugs for schizophrenia. Journal of Pharmacological and Toxicological Methods
Plain numerical DOI: 10.1016/j.vascn.2015.09.002
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“Schizophrenia is an important psychiatric disorder for which effective drugs are available. however, there are problems with current drug therapy of schizophrenia in that some patients do not respond adequately. moreover, some patients show treatment resistance and some patients show cognitive decline despite treatment. hence new and effective drugs will be useful for the treatment of this disorder. since there is increasing evidence that epigenetic mechanisms of gene expression are defective in schizophrenia, drugs that correct epigenetic defects, epigenetic drugs, could be useful in the treatment of this disorder. this paper discusses preclinical epigenetic models for screening epigenetic drugs for schizophrenia. it also discusses how such models could be useful for the discovery and development of such drugs.”
Ostrowska-Mazurek, A., Kasprzak, P., Kubala, S., Zaborowska, M., & Sobieszczuk-Nowicka, E.. (2020). Epigenetic landmarks of leaf senescence and crop improvement. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms21145125
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“This review synthesizes knowledge on epigenetic regulation of leaf senescence and discusses the possibility of using this knowledge to improve crop quality. this control level is implemented by different but interacting epigenetic mechanisms, including dna methylation, covalent histone modifications, and non-covalent chromatin remodeling. the genetic and epigenetic changes may act alone or together and regulate the gene expression, which may result in heritable (stress memory) changes and may lead to crop survival. in the review, the question also arises whether the mitotically stable epigenetic information can be used for crop improvement. the barley crop model for early and late events of dark-induced leaf senescence (dils), where the point of no return was defined, revealed differences in dna and rna modifications active in dils compared to developmental leaf senescence. this suggests the possibility of a yet-to-be-discovered epigenetic-based switch between cell survival and cell death. conclusions from the analyzed research contributed to the hypothesis that chromatin-remodeling mechanisms play a role in the control of induced leaf senescence. understanding this mechanism in crops might provide a tool for further exploitation toward sustainable agriculture: so-called epibreeding.”
Nacarelli, T., Liu, P., & Zhang, R.. (2017). Epigenetic basis of cellular senescence and its implications in aging. Genes
Plain numerical DOI: 10.3390/genes8120343
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“Cellular senescence is a tumor suppressive response that has become recognized as a major contributor of tissue aging. senescent cells undergo a stable proliferative arrest that protects against neoplastic transformation, but acquire a secretory phenotype that has long-term deleterious effects. studies are still unraveling the effector mechanisms that underlie these senescence responses with the goal to identify therapeutic interventions. such effector mechanisms have been linked to the dramatic remodeling in the epigenetic and chromatin landscape that accompany cellular senescence. we discuss these senescence-associated epigenetic changes and their impact on the senescence phenotypes, notably the proliferative arrest and senescence associated secretory phenotype (sasp). we also explore possible epigenetic targets to suppress the deleterious effects of senescent cells that contribute towards aging.”
Tee, W. W., & Reinberg, D.. (2014). Chromatin features and the epigenetic regulation of pluripotency states in ESCs. Development (Cambridge)
Plain numerical DOI: 10.1242/dev.096982
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“In pluripotent stem cells, the interplay between signaling cues, epigenetic regulators and transcription factors orchestrates developmental potency. flexibility in gene expression control is imparted by molecular changes to the nucleosomes, the building block of chromatin. here, we review the current understanding of the role of chromatin as a plastic and integrative platform to direct gene expression changes in pluripotent stem cells, giving rise to distinct pluripotent states. we will further explore the concept of epigenetic asymmetry, focusing primarily on histone stoichiometry and their associated modifications, that is apparent at both the nucleosome and chromosome-wide levels, and discuss the emerging importance of these asymmetric chromatin configurations in diversifying epigenetic states and their implications for cell fate control. © 2014. published by the company of biologists ltd.”
Tiffon, C.. (2018). The impact of nutrition and environmental epigenetics on human health and disease. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms19113425
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“Environmental epigenetics describes how environmental factors affect cellular epigenetics and, hence, human health. epigenetic marks alter the spatial conformation of chromatin to regulate gene expression. environmental factors with epigenetic effects include behaviors, nutrition, and chemicals and industrial pollutants. epigenetic mechanisms are also implicated during development in utero and at the cellular level, so environmental exposures may harm the fetus by impairing the epigenome of the developing organism to modify disease risk later in life. by contrast, bioactive food components may trigger protective epigenetic modifications throughout life, with early life nutrition being particularly important. beyond their genetics, the overall health status of an individual may be regarded as an integration of many environmental signals starting at gestation and acting through epigenetic modifications. this review explores how the environment affects the epigenome in health and disease, with a particular focus on cancer. understanding the molecular effects of behavior, nutrients, and pollutants might be relevant for developing preventative strategies and personalized heath programs. furthermore, by restoring cellular differentiation, epigenetic drugs could represent a potential strategy for the treatment of many diseases including cancer.”
Kint, S., Van Criekinge, W., Vandekerckhove, L., De Vos, W. H., Bomsztyk, K., Krause, D. S., & Denisenko, O.. (2021). Single cell epigenetic visualization assay. Nucleic Acids Research
Plain numerical DOI: 10.1093/nar/gkab009
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“Characterization of the epigenetic status of individual cells remains a challenge. current sequencing approaches have limited coverage, and it is difficult to assign an epigenetic status to the transcription state of individual gene alleles in the same cell. to address these limitations, a targeted microscopy-based epigenetic visualization assay (eva) was developed for detection and quantification of epigenetic marks at genes of interest in single cells. the assay is based on an in situ biochemical reaction between an antibody-conjugated alkaline phosphatase bound to the epigenetic mark of interest, and a 5′-phosphorylated fluorophore-labeled dna oligo tethered to a target gene by gene-specific oligonucleotides. when the epigenetic mark is present at the gene, phosphate group removal by the phosphatase protects the oligo from λ-exonuclease activity providing a quantitative fluorescent readout. we applied eva to measure 5-methylcytosine (5mc) and h3k9ac levels at different genes and the hiv-1 provirus in human cell lines. to link epigenetic marks to gene transcription, eva was combined with rna-fish. higher 5mc levels at the silenced compared to transcribed xist gene alleles in female somatic cells validated this approach and demonstrated that eva can be used to relate epigenetic marks to the transcription status of individual gene alleles. © 2021 the author(s). published by oxford university press on behalf of nucleic acids research.”
Torroglosa, A., Villalba-Benito, L., Luzón-Toro, B., Fernández, R. M., Antiñolo, G., & Borrego, S.. (2019). Epigenetic mechanisms in hirschsprung disease. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms20133123
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“Hirschsprung disease (hscr, omim 142623) is due to a failure of enteric precursor cells derived from neural crest (epcs) to proliferate, migrate, survive or differentiate during enteric nervous system (ens) formation. this is a complex process which requires a strict regulation that results in an ens specific gene expression pattern. alterations at this level lead to the onset of neurocristopathies such as hscr. gene expression is regulated by different mechanisms, such as dna modifications (at the epigenetic level), transcriptional mechanisms (transcription factors, silencers, enhancers and repressors), postranscriptional mechanisms (3’utr and ncrna) and regulation of translation. all these mechanisms are finally implicated in cell signaling to determine the migration, proliferation, differentiation and survival processes for correct ens development. in this review, we have performed an overview on the role of epigenetic mechanisms at transcriptional and posttranscriptional levels on these cellular events in neural crest cells (nccs), ens development, as well as in hscr.”
Pineda, B., Diaz-Lagares, A., Pérez-Fidalgo, J. A., Burgués, O., González-Barrallo, I., Crujeiras, A. B., … Eroles, P.. (2019). A two-gene epigenetic signature for the prediction of response to neoadjuvant chemotherapy in triple-negative breast cancer patients. Clinical Epigenetics
Plain numerical DOI: 10.1186/s13148-019-0626-0
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“Background: pathological complete response (pcr) after neoadjuvant chemotherapy (nac) in triple-negative breast cancer (tnbc) varies between 30 and 40% approximately. to provide further insight into the prediction of pcr, we evaluated the role of an epigenetic methylation-based signature. methods: epigenetic assessment of dna extracted from biopsy archived samples previous to nac from tnbc patients was performed. patients included were categorized according to previous response to nac in responder (pcr or residual cancer burden, rcb = 0) or non-responder (non-pcr or rcb > 0) patients. a methyloma study was performed in a discovery cohort by the infinium humanmethylation450 beadchip (450k array) from illumina. the epigenetic silencing of those methylated genes in the discovery cohort were validated by bisulfite pyrosequencing (pyromark q96 system version 2.0.6, qiagen) and qrt-pcr in an independent cohort of tn patients and in tn cell lines. results: twenty-four and 30 patients were included in the discovery and validation cohorts, respectively. in the discovery cohort, nine genes were differentially methylated: six presented higher methylation in non-responder patients (loc641519, lef1, hoxa5, evc2, tlx3, cdkl2) and three greater methylation in responder patients (ferd3l, chl1, and trip10). after validation, a two-gene (fer3l and trip10) epigenetic score predicted rcb = 0 with an area under the roc curve (auc) = 0.905 (95% ci = 0.805-1.000). patients with a positive epigenetic two-gene score showed 78.6% rcb = 0 versus only 10.7% rcb = 0 if signature were negative. conclusions: these results suggest that pcr in tnbc could be accurately predicted with an epigenetic signature of ferd3l and trip10 genes. further prospective validation of these findings is warranted.”
Santos, E. S. Dos, Rodrigues-Fernandes, C. I., Ramos, J. C., Fonseca, F. P., & Leme, A. F. P.. (2021). Epigenetic alterations in ameloblastomas: A literature review. Journal of Clinical and Experimental Dentistry
Plain numerical DOI: 10.4317/jced.56191
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“Background: ameloblastoma is a locally aggressive tumor, originated from odontogenic epithelium, and affects the jawbones with an elevated recurrence rate. the molecular mechanisms involved with the pathogenesis of this tumor remain undetermined. this review aimed to describe the current data regarding epigenetic alterations in ameloblastoma. material and methods: a systematized electronic search was performed in the english-language literature in three databases, combining the following keywords: ameloblastoma, epigenetic, methylation, noncoding rna, histone acetylation. results: according to the gathered results of 11 studies in this review, epigenetic alterations could induce the development and progression of ameloblastoma. dna methylation has been the most assessed mechanism in ameloblastomas. conclusions: current literature data indicate that epigenetic events can be involved in the etiopathogenesis of ameloblastomas.”
Westphal, M., Sant, P., Hauser, A. T., Jung, M., & Driever, W.. (2020). Chemical Genetics Screen Identifies Epigenetic Mechanisms Involved in Dopaminergic and Noradrenergic Neurogenesis in Zebrafish. Frontiers in Genetics
Plain numerical DOI: 10.3389/fgene.2020.00080
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“The cell type diversity and complexity of the nervous system is generated by a network of signaling events, transcription factors, and epigenetic regulators. signaling and transcriptional control have been easily amenable to forward genetic screens in model organisms like zebrafish. in contrast, epigenetic mechanisms have been somewhat elusive in genetic screens, likely caused by broad action in multiple developmental pathways that masks specific phenotypes, but also by genetic redundancies of epigenetic factors. here, we performed a screen using small molecule inhibitors of epigenetic mechanisms to reveal contributions to specific aspects of neurogenesis in zebrafish. we chose development of dopaminergic and noradrenergic neurons from neural progenitors as target of epigenetic regulation. we performed the screen in two phases: first, we tested a small molecule inhibitor library that targets a broad range of epigenetic protein classes and mechanisms, using expression of the dopaminergic and noradrenergic marker tyrosine hydroxylase as readout. we identified 10 compounds, including hdac, bromodomain and hat inhibitors, which interfered with dopaminergic and noradrenergic development in larval zebrafish. in the second screening phase, we aimed to identify neurogenesis stages affected by these 10 inhibitors. we analyzed treated embryos for effects on neural stem cells, growth progression of the retina, and apoptosis in neural tissues. in addition, we analyzed effects on islet1 expressing neuronal populations to determine potential selectivity of compounds for transmitter phenotypes. in summary, our targeted screen of epigenetic inhibitors identified specific compounds, which reveal chromatin regulator classes that contribute to dopaminergic and noradrenergic neurogenesis in vivo.”
Bintu, L., Yong, J., Antebi, Y. E., McCue, K., Kazuki, Y., Uno, N., … Elowitz, M. B.. (2016). Dynamics of epigenetic regulation at the single-cell level. Science
Plain numerical DOI: 10.1126/science.aab2956
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“Chromatin regulators play a major role in establishing and maintaining gene expression states. yet how they control gene expression in single cells, quantitatively and over time, remains unclear. we used time-lapse microscopy to analyze the dynamic effects of four silencers associated with diverse modifications: dna methylation, histone deacetylation, and histone methylation. for all regulators, silencing and reactivation occurred in all-or-none events, enabling the regulators to modulate the fraction of cells silenced rather than the amount of gene expression. these dynamics could be described by a three-state model involving stochastic transitions between active, reversibly silent, and irreversibly silent states. through their individual transition rates, these regulators operate over different time scales and generate distinct types of epigenetic memory. our results provide a framework for understanding and engineering mammalian chromatin regulation and epigenetic memory.”
Mazzone, R., Zwergel, C., Artico, M., Taurone, S., Ralli, M., Greco, A., & Mai, A.. (2019). The emerging role of epigenetics in human autoimmune disorders. Clinical Epigenetics
Plain numerical DOI: 10.1186/s13148-019-0632-2
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“Epigenetic pathways play a pivotal role in the development and function of the immune system. over the last decade, a growing body of studies has been published out seeking to explain a correlation between epigenetic modifications and the development of autoimmune disorders. epigenetic changes, such as dna methylation, histone modifications, and noncoding rnas, are involved in the pathogenesis of autoimmune diseases mainly by regulating gene expression. this paper reviews the importance of epigenetic alterations during the development of the most prevalent human autoimmune diseases, such as systemic lupus erythematosus (sle), rheumatoid arthritis (ra), systemic sclerosis (ssc), sjogren’s syndrome (ss), autoimmune thyroid diseases (aitd), and type 1 diabetes (t1d), aiming to provide new insights in the pathogenesis of autoimmune diseases and the possibility to develop novel therapeutic approaches targeting the epigenome.”
Kagohara, L. T., Stein-O’Brien, G. L., Kelley, D., Flam, E., Wick, H. C., Danilova, L. V., … Fertig, E. J.. (2018). Epigenetic regulation of gene expression in cancer: Techniques, resources and analysis. Briefings in Functional Genomics
Plain numerical DOI: 10.1093/bfgp/elx018
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“Cancer is a complex disease, driven by aberrant activity in numerous signaling pathways in even individual malignant cells. epigenetic changes are critical mediators of these functional changes that drive and maintain the malignant phenotype. changes in dna methylation, histone acetylation and methylation, noncoding rnas, posttranslational modifications are all epigenetic drivers in cancer, independent of changes in the dna sequence. these epigenetic alterations were once thought to be crucial only for the malignant phenotype maintenance. now, epigenetic alterations are also recognized as critical for disrupting essential pathways that protect the cells from uncontrolled growth, longer survival and establishment in distant sites from the original tissue. in this review, we focus on dna methylation and chromatin structure in cancer. the precise functional role of these alterations is an area of active research using emerging high-throughput approaches and bioinformatics analysis tools. therefore, this review also describes these high-throughput measurement technologies, public domain databases for high-throughput epigenetic data in tumors and model systems and bioinformatics algorithms for their analysis. advances in bioinformatics data that combine these epigenetic data with genomics data are essential to infer the function of specific epigenetic alterations in cancer. these integrative algorithms are also a focus of this review. future studies using these emerging technologies will elucidate how alterations in the cancer epigenome cooperate with genetic aberrations during tumor initiation and progression. this deeper understanding is essential to future studies with epigenetics biomarkers and precision medicine using emerging epigenetic therapies.”
Bayarsaihan, D.. (2011). Epigenetic mechanisms in inflammation. Journal of Dental Research
Plain numerical DOI: 10.1177/0022034510378683
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“Epigenetic modifications occur in response to environmental changes and play a fundamental role in gene expression following environmental stimuli. major epigenetic events include methylation and acetylation of histones and regulatory factors, dna methylation, and small non-coding rnas. diet, pollution, infections, and other environmental factors have profound effects on epigenetic modifications and trigger susceptibility to diseases. despite a growing body of literature addressing the role of the environment on gene expression, very little is known about the epigenetic pathways involved in the modulation of inflammatory and anti-inflammatory genes. this review summarizes the current knowledge about epigenetic control mechanisms during the inflammatory response. © 2011 international & american associations for dental research.”
Dong, B., Qiu, Z., & Wu, Y.. (2020). Tackle Epithelial-Mesenchymal Transition With Epigenetic Drugs in Cancer. Frontiers in Pharmacology
Plain numerical DOI: 10.3389/fphar.2020.596239
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“Epithelial-mesenchymal transition (emt) is a de-differentiation process in which epithelial cells lose their epithelial properties to acquire mesenchymal features. emt is essential for embryogenesis and wound healing but is aberrantly activated in pathological conditions like fibrosis and cancer. tumor-associated emt contributes to cancer cell initiation, invasion, metastasis, drug resistance and recurrence. this dynamic and reversible event is governed by emt-transcription factors (emt-tfs) with epigenetic complexes. in this review, we discuss recent advances regarding the mechanisms that modulate emt in the context of epigenetic regulation, with emphasis on epigenetic drugs, such as dna demethylating reagents, inhibitors of histone modifiers and non-coding rna medication. therapeutic contributions that improve epigenetic regulation of emt will translate the clinical manifestation as treating cancer progression more efficiently.”
Huan, Q., Mao, Z., Chong, K., & Zhang, J.. (2018). Global analysis of H3K4me3/H3K27me3 in Brachypodium distachyon reveals VRN3 as critical epigenetic regulation point in vernalization and provides insights into epigenetic memory. New Phytologist
Plain numerical DOI: 10.1111/nph.15288
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“Vernalization, the requirement of plants for long-term exposure to low environmental temperature for flowering, is an epigenetic phenomenon. histone modification regulation has been revealed in vernalization, but is limited to key genes. now, we know that vrn1 is epigenetically critical for monocots. genome-wide analysis is still unavailable, however. we performed chromatin immunoprecipitation-sequencing for h3k4me3/h3k27me3 in brachypodium distachyon to obtain a global view of histone modifications in vernalization on a genome-wide scale and for different pathways/genes. our data showed that h3k4me3 and h3k27me3 play distinct roles in vernalization. unlike h3k4me3, h3k27me3 exhibited regional regulation, showed main regulation targets in vernalization and contributed to epigenetic memory. for genes in four flowering regulation pathways, only ft2 (functional ortholog of vrn3 in b. distachyon) and vrn1 showed coordinated changes in h3k4me3/h3k27me3. the epigenetic response at vrn3 was weaker under short-day than under long-day conditions. vrn3 was revealed as an epigenetic regulation point integrating vernalization and day length signals. we globally identified genes maintaining vernalization-induced epigenetic changes. most of these genes showed dose-dependent vernalization responses, revealing a quantitative ‘recording system’ for vernalization. our studies shed light on the epigenetic role of vrn3 and h3k4me3/h3k27me3 in vernalization and reveal genes underlying epigenetic memory, laying the foundation for further study.”
Labbé, C., Lorenzo-Betancor, O., & Ross, O. A.. (2016). Epigenetic regulation in Parkinson’s disease. Acta Neuropathologica
Plain numerical DOI: 10.1007/s00401-016-1590-9
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“Recent efforts have shed new light on the epigenetic mechanisms driving gene expression alterations associated with parkinson’s disease (pd) pathogenesis. changes in gene expression are a well-established cause of pd, and epigenetic mechanisms likely play a pivotal role in regulation. studies in families with pd harboring duplications and triplications of the snca gene have demonstrated that gene dosage is associated with increased expression of both snca mrna and protein, and correlates with a fulminant disease course. furthermore, it is postulated that even subtle changes in snca expression caused by common variation is associated with disease risk. of note, genome-wide association studies have identified over 30 loci associated with pd with most signals located in non-coding regions of the genome, thus likely influencing transcript expression levels. in health, epigenetic mechanisms tightly regulate gene expression, turning genes on and off to balance homeostasis and this, in part, explains why two cells with the same dna sequence will have different rna expression profiles. understanding this phenomenon will be crucial to our interpretation of the selective vulnerability observed in neurodegeneration and specifically dopaminergic neurons in the pd brain. in this review, we discuss epigenetic mechanisms, such as dna methylation and histone modifications, involved in regulating the expression of genes relevant to pd, rna-based mechanisms, as well as the effect of toxins and potential epigenetic-based treatments for pd.”
Jeffries, A. R., Maroofian, R., Salter, C. G., Chioza, B. A., Cross, H. E., Patton, M. A., … Baple, E. L.. (2019). Growth disrupting mutations in epigenetic regulatory molecules are associated with abnormalities of epigenetic aging. Genome Research
Plain numerical DOI: 10.1101/gr.243584.118
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“Germline mutations in fundamental epigenetic regulatory molecules including dna methyltransferase 3 alpha (dnmt3a) are commonly associated with growth disorders, whereas somatic mutations are often associated with malignancy. we profiled genome-wide dna methylation patterns in dnmt3a c.2312g > a; p.(arg771gln) carriers in a large amish sibship with tatton-brown-rahman syndrome (tbrs), their mosaic father, and 15 tbrs patients with distinct pathogenic de novo dnmt3a variants. this defined widespread dna hypomethylation at specific genomic sites enriched at locations annotated as genes involved in morphogenesis, development, differentiation, and malignancy predisposition pathways. tbrs patients also displayed highly accelerated dna methylation aging. these findings were most marked in a carrier of the aml-associated driver mutation p.arg882cys. our studies additionally defined phenotype-related accelerated and decelerated epigenetic aging in two histone methyltransferase disorders: nsd1 sotos syndrome overgrowth disorder and kmt2d kabuki syndrome growth impairment. together, our findings provide fundamental new insights into aberrant epigenetic mechanisms, the role of epigenetic machinery maintenance, and determinants of biological aging in these growth disorders.”
Sen, D. R., Kaminski, J., Barnitz, R. A., Kurachi, M., Gerdemann, U., Yates, K. B., … Haining, W. N.. (2016). The epigenetic landscape of T cell exhaustion. Science
Plain numerical DOI: 10.1126/science.aae0491
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“Exhausted t cells in cancer and chronic viral infection express distinctive patterns of genes, including sustained expression of programmed cell death protein 1 (pd-1). however, the regulation of gene expression in exhausted t cells is poorly understood. here, we define the accessible chromatin landscape in exhausted cd8+ t cells and show that it is distinct from functional memory cd8+ t cells. exhausted cd8+ t cells in humans and a mouse model of chronic viral infection acquire a state-specific epigenetic landscape organized into functional modules of enhancers. genome editing shows that pd-1 expression is regulated in part by an exhaustion-specific enhancer that contains essential rar, t-bet, and sox3 motifs. functional enhancer maps may offer targets for genome editing that alter gene expression preferentially in exhausted cd8+ t cells.”
Nono, M., Kishimoto, S., Sato-Carlton, A., Carlton, P. M., Nishida, E., & Uno, M.. (2020). Intestine-to-Germline Transmission of Epigenetic Information Intergenerationally Ensures Systemic Stress Resistance in C. elegans. Cell Reports
Plain numerical DOI: 10.1016/j.celrep.2020.02.050
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“Changes in epigenetic states affect organismal homeostasis, including stress resistance. however, the mechanisms coordinating epigenetic states and systemic stress resistance remain largely unknown. here, we identify the intestine-to-germline communication of epigenetic states, which intergenerationally enhances stress resistance in c. elegans. the alterations in epigenetic states by deficiency of the histone h3k4me3 modifier ash-2 in the intestine or germline increase organismal stress resistance, which is abrogated by knockdown of the h3k4 demethylase rbr-2. remarkably, the increase in stress resistance induced by ash-2 deficiency in the intestine is abrogated by rbr-2 knockdown in the germline, suggesting the intestine-to-germline transmission of epigenetic information. this communication from intestine to germline in the parental generation increases stress resistance in the next generation. moreover, the intertissue communication is mediated partly by transcriptional regulation of f08f1.3. these results reveal that intertissue communication of epigenetic information provides mechanisms for intergenerational regulation of systemic stress resistance.”
Dusinska, M., Tulinska, J., El Yamani, N., Kuricova, M., Liskova, A., Rollerova, E., … Smolkova, B.. (2017). Immunotoxicity, genotoxicity and epigenetic toxicity of nanomaterials: New strategies for toxicity testing?. Food and Chemical Toxicology
Plain numerical DOI: 10.1016/j.fct.2017.08.030
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“The unique properties of nanomaterials (nms) are beneficial in numerous industrial and medical applications. however, they could also induce unintended effects. thus, a proper strategy for toxicity testing is essential in human hazard and risk assessment. toxicity can be tested in vivo and in vitro; in compliance with the 3rs, alternative strategies for in vitro testing should be further developed for nms. robust, standardized methods are of great importance in nanotoxicology, with comprehensive material characterization and uptake as an integral part of the testing strategy. oxidative stress has been shown to be an underlying mechanism of possible toxicity of nms, causing both immunotoxicity and genotoxicity. for testing nms in vitro, a battery of tests should be performed on cells of human origin, either cell lines or primary cells, in conditions as close as possible to an in vivo situation. novel toxicity pathways, particularly epigenetic modification, should be assessed along with conventional toxicity testing methods. however, to initiate epigenetic toxicity screens for nm exposure, there is a need to better understand their adverse effects on the epigenome, to identify robust and reproducible causal links between exposure, epigenetic changes and adverse phenotypic endpoints, and to develop improved assays to monitor epigenetic toxicity.”
Breitling, L. P., Saum, K. U., Perna, L., Schöttker, B., Holleczek, B., & Brenner, H.. (2016). Frailty is associated with the epigenetic clock but not with telomere length in a German cohort. Clinical Epigenetics
Plain numerical DOI: 10.1186/s13148-016-0186-5
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“Background: the epigenetic clock, in particular epigenetic pre-aging quantified by the so-called dna methylation age acceleration, has recently been suggested to closely correlate with a variety of disease phenotypes. there remains a dearth of data, however, on its association with telomere length and frailty, which can be considered major correlates of age on the genomic and clinical level, respectively. results: in this cross-sectional observational study on altogether 1820 subjects from two subsets (n = 969 and n = 851; mean ± standard deviation age 62.1 ± 6.5 and 63.0 ± 6.7 years, respectively) of the esther cohort study of the elderly general population in germany, dna methylation age was calculated based on a 353 loci predictor previously developed in a large meta-study, and the difference-based epigenetic age acceleration was calculated as predicted methylation age minus chronological age. no correlation of epigenetic age acceleration with telomere length was found in our study (p = 0.63). however, there was an association of dna methylation age acceleration with a comprehensive frailty measure, such that the accumulated deficits significantly increased with increasing age acceleration. quantitatively, about half an additional deficit was added per 6 years of methylation age acceleration (p = 0.0004). this association was independent from age, sex, and estimated leukocyte distribution, as well as from a variety of other confounding variables considered. conclusions: the results of the present study suggest that epigenetic age acceleration is correlated with clinically relevant aging-related phenotypes through pathways unrelated to cellular senescence as assessed by telomere length. innovative approaches like mendelian randomization will be needed to elucidate whether epigenetic age acceleration indeed plays a causal role for the development of clinical phenotypes.”
Martínez-Cano, J., Campos-Sánchez, E., & Cobaleda, C.. (2019). Epigenetic Priming in Immunodeficiencies. Frontiers in Cell and Developmental Biology
Plain numerical DOI: 10.3389/fcell.2019.00125
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“Immunodeficiencies are disorders of the immune system that increase susceptibility to infections and cancer, and are therefore associated with elevated morbidity and mortality. immunodeficiencies can be primary (not caused by other condition or exposure) or secondary due to the exposure to different agents (infections, chemicals, aging, etc.). most primary immunodeficiencies (pids) are of genetic origin, caused by mutations affecting genes with key roles in the development or function of the cells of the immune system. a large percentage of pids are associated with a defective development and/or function of lymphocytes and, especially, b cells, the ones in charge of generating the different types of antibodies. b cell development is a tightly regulated process in which many different factors participate. among the regulators of b cell differentiation, a correct epigenetic control of cellular identity is essential for normal cell function. with the advent of next-generation sequencing techniques, more and more alterations in different types of epigenetic regulators are being described at the root of pids, both in humans and in animal models. at the same time, it is becoming increasingly clear that epigenetic alterations triggered by the exposure to environmental agents have a key role in the development of secondary immunodeficiencies (sids). due to their largely reversible nature, epigenetic modifications are quickly becoming key therapeutic targets in other diseases where their contribution has been known for more time, like cancer. here, we establish a parallelism between immunodeficiencies and the nowadays accepted role of epigenetics in cancer initiation and progression, and propose that epigenetics forms a ‘third axis’ (together with genetics and external agents) to be considered in the etiology of immunodeficiencies, and linking pids and sids at the molecular level. we therefore postulate that immunodeficiencies arise due to a variable contribution of i) genetic, ii) environmental and iii) epigenetic causes, which in fact form a continuum landscape of all possible combinations of these factors. additionally, this implies the possibility of a fully epigenetically-triggered mechanism for some immunodeficiencies. this concept would have important prophylactic and translational implications, and would also imply a more blurred frontier between primary and secondary immunodeficiencies.”
Peedicayil, J.. (2016). Preclinical epigenetic models for screening epigenetic drugs for schizophrenia. Journal of Pharmacological and Toxicological Methods
Plain numerical DOI: 10.1016/j.vascn.2015.09.002
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“Schizophrenia is an important psychiatric disorder for which effective drugs are available. however, there are problems with current drug therapy of schizophrenia in that some patients do not respond adequately. moreover, some patients show treatment resistance and some patients show cognitive decline despite treatment. hence new and effective drugs will be useful for the treatment of this disorder. since there is increasing evidence that epigenetic mechanisms of gene expression are defective in schizophrenia, drugs that correct epigenetic defects, epigenetic drugs, could be useful in the treatment of this disorder. this paper discusses preclinical epigenetic models for screening epigenetic drugs for schizophrenia. it also discusses how such models could be useful for the discovery and development of such drugs.”
Gangoso, E., Southgate, B., Bradley, L., Rus, S., Galvez-Cancino, F., McGivern, N., … Pollard, S. M.. (2021). Glioblastomas acquire myeloid-affiliated transcriptional programs via epigenetic immunoediting to elicit immune evasion. Cell
Plain numerical DOI: 10.1016/j.cell.2021.03.023
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“Glioblastoma multiforme (gbm) is an aggressive brain tumor for which current immunotherapy approaches have been unsuccessful. here, we explore the mechanisms underlying immune evasion in gbm. by serially transplanting gbm stem cells (gscs) into immunocompetent hosts, we uncover an acquired capability of gscs to escape immune clearance by establishing an enhanced immunosuppressive tumor microenvironment. mechanistically, this is not elicited via genetic selection of tumor subclones, but through an epigenetic immunoediting process wherein stable transcriptional and epigenetic changes in gscs are enforced following immune attack. these changes launch a myeloid-affiliated transcriptional program, which leads to increased recruitment of tumor-associated macrophages. furthermore, we identify similar epigenetic and transcriptional signatures in human mesenchymal subtype gscs. we conclude that epigenetic immunoediting may drive an acquired immune evasion program in the most aggressive mesenchymal gbm subtype by reshaping the tumor immune microenvironment.”
Regis, S., Dondero, A., Caliendo, F., Bottino, C., & Castriconi, R.. (2020). NK Cell Function Regulation by TGF-β-Induced Epigenetic Mechanisms. Frontiers in Immunology
Plain numerical DOI: 10.3389/fimmu.2020.00311
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“TGF-β is a potent immunosuppressive cytokine that severely affects the function of nk cells. tumor cells can take advantage of this ability, enriching their surrounding microenvironment with tgf-β. tgf-β can alter the expression of effector molecules and of activating and chemokine receptors, influence metabolism, induce the nk cell conversion toward the less cytolytic ilc1s. these and other changes possibly occur by the induction of complex gene expression programs, involving epigenetic mechanisms. while most of these programs are at present unexplored, the role of certain transcription factors, micrornas and chromatin changes determined by tgf-β in nk cells start to be elucidated in human and/or mouse nk cells. the deep understanding of these mechanisms will be useful to design therapies contributing to restore the full nk function.”
Hauser, M. T., Aufsatz, W., Jonak, C., & Luschnig, C.. (2011). Transgenerational epigenetic inheritance in plants. Biochimica et Biophysica Acta – Gene Regulatory Mechanisms
Plain numerical DOI: 10.1016/j.bbagrm.2011.03.007
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“Interest in transgenerational epigenetic inheritance has intensified with the boosting of knowledge on epigenetic mechanisms regulating gene expression during development and in response to internal and external signals such as biotic and abiotic stresses. starting with an historical background of scantily documented anecdotes and their consequences, we recapitulate the information gathered during the last 60. years on naturally occurring and induced epialleles and paramutations in plants. we present the major players of epigenetic regulation and their importance in controlling stress responses. the effect of diverse stressors on the epigenetic status and its transgenerational inheritance is summarized from a mechanistic viewpoint. the consequences of transgenerational epigenetic inheritance are presented, focusing on the knowledge about its stability, and in relation to genetically fixed mutations, recombination, and genomic rearrangement. we conclude with an outlook on the importance of transgenerational inheritance for adaptation to changing environments and for practical applications. this article is part of a special issue entitled ‘epigenetic control of cellular and developmental processes in plants’. © 2011 elsevier b.v.”
Yang, Z., Wong, A., Kuh, D., Paul, D. S., Rakyan, V. K., Leslie, R. D., … Teschendorff, A. E.. (2016). Correlation of an epigenetic mitotic clock with cancer risk. Genome Biology
Plain numerical DOI: 10.1186/s13059-016-1064-3
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“Background: variation in cancer risk among somatic tissues has been attributed to variations in the underlying rate of stem cell division. for a given tissue type, variable cancer risk between individuals is thought to be influenced by extrinsic factors which modulate this rate of stem cell division. to date, no molecular mitotic clock has been developed to approximate the number of stem cell divisions in a tissue of an individual and which is correlated with cancer risk. results: here, we integrate mathematical modeling with prior biological knowledge to construct a dna methylation-based age-correlative model which approximates a mitotic clock in both normal and cancer tissue. by focusing on promoter cpg sites that localize to polycomb group target genes that are unmethylated in 11 different fetal tissue types, we show that increases in dna methylation at these sites defines a tick rate which correlates with the estimated rate of stem cell division in normal tissues. using matched dna methylation and rna-seq data, we further show that it correlates with an expression-based mitotic index in cancer tissue. we demonstrate that this mitotic-like clock is universally accelerated in cancer, including pre-cancerous lesions, and that it is also accelerated in normal epithelial cells exposed to a major carcinogen. conclusions: unlike other epigenetic and mutational clocks or the telomere clock, the epigenetic clock proposed here provides a concrete example of a mitotic-like clock which is universally accelerated in cancer and precancerous lesions.”
Morales, S., Monzo, M., & Navarro, A.. (2017). Epigenetic regulation mechanisms of microRNA expression. Biomolecular Concepts
Plain numerical DOI: 10.1515/bmc-2017-0024
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“MicroRNAs (mirnas) are single-stranded rnas of 18-25 nucleotides that regulate gene expression at the post-transcriptional level. they are involved in many physiological and pathological processes, including cell proliferation, apoptosis, development and carcinogenesis. because of the central role of mirnas in the regulation of gene expression, their expression needs to be tightly controlled. here, we summarize the different mechanisms of epigenetic regulation of mirnas, with a particular focus on dna methylation and histone modification.”
Bewersdorf, J. P., Shallis, R., Stahl, M., & Zeidan, A. M.. (2019). Epigenetic therapy combinations in acute myeloid leukemia: what are the options?. Therapeutic Advances in Hematology
Plain numerical DOI: 10.1177/2040620718816698
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“Epigenetics refers to the regulation of gene expression mainly by changes in dna methylation and modifications of histone proteins without altering the actual dna sequence. while epigenetic modifications are essential for normal cell differentiation, several driver mutations in leukemic pathogenesis have been identified in genes that affect epigenetic processes, such as dna methylation and histone acetylation. several therapeutic options to target epigenetic alterations in acute myeloid leukemia (aml) have been successfully tested in preclinical studies and various drugs have already been approved for use in clinical practice. among these already approved therapeutics are hypomethylating agents (azacitidine and decitabine) and isocitrate dehydrogenase inhibitors (ivosidenib, enasidenib). other agents such as bromodomain-containing epigenetic reader proteins and histone methylation (e.g. dot1l) inhibitors are currently in advanced clinical testing. as several epigenetic therapies have only limited efficacy when used as single agents, combination therapies that target aml pathogenesis at different levels and exploit synergistic mechanisms are also in clinical trials. combinations of either epigenetic therapies with conventional chemotherapy, different forms of epigenetic therapies, or epigenetic therapies with immunotherapy are showing promising early results. in this review we summarize the underlying pathophysiology and rationale for epigenetically-based combination therapies, review current preclinical and clinical data and discuss the future directions of epigenetic therapy combinations in aml.”
Hu, N., Strobl-Mazzulla, P. H., & Bronner, M. E.. (2014). Epigenetic regulation in neural crest development. Developmental Biology
Plain numerical DOI: 10.1016/j.ydbio.2014.09.034
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“The neural crest is a migratory and multipotent cell population that plays a crucial role in many aspects of embryonic development. in all vertebrate embryos, these cells emerge from the dorsal neural tube then migrate long distances to different regions of the body, where they contribute to formation of many cell types and structures. these include much of the peripheral nervous system, craniofacial skeleton, smooth muscle, and pigmentation of the skin. the best-studied regulatory events guiding neural crest development are mediated by transcription factors and signaling molecules. in recent years, however, growing evidence supports an important role for epigenetic regulation as an additional mechanism for controlling the timing and level of gene expression at different stages of neural crest development. here, we summarize the process of neural crest formation, with focus on the role of epigenetic regulation in neural crest specification, migration, and differentiation as well as in neural crest related birth defects and diseases.”
Nedoszytko, B., Reszka, E., Gutowska-Owsiak, D., Trzeciak, M., Lange, M., Jarczak, J., … Kalinowski, L.. (2020). Genetic and epigenetic aspects of atopic dermatitis. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms21186484
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“Atopic dermatitis is a heterogeneous disease, in which the pathogenesis is associated with mutations in genes encoding epidermal structural proteins, barrier enzymes, and their inhibitors; the role of genes regulating innate and adaptive immune responses and environmental factors inducing the disease is also noted. recent studies point to the key role of epigenetic changes in the development of the disease. epigenetic modifications are mainly mediated by dna methylation, histone acetylation, and the action of specific non-coding rnas. it has been documented that the profile of epigenetic changes in patients with atopic dermatitis (ad) differs from that observed in healthy people. this applies to the genes affecting the regulation of immune response and inflammatory processes, e.g., both affecting th1 bias and promoting th2 responses and the genes of innate immunity, as well as those encoding the structural proteins of the epidermis. understanding of the epigenetic alterations is therefore pivotal to both create new molecular classifications of atopic dermatitis and to enable the development of personalized treatment strategies.”
Jeremias, G., Gonçalves, F. J. M., Pereira, J. L., & Asselman, J.. (2020). Prospects for incorporation of epigenetic biomarkers in human health and environmental risk assessment of chemicals. Biological Reviews
Plain numerical DOI: 10.1111/brv.12589
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“Epigenetic mechanisms have gained relevance in human health and environmental studies, due to their pivotal role in disease, gene × environment interactions and adaptation to environmental change and/or contamination. epigenetic mechanisms are highly responsive to external stimuli and a wide range of chemicals has been shown to determine specific epigenetic patterns in several organisms. furthermore, the mitotic/meiotic inheritance of such epigenetic marks as well as the resulting changes in gene expression and cell/organismal phenotypes has now been demonstrated. therefore, epigenetic signatures are interesting candidates for linking environmental exposures to disease as well as informing on past exposures to stressors. accordingly, epigenetic biomarkers could be useful tools in both prospective and retrospective risk assessment but epigenetic endpoints are currently not yet incorporated into risk assessments. achieving a better understanding on this apparent impasse, as well as identifying routes to promote the application of epigenetic biomarkers within environmental risk assessment frameworks are the objectives of this review. we first compile evidence from human health studies supporting the use of epigenetic exposure-associated changes as reliable biomarkers of exposure. then, specifically focusing on environmental science, we examine the potential and challenges of developing epigenetic biomarkers for environmental fields, and discuss useful organisms and appropriate sequencing techniques to foster their development in this context. finally, we discuss the practical incorporation of epigenetic biomarkers in the environmental risk assessment of chemicals, highlighting critical data gaps and making key recommendations for future research within a regulatory context.”
Jacques, M., Hiam, D., Craig, J., Barrès, R., Eynon, N., & Voisin, S.. (2019). Epigenetic changes in healthy human skeletal muscle following exercise– a systematic review. Epigenetics
Plain numerical DOI: 10.1080/15592294.2019.1614416
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“Exercise training is continually challenging whole-body homeostasis, leading to improvements in performance and health. adaptations to exercise training are complex and are influenced by both environmental and genetic factors. epigenetic factors regulate gene expression in a tissue-specific manner and constitute a link between the genotype and the environment. moreover, epigenetic factors are emerging as potential biomarkers that could predict the response to exercise training. this systematic review aimed to identify epigenetic changes that have been reported in skeletal muscle following exercise training in healthy populations. a literature search of five databases (pubmed, medline, cinhal, scopus and sportdiscuss) was conducted in november 2018. articles were included if they examined epigenetic modifications (dna methylation, histone modifications and non-coding rnas) in skeletal muscle, following either an acute bout of exercise, an exercise intervention in a pre/post design, or a case/control type of study. twenty-two studies met the inclusion criteria. several epigenetic markers including dna methylation of genes known to be differentially expressed after exercise and myomirs were reported to be modified after exercise. several epigenetic marks were identified to be altered in response to exercise, with potential influence on skeletal muscle metabolism. however, whether these epigenetic marks play a role in the physiological impact of exercise is unclear. exercise epigenetics is still a very young research field, and it is expected that in the future the causality of such changes will be elucidated via the utilization of emerging experimental models able to target the epigenome.”
Le, N. T., Harukawa, Y., Miura, S., Boer, D., Kawabe, A., & Saze, H.. (2020). Epigenetic regulation of spurious transcription initiation in Arabidopsis. Nature Communications
Plain numerical DOI: 10.1038/s41467-020-16951-w
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“In plants, epigenetic regulation is critical for silencing transposons and maintaining proper gene expression. however, its impact on the genome-wide transcription initiation landscape remains elusive. by conducting a genome-wide analysis of transcription start sites (tsss) using cap analysis of gene expression (cage) sequencing, we show that thousands of tsss are exclusively activated in various epigenetic mutants of arabidopsis thaliana and referred to as cryptic tsss. many have not been identified in previous studies, of which up to 65% are contributed by transposons. they possess similar genetic features to regular tsss and their activation is strongly associated with the ectopic recruitment of rnapii machinery. the activation of cryptic tsss significantly alters transcription of nearby tsss, including those of genes important for development and stress responses. our study, therefore, sheds light on the role of epigenetic regulation in maintaining proper gene functions in plants by suppressing transcription from cryptic tsss.”
Ibáñez-Cabellos, J. S., Seco-Cervera, M., Osca-Verdegal, R., Pallardó, F. V., & García-Giménez, J. L.. (2019). Epigenetic Regulation in the Pathogenesis of Sjögren Syndrome and Rheumatoid Arthritis. Frontiers in Genetics
Plain numerical DOI: 10.3389/fgene.2019.01104
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“Autoimmune rheumatic diseases, such as sjögren syndrome (ss) and rheumatoid arthritis (ra), are characterized by chronic inflammation and autoimmunity, which cause joint tissue damage and destruction by triggering reduced mobility and debilitation in patients with these diseases. initiation and maintenance of chronic inflammatory stages account for several mechanisms that involve immune cells as key players and the interaction of the immune cells with other tissues. indeed, the overlapping of certain clinical and serologic manifestations between ss and ra may indicate that numerous immunologic-related mechanisms are involved in the physiopathology of both these diseases. it is widely accepted that epigenetic pathways play an essential role in the development and function of the immune system. although many published studies have attempted to elucidate the relation between epigenetic modifications (e.g. dna methylation, histone post-translational modifications, mirnas) and autoimmune disorders, the contribution of epigenetic regulation to the pathogenesis of ss and ra is at present poorly understood. this review attempts to shed light from a critical point of view on the identification of the most relevant epigenetic mechanisms related to ra and ss by explaining intricate regulatory processes and phenotypic features of both autoimmune diseases. moreover, we point out some epigenetic markers which can be used to monitor the inflammation status and the dysregulated immunity in ss and ra. finally, we discuss the inconvenience of using epigenetic data obtained from bulk immune cell populations instead specific immune cell subpopulations.”
Becker, L. M., O’Connell, J. T., Vo, A. P., Cain, M. P., Tampe, D., Bizarro, L., … Kalluri, R.. (2020). Epigenetic Reprogramming of Cancer-Associated Fibroblasts Deregulates Glucose Metabolism and Facilitates Progression of Breast Cancer. Cell Reports
Plain numerical DOI: 10.1016/j.celrep.2020.107701
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“Becker et al. demonstrate that cafs present with a pro-glycolytic phenotype, which helps to fuel the metabolism of breast cancer cells and promotes tumor growth. chronic hypoxia induces the metabolic rewiring of normal fibroblasts toward a caf-like, pro-glycolytic phenotype. these microenvironmental changes enabled the epigenetic alterations and expression of key glycolytic enzymes in cafs.”
De Groote, M. L., Verschure, P. J., & Rots, M. G.. (2012). Epigenetic Editing: Targeted rewriting of epigenetic marks to modulate expression of selected target genes. Nucleic Acids Research
Plain numerical DOI: 10.1093/nar/gks863
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“Despite significant advances made in epigenetic research in recent decades, many questions remain unresolved, especially concerning cause and consequence of epigenetic marks with respect to gene expression modulation (gem). technologies allowing the targeting of epigenetic enzymes to predetermined dna sequences are uniquely suited to answer such questions and could provide potent (bio)medical tools. toward the goal of gene-specific gem by overwriting epigenetic marks (epigenetic editing, ege), instructive epigenetic marks need to be identified and their writers/erasers should then be fused to gene-specific dna binding domains. the appropriate epigenetic mark(s) to change in order to efficiently modulate gene expression might have to be validated for any given chromatin context and should be (mitotically) stable. various insights in such issues have been obtained by sequence-specific targeting of epigenetic enzymes, as is presented in this review. features of such studies provide critical aspects for further improving ege. an example of this is the direct effect of the edited mark versus the indirect effect of recruited secondary proteins by targeting epigenetic enzymes (or their domains). proof-of-concept of expression modulation of an endogenous target gene is emerging from the few ege studies reported. apart from its promise in correcting disease-associated epi-mutations, ege represents a powerful tool to address fundamental epigenetic questions. © 2012 the author(s).”
Levine, M. E., Lu, A. T., Bennett, D. A., & Horvath, S.. (2015). Epigenetic age of the pre-frontal cortex is associated with neuritic plaques, amyloid load, and Alzheimer’s disease related cognitive functioning. Aging
Plain numerical DOI: 10.18632/aging.100864
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“There is an urgent need to develop molecular biomarkers of brain age in order to advance our understanding of age related neurodegeneration. recently, we developed a highly accurate epigenetic biomarker of tissue age (known as epigenetic clock) which is based on dna methylation levels. here we use n=700 dorsolateral prefrontal cortex (dlpfc) samples from caucasian subjects of the religious order study and the rush memory and aging project to examine the association between epigenetic age and alzheimer’s disease (ad) related cognitive decline, and ad related neuropathological markers. epigenetic age acceleration of dlpfc is correlated with several neuropathological measurements including diffuse plaques (r=0.12, p=0.0015), neuritic plaques (r=0.11, p=0.0036), and amyloid load (r=0.091, p=0.016). further, it is associated with a decline in global cognitive functioning (β=-0.500, p=0.009), episodic memory (β=-0.411, p=0.009) and working memory (β=- 0.405, p=0.011) among individuals with ad. the neuropathological markers may mediate the association between epigenetic age and cognitive decline. genetic complex trait analysis (gcta) revealed that epigenetic age acceleration is heritable (h2=0.41) and has significant genetic correlations with diffuse plaques (r=0.24, p=0.010) and possibly working memory (r=-0.35, p=0.065). overall, these results suggest that the epigenetic clock may lend itself as a molecular biomarker of brain age.”
Grønbæk, K., Hother, C., & Jones, P. A.. (2007). Epigenetic changes in cancer. APMIS
Plain numerical DOI: 10.1111/j.1600-0463.2007.apm_636.xml.x
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“A cancer develops when a cell acquires specific growth advantages through the stepwise accumulation of heritable changes in gene function. basically, this process is directed by changes in two different classes of genes: tumor suppressor genes that inhibit cell growth and survival and oncogenes that promote cell growth and survival. since several alterations are usually required for a cancer to fully develop, the malignant phenotype is determined by the compound status of tumor suppressor genes and oncogenes. cancer genes may be changed by several mechanisms, which potentially alter the protein encoding nucleotide template, change the copy number of genes, or lead to increased gene transcription. epigenetic alterations, which, by definition, comprise mitotically and meiotically heritable changes in gene expression that are not caused by changes in the primary dna sequence, are increasingly being recognized for their roles in carcinogenesis. these epigenetic alterations may involve covalent modifications of amino acid residues in the histones around which the dna is wrapped, and changes in the methylation status of cytosine bases (c) in the context of cpg dinucleotides within the dna itself. methylation of clusters of cpgs called ‘cpg-islands’ in the promoters of genes has been associated with heritable gene silencing. the present review will focus on how disruption of the epigenome can contribute to cancer. in contrast to genetic alterations, gene silencing by epigenetic modifications is potentially reversible. treatment by agents that inhibit cytosine methylation and histone deacetylation can initiate chromatin decondensation, demethylation and reestablishment of gene transcription. accordingly, in the clinical setting, dna methylation and histone modifications are very attractive targets for the development and implementation of new therapeutic approaches. many clinical trials are ongoing, and epigenetic therapy has recently been approved by the united states food and drug administration (us fda) for use in the treatment of myelodysplastic syndrome (mds) and primary cutaneous t-cell lymphoma (ctcl). © 2007 the authors.”
Jakubowski, J. L., & Labrie, V.. (2017). Epigenetic Biomarkers for Parkinson’s Disease: From Diagnostics to Therapeutics. Journal of Parkinson’s Disease
Plain numerical DOI: 10.3233/JPD-160914
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“Parkinson’s disease (pd) is a prevalent neurodegenerative illness that is often diagnosed after significant pathology and neuronal cell loss has occurred. biomarkers of pd are greatly needed for early diagnosis, as well as for the prediction of disease progression and treatment outcome. in this regard, the epigenome, which is partially dynamic, holds considerable promise for the development of molecular biomarkers for pd. epigenetic marks are modified by both dna sequence and environmental factors associated with pd, and such marks could serve as a unifying predictor of at-risk individuals. epigenetic abnormalities have been detected in pd and other age-dependent neurodegenerative diseases, some of which were reported to occur early on and were reversible by pd medications. emerging reports indicate that certain epigenetic differences observed in the pd brain are detectable in more easily accessible tissues. in this review, we examine epigenetic-based strategies for the development of pd biomarkers. despite the complexities and challenges faced, the epigenome offers a new source of biomarkers with potential etiological relevance to pd, and may expand opportunities for personalized therapies.”
Lim, J. P., & Brunet, A.. (2013). Bridging the transgenerational gap with epigenetic memory. Trends in Genetics
Plain numerical DOI: 10.1016/j.tig.2012.12.008
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“It is textbook knowledge that inheritance of traits is governed by genetics, and that the epigenetic modifications an organism acquires are largely reset between generations. recently, however, transgenerational epigenetic inheritance has emerged as a rapidly growing field, providing evidence suggesting that some epigenetic changes result in persistent phenotypes across generations. here, we survey some of the most recent examples of transgenerational epigenetic inheritance in animals, ranging from caenorhabditis elegans to humans, and describe approaches and limitations to studying this phenomenon. we also review the current body of evidence implicating chromatin modifications and rna molecules in mechanisms underlying this unconventional mode of inheritance and discuss its evolutionary implications. © 2013 elsevier ltd.”
Pearson, A. D., Stegmaier, K., Bourdeaut, F., Reaman, G., Heenen, D., Meyers, M. L., … Vassal, G.. (2020). Paediatric Strategy Forum for medicinal product development of epigenetic modifiers for children: ACCELERATE in collaboration with the European Medicines Agency with participation of the Food and Drug Administration. European Journal of Cancer
Plain numerical DOI: 10.1016/j.ejca.2020.08.014
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“The fifth multistakeholder paediatric strategy forum focussed on epigenetic modifier therapies for children and adolescents with cancer. as most mutations in paediatric malignancies influence chromatin-associated proteins or transcription and paediatric cancers are driven by developmental gene expression programs, targeting epigenetic mechanisms is predicted to be a very important therapeutic approach in paediatric cancer. the research to accelerate cures and equity (race) for children act fdara amendments to section 505b of the fd&c act was implemented in august 2020, and as there are many epigenetic targets on the fda paediatric molecular targets list, clinical evaluation of epigenetic modifiers in paediatric cancers should be considered early in drug development. companies are also required to submit to the ema paediatric investigation plans aiming to ensure that the necessary data to support the authorisation of a medicine for children in eu are of high quality and ethically researched. the specific aims of the forum were i) to identify epigenetic targets or mechanisms of action associated with epigenetic modification relevant to paediatric cancers and ii) to define the landscape for paediatric drug development of epigenetic modifier therapies. dna methyltransferase inhibitors/hypomethylating agents and histone deacetylase inhibitors were largely excluded from discussion as the aim was to discuss those targets for which therapeutic agents are currently in early paediatric and adult development. epigenetics is an evolving field and could be highly relevant to many paediatric cancers; the biology is multifaceted and new targets are frequently emerging. targeting epigenetic mechanisms in paediatric malignancy has in most circumstances yet to reach or extend beyond clinical proof of concept, as many targets do not yet have available investigational drugs developed. eight classes of medicinal products were discussed and prioritised based on the existing level of science to support early evaluation in children: inhibitors of menin, dot1l, ezh2, eed, bet, prmt5 and lsd1 and a retinoic acid receptor alpha agonist. menin inhibitors should be moved rapidly into paediatric development, in view of their biological rationale, strong preclinical activity and ability to fulfil an unmet clinical need. a combination approach is critical for successful utilisation of any epigenetic modifiers (e.g. ezh2 and eed) and exploration of the optimum combination(s) should be …”
Janssens, Y., Wynendaele, E., Vanden Berghe, W., & De Spiegeleer, B.. (2019). Peptides as epigenetic modulators: Therapeutic implications. Clinical Epigenetics
Plain numerical DOI: 10.1186/s13148-019-0700-7
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“Peptides originating from different sources (endogenous, food derived, environmental, and synthetic) are able to influence different aspects of epigenetic regulation. endogenous short peptides, resulting from proteolytic cleavage of proteins or upon translation of non-annotated out of frame transcripts, can block dna methylation and hereby regulate gene expression. peptides entering the body by digestion of food-related proteins can modulate dna methylation and/or histone acetylation while environmental peptides, synthesized by bacteria, fungi, and marine sponges, mainly inhibit histone deacetylation. in addition, synthetic peptides that reverse or inhibit different epigenetic modifications of both histones and the dna can be developed as well. next to these dna and histone modifications, peptides can also influence the expression of non-coding rnas such as lncrnas and the maturation of mirnas. seen the advantages over small molecules, the development of peptide therapeutics is an interesting approach to treat diseases with a strong epigenetic basis like cancer and alzheimer’s disease. to date, only a limited number of drugs with a proven epigenetic mechanism of action have been approved by the fda of which two (romidepsin and nesiritide) are peptides. a large knowledge gap concerning epigenetic effects of peptides is present, and this class of molecules deserves more attention in the development as epigenetic modulators. in addition, none of the currently approved peptide drugs are under investigation for their potential effects on epigenetics, hampering drug repositioning of these peptides to other indications with an epigenetic etiology.”
Gomez, S., Tabernacki, T., Kobyra, J., Roberts, P., & Chiappinelli, K. B.. (2020). Combining epigenetic and immune therapy to overcome cancer resistance. Seminars in Cancer Biology
Plain numerical DOI: 10.1016/j.semcancer.2019.12.019
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“Cancer undergoes ‘immune editing’ to evade destruction by cells of the host immune system including natural killer (nk) cells and cytotoxic t lymphocytes (ctls). current adoptive cellular immune therapies include car t cells and dendritic cell vaccines, strategies that have yet to show success for a wide range of tumors. cancer resistance to immune therapy is driven by extrinsic factors and tumor cell intrinsic factors that contribute to immune evasion. these extrinsic factors include immunosuppressive cell populations such as regulatory t cells (tregs), tumor-associated macrophages (tams), and myeloid-derived suppressor cells (mdscs). these cells produce and secrete immunosuppressive factors and express inhibitory ligands that interact with receptors on t cells including pd-1 and ctla-4. immune checkpoint blockade (icb) therapies such as anti-pd-1 and anti-ctla-4 have shown success by increasing immune activation to eradicate cancer, though both primary and acquired resistance remain a problem. tumor cell intrinsic factors driving primary and acquired resistance to these immune therapies include genetic and epigenetic mechanisms. epigenetic therapies for cancer including dna methyltransferase inhibitors (dnmti), histone deacetylase inhibitors (hdaci), and histone methyltransferase inhibitors (hmti) can stimulate anti-tumor immunity in both tumor cells and host immune cells. here we discuss in detail tumor mechanisms of immune evasion and how common epigenetic therapies for cancer may be used to reverse immune evasion. lastly, we summarize current clinical trials combining epigenetic therapies with immune therapies to reverse cancer immune resistance mechanisms.”
Grazioli, E., Dimauro, I., Mercatelli, N., Wang, G., Pitsiladis, Y., Di Luigi, L., & Caporossi, D.. (2017). Physical activity in the prevention of human diseases: Role of epigenetic modifications. BMC Genomics
Plain numerical DOI: 10.1186/s12864-017-4193-5
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“Epigenetic modification refers to heritable changes in gene function that cannot be explained by alterations in the dna sequence. the current literature clearly demonstrates that the epigenetic response is highly dynamic and influenced by different biological and environmental factors such as aging, nutrient availability and physical exercise. as such, it is well accepted that physical activity and exercise can modulate gene expression through epigenetic alternations although the type and duration of exercise eliciting specific epigenetic effects that can result in health benefits and prevent chronic diseases remains to be determined. this review highlights the most significant findings from epigenetic studies involving physical activity/exercise interventions known to benefit chronic diseases such as metabolic syndrome, diabetes, cancer, cardiovascular and neurodegenerative diseases.”
D’Urso, A., & Brickner, J. H.. (2014). Mechanisms of epigenetic memory. Trends in Genetics
Plain numerical DOI: 10.1016/j.tig.2014.04.004
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“Although genetics has an essential role in defining the development, morphology, and physiology of an organism, epigenetic mechanisms have an essential role in modulating these properties by regulating gene expression. during development, epigenetic mechanisms establish stable gene expression patterns to ensure proper differentiation. such mechanisms also allow organisms to adapt to environmental changes and previous experiences can impact the future responsiveness of an organism to a stimulus over long timescales and even over generations. here, we discuss the concept of epigenetic memory, defined as the stable propagation of a change in gene expression or potential induced by developmental or environmental stimuli. we highlight three distinct paradigms of epigenetic memory that operate on different timescales. © 2014 elsevier ltd.”
Du, S., Chen, L., Ge, L., & Huang, W.. (2019). A novel loop: Mutual regulation between epigenetic modification and the circadian clock. Frontiers in Plant Science
Plain numerical DOI: 10.3389/fpls.2019.00022
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“In response to periodic environmental fluctuations generated by the rotation of the earth, nearly all organisms have evolved an intrinsic timekeeper, the circadian clock, which can maintain approximate 24-h rhythmic oscillations in biological processes, ultimately conferring fitness benefits. in the model plant arabidopsis, the core mechanics of the circadian clock can be described as a complex regulatory network of three feedback loops composed of core oscillator genes. transcriptional regulation of each oscillator gene is necessary to maintain the structure of the circadian clock. as a gene transcription regulatory mechanism, the epigenetic modification of chromatin affects the spatiotemporal expression of multiple genes. accumulating evidence indicates that epigenetic modification is associated with circadian clock function in animals and plants. in addition, the rhythms of epigenetic modification have a significant influence on the timing of molecular processes, including gene transcription. in this review, we summarize recent progress in research on the roles of histone acetylation, methylation, and phosphorylation in the regulation of clock gene expression in arabidopsis.”
Liao, P., Ostrom, Q. T., Stetson, L., & Barnholtz-Sloan, J. S.. (2018). Models of epigenetic age capture patterns of DNA methylation in glioma associated with molecular subtype, survival, and recurrence. Neuro-Oncology
Plain numerical DOI: 10.1093/neuonc/noy003
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“Background models of epigenetic aging (epigenetic clocks) have been implicated as potentially useful markers for cancer risk and prognosis. using 2 previously published methods for modeling epigenetic age, horvath’s clock and epitoc, we investigated epigenetic aging patterns related to world health organization grade and molecular subtype as well as associations of epigenetic aging with glioma survival and recurrence. methods epigenetic ages were calculated using horvath’s clock and epitoc on 516 lower-grade glioma and 141 glioblastoma cases along with 136 nontumor (normal) brain samples. associations of tumor epigenetic age with patient chronological age at diagnosis were assessed with correlation and linear regression, and associations were validated in an independent cohort of 203 gliomas. contribution of epigenetic age to survival prediction was assessed using cox proportional hazards modeling. sixty-three samples from 18 patients with primary-recurrent glioma pairs were also analyzed and epigenetic age difference and rate of epigenetic aging of primary-recurrent tumors were correlated to time to recurrence. results epigenetic ages of gliomas were near-universally accelerated using both horvath’s clock and epitoc compared with normal tissue. the 2 independent models of epigenetic aging were highly associated with each other and exhibited distinct aging patterns reflective of molecular subtype. epitoc was found to be a significant independent predictor of survival. epigenetic aging of gliomas between primary and recurrent tumors was found to be highly variable and not significantly associated with time to recurrence. conclusions we demonstrate that epigenetic aging reflects coherent modifications of the epigenome and can potentially provide additional prognostic power for gliomas.”
Shin, T. J., Lee, K. H., & Cho, J. Y.. (2020). Epigenetic mechanisms of lncrnas binding to protein in carcinogenesis. Cancers
Plain numerical DOI: 10.3390/cancers12102925
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“Epigenetic dysregulation is an important feature for cancer initiation and progression. long non-coding rnas (lncrnas) are transcripts that stably present as rna forms with no translated protein and have lengths larger than 200 nucleotides. lncrna can epigenetically regulate either oncogenes or tumor suppressor genes. nowadays, the combined research of lncrna plus protein analysis is gaining more attention. lncrna controls gene expression directly by binding to transcription factors of target genes and indirectly by complexing with other proteins to bind to target proteins and cause protein degradation, reduced protein stability, or interference with the binding of other proteins. various studies have indicated that lncrna contributes to cancer development by modulating genes epigenetically and studies have been done to determine which proteins are combined with lncrna and contribute to cancer development. in this review, we look in depth at the epigenetic regulatory function of lncrnas that are capable of complexing with other proteins in cancer development.”
Wu, J., Zhang, L., Song, Q., Yu, L., Wang, S., Zhang, B., … Xu, C.. (2021). Systematical identification of cell-specificity of CTCF-gene binding based on epigenetic modifications. Briefings in Bioinformatics
Plain numerical DOI: 10.1093/bib/bbaa004
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“The ccctc-binding factor (ctcf) mediates transcriptional regulation and implicates epigenetic modifications in cancers. however, the systematically unveiling inverse regulatory relationship between ctcf and epigenetic modifications still remains unclear, especially the mechanism by which histone modification mediates ctcf binding. here, we developed a systematic approach to investigate how epigenetic changes affect ctcf binding. through integration analysis of ctcf binding in 30 cell lines, we concluded that ctcf generally binds with higher intensity in normal cell lines than that in cancers, and higher intensity in genome regions closed to transcription start sites. to facilitate the better understanding of their associations, we constructed linear mixed-effect models to analyze the effects of the epigenetic modifications on ctcf binding in four cancer cell lines and six normal cell lines, and identified seven epigenetic modifications as potential epigenetic patterns that influence ctcf binding intensity in promoter regions and six epigenetic modifications in enhancer regions. further analysis of the effects in different locations revealed that the epigenetic regulation of ctcf binding was location-specific and cancer cell line-specific. moreover, h3k4me2 and h3k9ac showed the potential association with immune regulation of disease. taken together, our method can contribute to improve the understanding of the epigenetic regulation of ctcf binding and provide potential therapeutic targets for treating tumors associated with ctcf.”
Elwood, J., Murray, E., Bell, A., Sinclair, M., Kernohan, W. G., & Stockdale, J.. (2019). A systematic review investigating if genetic or epigenetic markers are associated with postnatal depression. Journal of Affective Disorders
Plain numerical DOI: 10.1016/j.jad.2019.04.059
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“Background: postnatal depression (pnd) is common, affects the health of the mother, the development of the infant and places a large financial burden on services. genetic and epigenetic biomarkers for pnd could potentially improve the accuracy of current antenatal screening approaches. the aim of this systematic review is to report on the evidence for an association between genetic or epigenetic factors and postnatal depression. method: a systematic search of five databases (medline, embase, pilot, psychinfo and scopus) was carried out using the following (mesh) terms and keywords: postpartum, depression, postnatal depression, genetics, genetic polymorphisms and epigenetics. inclusion criteria were applied and quality of studies was assessed using guidelines from the huge review handbook (little and higgins, 2006). results: following removal of duplicate articles, 543 remained; of these 37 met the inclusion criteria. positive associations have been reported between pnd and polymorphisms in the hmnc1, comt, maot, prkcb, esr1, slc6a4 genes in the presence of stressful life events, the bdnf gene when the postnatal period occurs during autumn and winter months and the oxt and oxtr genes in the presence of childhood adversity experienced by the mother. epigenetic interactions with genotype, estrogen, and childhood adversity were identified that are predictive of pnd. limitations: the number of studies investigating some of the markers was small and grey literature was not included. conclusion: this review highlights the importance of examining the interaction between epigenetic, genetic, hormonal and environmental factors in order to fully understand the risk factors for pnd and to improve the accuracy of current antenatal and early postnatal screening procedures. women susceptible to pnd appear to have heightened epigenetic sensitivity to the physiological changes of childbirth or to environmental factors conferred by genotype.”
Zhou, Y., Wang, L., Vaseghi, H. R., Liu, Z., Lu, R., Alimohamadi, S., … Qian, L.. (2016). Bmi1 Is a Key Epigenetic Barrier to Direct Cardiac Reprogramming. Cell Stem Cell
Plain numerical DOI: 10.1016/j.stem.2016.02.003
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“Summary direct reprogramming of induced cardiomyocytes (icms) suffers from low efficiency and requires extensive epigenetic repatterning, although the underlying mechanisms are largely unknown. to address these issues, we screened for epigenetic regulators of icm reprogramming and found that reducing levels of the polycomb complex gene bmi1 significantly enhanced induction of beating icms from neonatal and adult mouse fibroblasts. the inhibitory role of bmi1 in icm reprogramming is mediated through direct interactions with regulatory regions of cardiogenic genes, rather than regulation of cell proliferation. reduced bmi1 expression corresponded with increased levels of the active histone mark h3k4me3 and reduced levels of repressive h2ak119ub at cardiogenic loci, and de-repression of cardiogenic gene expression during icm conversion. furthermore, bmi1 deletion could substitute for gata4 during icm reprogramming. thus, bmi1 acts as a critical epigenetic barrier to icm production. bypassing this barrier simplifies icm generation and increases yield, potentially streamlining icm production for therapeutic purposes.”
Rothbart, S. B., & Baylin, S. B.. (2020). Epigenetic Therapy for Epithelioid Sarcoma. Cell
Plain numerical DOI: 10.1016/j.cell.2020.03.042
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“Tazemetostat is the first epigenetic therapy to gain fda approval in a solid tumor. this lysine methyltransferase inhibitor targets ezh2, the enzymatic subunit of the prc2 transcriptional silencing complex. tumors with mutations in subunits of the swi/snf chromatin remodeling complex, inclusive of most epithelioid sarcomas, are sensitive to ezh2 inhibition.”
Fischer, A.. (2014). Epigenetic memory: The Lamarckian brain. EMBO Journal
Plain numerical DOI: 10.1002/embj.201387637
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“Recent data support the view that epigenetic processes play a role in memory consolidation and help to transmit acquired memories even across generations in a lamarckian manner. drugs that target the epigenetic machinery were found to enhance memory function in rodents and ameliorate disease phenotypes in models for brain diseases such as alzheimer’s disease, chorea huntington, depression or schizophrenia. in this review, i will give an overview on the current knowledge of epigenetic processes in memory function and brain disease with a focus on morbus alzheimer as the most common neurodegenerative disease. i will address the question whether an epigenetic therapy could indeed be a suitable therapeutic avenue to treat brain diseases and discuss the necessary steps that should help to take neuroepigenetic research to the next level. as part of our review series on molecular memory, andre fischer discusses epigenetic processes leading to memory formation and transgenerational inheritance under physiological and pathological conditions such as alzheimer’s disease. © 2014 the author. published under the terms of the cc by nc nd license.”
Ou, X. H., Zhu, C. C., & Sun, S. C.. (2019). Effects of obesity and diabetes on the epigenetic modification of mammalian gametes. Journal of Cellular Physiology
Plain numerical DOI: 10.1002/jcp.27847
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“Obesity and diabetes are closely associated with numerous reproductive disorders, including termination of ovulation, irregular menstruation, low fertility, abortion, and risky pregnancy, which are now regarded as global health problems. paternal/maternal obesity and diabetes can also be transmitted to the subsequent generation via gametes, suggesting the association of epigenetic inheritance with obesity and diabetes, particularly for its effects on offspring. recent studies indicate that both obesity and diabetes change dna and histone methylation levels, histone acetylation, and noncoding rnas such as micrornas (mirnas) in oocytes and sperm. several important genes, such as ppar-α, igf2, h19, fyn, stella, sirt3, sirt6, and peg3 as well as mirnas, such as let-7c, reportedly participate in the regulation of epigenetic modifications in mammalian gametes. this review summarizes the recent progress that links obesity/diabetes and reproductive disorders from the perspective of gamete epigenetic modifications.”
Ornoy, A., Becker, M., Weinstein-Fudim, L., & Ergaz, Z.. (2020). S-adenosine methionine (SAME) and valproic acid (VPA) as epigenetic modulators: Special emphasis on their interactions affecting nervous tissue during pregnancy. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms21103721
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“S-adenosylmethionine (same) is involved in many transmethylation reactions in most living organisms and is also required in the synthesis of several substances such as monoamine neurotransmitters and the n-methyl-d-aspartate (nmda) receptor. due to its important role as an epigenetic modulator, we discuss in some length the process of dna methylation and demethylation and the critical periods of epigenetic modifications in the embryo, fetus, and thereafter. we also discuss the effects of same deficiency and the attempts to use same for therapeutic purposes such as the treatment of major depressive disorder, alzheimer disease, and other neuropsychiatric disorders. same is an approved food additive and as such is also used during pregnancy. yet, there seems to scanty data on the possible effects of same on the developing embryo and fetus. valproic acid (vpa) is a well-tolerated and effective antiepileptic drug that is also used as a mood stabilizer. due to its high teratogenicity, it is contraindicated in pregnancy. a major mechanism of its action is histone deacetylase inhibition, and therefore, it acts as an epigenetic modulator, mainly on the brain. this prompted clinical trials using vpa for additional indications i.e., treating degenerative brain disease such as alzheimer disease, dementia, hiv, and even cancer. therefore, we discuss the possible effects of vpa and same on the conceptus and early postnatally, during periods of susceptibility to epigenetic modifications. vpa is also used as an inducer of autistic-like behavior in rodents and was found by us to modify gene expression when administered during the first postnatal week but not when administered to the pregnant dams on day 12 of gestation. in contrast, same modified gene expression when administered on day 12 of pregnancy but not postnatally. if administered together, vpa prevented the changes in gene expression induced by prenatal same administration, and same prevented the gene expression changes and autistic-like behavior induced by early postnatal vpa. it is concluded that both vpa and same are powerful epigenetic modifiers with antagonistic actions on the brain that will probably be used in the future more extensively for the treatment of a variety of epigenetic diseases of the nervous system.”
Lyko, F.. (2018). The DNA methyltransferase family: A versatile toolkit for epigenetic regulation. Nature Reviews Genetics
Plain numerical DOI: 10.1038/nrg.2017.80
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“The dna methyltransferase (dnmt) family comprises a conserved set of dna-modifying enzymes that have a central role in epigenetic gene regulation. recent studies have shown that the functions of the canonical dnmt enzymes-dnmt1, dnmt3a and dnmt3b-go beyond their traditional roles of establishing and maintaining dna methylation patterns. this review analyses how molecular interactions and changes in gene copy numbers modulate the activity of dnmts in diverse gene regulatory functions, including transcriptional silencing, transcriptional activation and post-transcriptional regulation by dnmt2-dependent trna methylation. this mechanistic diversity enables the dnmt family to function as a versatile toolkit for epigenetic regulation.”
Abdelfatah, E., Kerner, Z., Nanda, N., & Ahuja, N.. (2016). Epigenetic therapy in gastrointestinal cancer: The right combination. Therapeutic Advances in Gastroenterology
Plain numerical DOI: 10.1177/1756283X16644247
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“Epigenetics is a relatively recent field of molecular biology that has arisen over the past 25 years. cancer is now understood to be a disease of widespread epigenetic dysregulation that interacts extensively with underlying genetic mutations. the development of drugs targeting these processes has rapidly progressed; with several drugs already fda approved as first-line therapy in hematological malignancies. gastrointestinal (gi) cancers possess high degrees of epigenetic dysregulation, exemplified by subtypes such as cpg island methylator phenotype (cimp), and the potential benefit of epigenetic therapy in these cancers is evident. the application of epigenetic drugs in solid tumors, including gi cancers, is just emerging, with increased understanding of the cancer epigenome. in this review, we provide a brief overview of cancer epigenetics and the epigenetic targets of therapy including deoxyribonucleic acid (dna) methylation, histone modifications, and chromatin remodeling. we discuss the epigenetic drugs currently in use, with a focus on dna methyltransferase (dnmt) and histone deacetylase (hdac) inhibitors, and explain the pharmacokinetic and mechanistic challenges in their application. we present the strategies employed in incorporating these drugs into the treatment of gi cancers, and explain the concept of the cancer stem cell in epigenetic reprogramming and reversal of chemo resistance. we discuss the most promising combination strategies in gi cancers including: (1) epigenetic sensitization to radiotherapy, (2) epigenetic sensitization to cytotoxic chemotherapy, and (3) epigenetic immune modulation and priming for immune therapy. finally, we present preclinical and clinical trial data employing these strategies thus far in various gi cancers including colorectal, esophageal, gastric, and pancreatic cancer.”
Hernando-Requejo, O., Quinto, H. G., & Rodríguez, C. R.. (2019). Nutrition as an epigenetic factor in develops of cancer. Nutricion Hospitalaria
Plain numerical DOI: 10.20960/nh.02810
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“Introduction: the incidence and prevalence of cancer disease is growing in the last years, cancer is currently the second cause of death in spain. for years nutrition has been linked with cancer as etiologic factor, but evidence levels are poorer than expected. with science advances, epigenetic have became a large field in nutrition to try to find solid relationships between nutrition and cancer development. objectives: this paper reviews the scientific evidence and the possible links between cancer etiology and nutrition. methods: bibliographic review and selection of the most relevant studies found. results and discussion: there is a relationship between nutrition and epigenetic modifications that can cause or prevent different types of cancer, by knowing those alterations we will be able to perform some primary prevention strategies trying to reduce cancer incidence. there is evidence that folates, polyphenols, selenium, isothiocyanates and vitamin d, among others, can be related with cancer development. with a growing knowledge on the relationship between cancer, nutrition and epigenetics we will have the opportunity to use it as an important protective factor for the general population.”
Belsky, D. W., Moffitt, T. E., Cohen, A. A., Corcoran, D. L., Levine, M. E., Prinz, J. A., … Caspi, A.. (2018). Eleven Telomere, Epigenetic Clock, and Biomarker-Composite Quantifications of Biological Aging: Do They Measure the Same Thing?. American Journal of Epidemiology
Plain numerical DOI: 10.1093/aje/kwx346
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“The geroscience hypothesis posits that therapies to slow biological processes of aging can prevent disease and extend healthy years of life. to test such ‘geroprotective’ therapies in humans, outcome measures are needed that can assess extension of disease-free life span. this need has spurred development of different methods to quantify biological aging. but different methods have not been systematically compared in the same humans. we implemented 7 methods to quantify biological aging using repeated-measures physiological and genomic data in 964 middle-aged humans in the dunedin study (new zealand; persons born 1972-1973). we studied 11 measures in total: telomere-length and erosion, 3 epigenetic-clocks and their ticking rates, and 3 biomarker-composites. contrary to expectation, we found low agreement between different measures of biological aging. we next compared associations between biological aging measures and outcomes that geroprotective therapies seek to modify: physical functioning, cognitive decline, and subjective signs of aging, including aged facial appearance. the 71-cytosine-phosphate-guanine epigenetic clock and biomarker composites were consistently related to these aging-related outcomes. however, effect sizes were modest. results suggested that various proposed approaches to quantifying biological aging may not measure the same aspects of the aging process. further systematic evaluation and refinement of measures of biological aging is needed to furnish outcomes for geroprotector trials.”
Aristizabal, M. J., Anreiter, I., Halldorsdottir, T., Odgers, C. L., McDade, T. W., Goldenberg, A., … O’Donnell, K. J.. (2020). Biological embedding of experience: A primer on epigenetics. Proceedings of the National Academy of Sciences of the United States of America
Plain numerical DOI: 10.1073/pnas.1820838116
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“Biological embedding occurs when life experience alters biological processes to affect later life health and well-being. although extensive correlative data exist supporting the notion that epigenetic mechanisms such as dna methylation underlie biological embedding, causal data are lacking. we describe specific epigenetic mechanisms and their potential roles in the biological embedding of experience. we also consider the nuanced relationships between the genome, the epigenome, and gene expression. our ability to connect biological embedding to the epigenetic landscape in its complexity is challenging and complicated by the influence of multiple factors. these include cell type, age, the timing of experience, sex, and dna sequence. recent advances in molecular profiling and epigenome editing, combined with the use of comparative animal and human longitudinal studies, should enable this field to transition from correlative to causal analyses.”
King, S. E., & Skinner, M. K.. (2020). Epigenetic Transgenerational Inheritance of Obesity Susceptibility. Trends in Endocrinology and Metabolism
Plain numerical DOI: 10.1016/j.tem.2020.02.009
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“The prevalence of obesity and associated diseases has reached pandemic levels. obesity is often associated with overnutrition and a sedentary lifestyle, but clearly other factors also increase the susceptibility of metabolic disease states. ancestral and direct exposures to environmental toxicants and altered nutrition have been shown to increase susceptibility for obesity and metabolic dysregulation. environmental insults can reprogram the epigenome of the germline (sperm and eggs), which transmits the susceptibility for disease to future generations through epigenetic transgenerational inheritance. in this review, we discuss current evidence and molecular mechanisms for epigenetic transgenerational inheritance of obesity susceptibility. understanding ancestral environmental insults and epigenetic transgenerational impacts on future generations will be critical to fully understand the etiology of obesity and to develop preventative therapy options.”
Becker, L. M., O’Connell, J. T., Vo, A. P., Cain, M. P., Tampe, D., Bizarro, L., … Kalluri, R.. (2020). Epigenetic Reprogramming of Cancer-Associated Fibroblasts Deregulates Glucose Metabolism and Facilitates Progression of Breast Cancer. Cell Reports
Plain numerical DOI: 10.1016/j.celrep.2020.107701
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“Becker et al. demonstrate that cafs present with a pro-glycolytic phenotype, which helps to fuel the metabolism of breast cancer cells and promotes tumor growth. chronic hypoxia induces the metabolic rewiring of normal fibroblasts toward a caf-like, pro-glycolytic phenotype. these microenvironmental changes enabled the epigenetic alterations and expression of key glycolytic enzymes in cafs.”
De Groote, M. L., Verschure, P. J., & Rots, M. G.. (2012). Epigenetic Editing: Targeted rewriting of epigenetic marks to modulate expression of selected target genes. Nucleic Acids Research
Plain numerical DOI: 10.1093/nar/gks863
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“Despite significant advances made in epigenetic research in recent decades, many questions remain unresolved, especially concerning cause and consequence of epigenetic marks with respect to gene expression modulation (gem). technologies allowing the targeting of epigenetic enzymes to predetermined dna sequences are uniquely suited to answer such questions and could provide potent (bio)medical tools. toward the goal of gene-specific gem by overwriting epigenetic marks (epigenetic editing, ege), instructive epigenetic marks need to be identified and their writers/erasers should then be fused to gene-specific dna binding domains. the appropriate epigenetic mark(s) to change in order to efficiently modulate gene expression might have to be validated for any given chromatin context and should be (mitotically) stable. various insights in such issues have been obtained by sequence-specific targeting of epigenetic enzymes, as is presented in this review. features of such studies provide critical aspects for further improving ege. an example of this is the direct effect of the edited mark versus the indirect effect of recruited secondary proteins by targeting epigenetic enzymes (or their domains). proof-of-concept of expression modulation of an endogenous target gene is emerging from the few ege studies reported. apart from its promise in correcting disease-associated epi-mutations, ege represents a powerful tool to address fundamental epigenetic questions. © 2012 the author(s).”
Gomez, S., Tabernacki, T., Kobyra, J., Roberts, P., & Chiappinelli, K. B.. (2020). Combining epigenetic and immune therapy to overcome cancer resistance. Seminars in Cancer Biology
Plain numerical DOI: 10.1016/j.semcancer.2019.12.019
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“Cancer undergoes ‘immune editing’ to evade destruction by cells of the host immune system including natural killer (nk) cells and cytotoxic t lymphocytes (ctls). current adoptive cellular immune therapies include car t cells and dendritic cell vaccines, strategies that have yet to show success for a wide range of tumors. cancer resistance to immune therapy is driven by extrinsic factors and tumor cell intrinsic factors that contribute to immune evasion. these extrinsic factors include immunosuppressive cell populations such as regulatory t cells (tregs), tumor-associated macrophages (tams), and myeloid-derived suppressor cells (mdscs). these cells produce and secrete immunosuppressive factors and express inhibitory ligands that interact with receptors on t cells including pd-1 and ctla-4. immune checkpoint blockade (icb) therapies such as anti-pd-1 and anti-ctla-4 have shown success by increasing immune activation to eradicate cancer, though both primary and acquired resistance remain a problem. tumor cell intrinsic factors driving primary and acquired resistance to these immune therapies include genetic and epigenetic mechanisms. epigenetic therapies for cancer including dna methyltransferase inhibitors (dnmti), histone deacetylase inhibitors (hdaci), and histone methyltransferase inhibitors (hmti) can stimulate anti-tumor immunity in both tumor cells and host immune cells. here we discuss in detail tumor mechanisms of immune evasion and how common epigenetic therapies for cancer may be used to reverse immune evasion. lastly, we summarize current clinical trials combining epigenetic therapies with immune therapies to reverse cancer immune resistance mechanisms.”
Davies, A., Zoubeidi, A., & Selth, L. A.. (2020). The epigenetic and transcriptional landscape of neuroendocrine prostate cancer. Endocrine-Related Cancer
Plain numerical DOI: 10.1530/ERC-19-0420
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“Tumours adapt to increasingly potent targeted therapies by transitioning to alternative lineage states. in prostate cancer, the widespread clinical application of androgen receptor (ar) pathway inhibitors has led to the insurgence of tumours relapsing with a neuroendocrine phenotype, termed neuroendocrine prostate cancer (nepc). recent evidence suggests that this lineage reprogramming is driven largely by dysregulation of the epigenome and transcriptional networks. indeed, aberrant dna methylation patterning and altered expression of epigenetic modifiers, such as ezh2, transcription factors, and rna-modifying factors, are hallmarks of nepc tumours. in this review, we explore the nature of the epigenetic and transcriptional landscape as prostate cancer cells lose their ar-imposed identity and transition to the neuroendocrine lineage. beyond addressing the mechanisms underlying epithelial-to-neuroendocrine lineage reprogramming, we discuss how oncogenic signaling and metabolic shifts fuel epigenetic/ transcriptional changes as well as the current state of epigenetic therapies for nepc.”
Wouters, B. J., & Delwel, R.. (2016). Epigenetics and approaches to targeted epigenetic therapy in acute myeloid leukemia. Blood
Plain numerical DOI: 10.1182/blood-2015-07-604512
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“Acute myeloid leukemia (aml) is the most common type of acute leukemia in adults. aml is a heterogeneous malignancy characterized by distinct genetic abnormalities. recent discoveries have highlighted an additional important role of dysregulated epigenetic mechanisms in the pathogenesis of the disease. in contrast to genetic changes, epigenetic modifications are frequently reversible, which provides opportunities for targeted treatment using specific inhibitors. in this review, we will provide an overview of the current state of epigenetics and epigenetic therapy in aml and will describe perspectives on how to identify promising new approaches for epigenetic targeted treatment.”
Akbarian, S.. (2014). Epigenetic mechanisms in schizophrenia. Dialogues in Clinical Neuroscience
Plain numerical DOI: 10.31887/dcns.2014.16.3/sakbarian
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“Schizophrenia is a major psychiatric disorder that lacks a unifying neuropathology, while currently available pharmacological treatments provide only limited benefits to many patients. this review will discuss how the field of neuroepigenetics could contribute to advancements of the existing knowledge on the neurobiology and treatment of psychosis. genome-scale mapping of dna methylation, histone modifications and variants, and chromosomal loopings for promoter-enhancer interactions and other epigenetic determinants of genome organization and function are likely to provide important clues about mechanisms contributing to dysregulated expression of synaptic and metabolic genes in schizophrenia brain, including the potential links to the underlying genetic risk architecture and environmental exposures. in addition, studies in animal models are providing a rapidly increasing list of chromatin- regulatory mechanisms with significant effects on cognition and complex behaviors, thereby pointing to the therapeutic potential of epigenetic drug targets in the nervous system.”
Grazioli, E., Dimauro, I., Mercatelli, N., Wang, G., Pitsiladis, Y., Di Luigi, L., & Caporossi, D.. (2017). Physical activity in the prevention of human diseases: Role of epigenetic modifications. BMC Genomics
Plain numerical DOI: 10.1186/s12864-017-4193-5
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“Epigenetic modification refers to heritable changes in gene function that cannot be explained by alterations in the dna sequence. the current literature clearly demonstrates that the epigenetic response is highly dynamic and influenced by different biological and environmental factors such as aging, nutrient availability and physical exercise. as such, it is well accepted that physical activity and exercise can modulate gene expression through epigenetic alternations although the type and duration of exercise eliciting specific epigenetic effects that can result in health benefits and prevent chronic diseases remains to be determined. this review highlights the most significant findings from epigenetic studies involving physical activity/exercise interventions known to benefit chronic diseases such as metabolic syndrome, diabetes, cancer, cardiovascular and neurodegenerative diseases.”
Le, N. T., Harukawa, Y., Miura, S., Boer, D., Kawabe, A., & Saze, H.. (2020). Epigenetic regulation of spurious transcription initiation in Arabidopsis. Nature Communications
Plain numerical DOI: 10.1038/s41467-020-16951-w
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“In plants, epigenetic regulation is critical for silencing transposons and maintaining proper gene expression. however, its impact on the genome-wide transcription initiation landscape remains elusive. by conducting a genome-wide analysis of transcription start sites (tsss) using cap analysis of gene expression (cage) sequencing, we show that thousands of tsss are exclusively activated in various epigenetic mutants of arabidopsis thaliana and referred to as cryptic tsss. many have not been identified in previous studies, of which up to 65% are contributed by transposons. they possess similar genetic features to regular tsss and their activation is strongly associated with the ectopic recruitment of rnapii machinery. the activation of cryptic tsss significantly alters transcription of nearby tsss, including those of genes important for development and stress responses. our study, therefore, sheds light on the role of epigenetic regulation in maintaining proper gene functions in plants by suppressing transcription from cryptic tsss.”
Crimmins, E. M., Thyagarajan, B., Levine, M. E., Weir, D. R., & Faul, J.. (2021). Associations of age, sex, race/ethnicity, and education with 13 epigenetic clocks in a nationally representative U.S. sample: The health and retirement study. Journals of Gerontology – Series A Biological Sciences and Medical Sciences
Plain numerical DOI: 10.1093/gerona/glab016
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“Background: many dna methylation-based indicators have been developed as summary measures of epigenetic aging. we examine the associations between 13 epigenetic clocks, including 4 second generation clocks, as well as the links of the clocks to social, demographic, and behavioral factors known to be related to health outcomes: sex, race/ethnicity, socioeconomic status, obesity, and lifetime smoking pack-years. methods: the health and retirement study is the data source which is a nationally representative sample of americans over age 50. assessment of dna methylation was based on the epic chip and epigenetic clocks were developed based on existing literature. results: the clocks vary in the strength of their relationships with age, with each other and with independent variables. second generation clocks trained on health-related characteristics tend to relate more strongly to the sociodemographic and health behaviors known to be associated with health outcomes in this age group. conclusions: users of this publicly available data set should be aware that epigenetic clocks vary in their relationships to age and to variables known to be related to the process of health change with age.”
Arif, M., Sadayappan, S., Becker, R. C., Martin, L. J., & Urbina, E. M.. (2019). Epigenetic modification: a regulatory mechanism in essential hypertension. Hypertension Research
Plain numerical DOI: 10.1038/s41440-019-0248-0
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“Essential hypertension (eh) is a multifactorial disease of the cardiovascular system that is influenced by the interplay of genetic, epigenetic, and environmental factors. the molecular dynamics underlying eh etiopathogenesis is unknown; however, earlier studies have revealed eh-associated genetic variants. nevertheless, this finding alone is not sufficient to explain the variability in blood pressure, suggesting that other risk factors are involved, such as epigenetic modifications. therefore, this review highlights the potential contribution of well-defined epigenetic mechanisms in eh, specifically, dna methylation, post-translational histone modifications, and micrornas. we further emphasize global and gene-specific dna methylation as one of the most well-studied hallmarks among all epigenetic modifications in eh. in addition, post-translational histone modifications, such as methylation, acetylation, and phosphorylation, are described as important epigenetic markers associated with eh. finally, we discuss micrornas that affect blood pressure by regulating master genes such as those implicated in the renin-angiotensin-aldosterone system. these epigenetic modifications, which appear to contribute to various cardiovascular diseases, including eh, may be a promising research area for the development of novel future strategies for eh prevention and therapeutics.”
Sen, D. R., Kaminski, J., Barnitz, R. A., Kurachi, M., Gerdemann, U., Yates, K. B., … Haining, W. N.. (2016). The epigenetic landscape of T cell exhaustion. Science
Plain numerical DOI: 10.1126/science.aae0491
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“Exhausted t cells in cancer and chronic viral infection express distinctive patterns of genes, including sustained expression of programmed cell death protein 1 (pd-1). however, the regulation of gene expression in exhausted t cells is poorly understood. here, we define the accessible chromatin landscape in exhausted cd8+ t cells and show that it is distinct from functional memory cd8+ t cells. exhausted cd8+ t cells in humans and a mouse model of chronic viral infection acquire a state-specific epigenetic landscape organized into functional modules of enhancers. genome editing shows that pd-1 expression is regulated in part by an exhaustion-specific enhancer that contains essential rar, t-bet, and sox3 motifs. functional enhancer maps may offer targets for genome editing that alter gene expression preferentially in exhausted cd8+ t cells.”
Belsky, D. W., Moffitt, T. E., Cohen, A. A., Corcoran, D. L., Levine, M. E., Prinz, J. A., … Caspi, A.. (2018). Eleven Telomere, Epigenetic Clock, and Biomarker-Composite Quantifications of Biological Aging: Do They Measure the Same Thing?. American Journal of Epidemiology
Plain numerical DOI: 10.1093/aje/kwx346
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“The geroscience hypothesis posits that therapies to slow biological processes of aging can prevent disease and extend healthy years of life. to test such ‘geroprotective’ therapies in humans, outcome measures are needed that can assess extension of disease-free life span. this need has spurred development of different methods to quantify biological aging. but different methods have not been systematically compared in the same humans. we implemented 7 methods to quantify biological aging using repeated-measures physiological and genomic data in 964 middle-aged humans in the dunedin study (new zealand; persons born 1972-1973). we studied 11 measures in total: telomere-length and erosion, 3 epigenetic-clocks and their ticking rates, and 3 biomarker-composites. contrary to expectation, we found low agreement between different measures of biological aging. we next compared associations between biological aging measures and outcomes that geroprotective therapies seek to modify: physical functioning, cognitive decline, and subjective signs of aging, including aged facial appearance. the 71-cytosine-phosphate-guanine epigenetic clock and biomarker composites were consistently related to these aging-related outcomes. however, effect sizes were modest. results suggested that various proposed approaches to quantifying biological aging may not measure the same aspects of the aging process. further systematic evaluation and refinement of measures of biological aging is needed to furnish outcomes for geroprotector trials.”
Strauss, J., & Figg, W. D.. (
2016).
Using epigenetic therapy to overcome chemotherapy resistance.
Anticancer Research
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“It has been known for decades that as cancer progresses, tumors develop genetic alterations, making them highly prone to developing resistance to therapies. classically, it has been thought that these acquired genetic changes are fixed. this has led to the paradigm of moving from one cancer therapy to the next while avoiding past therapies. however, emerging data on epigenetic changes during tumor progression and use of epigenetic therapies have shown that epigenetic modifications leading to chemotherapy resistance have the potential to be reversible with epigenetic therapy. in fact, promising clinical data exist that treatment with epigenetic agents can diminish chemotherapy resistance in a number of tumor types including chronic myelogenous leukemia, colorectal, ovarian, lung and breast cancer. the potential for epigenetic-modifying drugs to allow for treatment of resistant disease is exciting and clinical trials have just begun to evaluate this area.”
Weng, Y. L., An, R., Cassin, J., Joseph, J., Mi, R., Wang, C., … Ming, G. li. (2017). An Intrinsic Epigenetic Barrier for Functional Axon Regeneration. Neuron
Plain numerical DOI: 10.1016/j.neuron.2017.03.034
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“Mature neurons in the adult peripheral nervous system can effectively switch from a dormant state with little axonal growth to robust axon regeneration upon injury. the mechanisms by which injury unlocks mature neurons’ intrinsic axonal growth competence are not well understood. here, we show that peripheral sciatic nerve lesion in adult mice leads to elevated levels of tet3 and 5-hydroxylmethylcytosine in dorsal root ganglion (drg) neurons. functionally, tet3 is required for robust axon regeneration of drg neurons and behavioral recovery. mechanistically, peripheral nerve injury induces dna demethylation and upregulation of multiple regeneration-associated genes in a tet3- and thymine dna glycosylase-dependent fashion in drg neurons. in addition, pten deletion-induced axon regeneration of retinal ganglion neurons in the adult cns is attenuated upon tet1 knockdown. together, our study suggests an epigenetic barrier that can be removed by active dna demethylation to permit axon regeneration in the adult mammalian nervous system.”
Trejo Banos, D., McCartney, D. L., Patxot, M., Anchieri, L., Battram, T., Christiansen, C., … Robinson, M. R.. (2020). Bayesian reassessment of the epigenetic architecture of complex traits. Nature Communications
Plain numerical DOI: 10.1038/s41467-020-16520-1
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“Linking epigenetic marks to clinical outcomes improves insight into molecular processes, disease prediction, and therapeutic target identification. here, a statistical approach is presented to infer the epigenetic architecture of complex disease, determine the variation captured by epigenetic effects, and estimate phenotype-epigenetic probe associations jointly. implicitly adjusting for probe correlations, data structure (cell-count or relatedness), and single-nucleotide polymorphism (snp) marker effects, improves association estimates and in 9,448 individuals, 75.7% (95% ci 71.70–79.3) of body mass index (bmi) variation and 45.6% (95% ci 37.3–51.9) of cigarette consumption variation was captured by whole blood methylation array data. pathway-linked probes of blood cholesterol, lipid transport and sterol metabolism for bmi, and xenobiotic stimuli response for smoking, showed >1.5 times larger associations with >95% posterior inclusion probability. prediction accuracy improved by 28.7% for bmi and 10.2% for smoking over a lasso model, with age-, and tissue-specificity, implying associations are a phenotypic consequence rather than causal.”
Kim, M., & Costello, J.. (2017). DNA methylation: An epigenetic mark of cellular memory. Experimental and Molecular Medicine
Plain numerical DOI: 10.1038/emm.2017.10
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“DNA methylation is a stable epigenetic mark that can be inherited through multiple cell divisions. during development and cell differentiation, dna methylation is dynamic, but some dna methylation patterns may be retained as a form of epigenetic memory. dna methylation profiles can be useful for the lineage classification and quality control of stem cells such as embryonic stem cells, induced pluripotent cells and mesenchymal stem cells. during cancer initiation and progression, genomewide and gene-specific dna methylation changes occur as a consequence of mutated or deregulated chromatin regulators. early aberrant dna methylation states occurring during transformation appear to be retained during tumor evolution. similarly, dna methylation differences among different regions of a tumor reflect the history of cancer cells and their response to the tumor microenvironment. therefore, dna methylation can be a useful molecular marker for cancer diagnosis and drug treatment.”
Huang, D., Cui, L. Q., Ahmed, S., Zainab, F., Wu, Q., Wang, X., & Yuan, Z.. (2019). An overview of epigenetic agents and natural nutrition products targeting DNA methyltransferase, histone deacetylases and microRNAs. Food and Chemical Toxicology
Plain numerical DOI: 10.1016/j.fct.2018.10.052
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“Several humans’ diseases such as; cancer, heart disease, diabetes retain an etiology of epigenetic, and a new therapeutic option termed as ‘epigenetic therapy’ can offer a potential way to treat these diseases. a numbers of epigenetic agents such as; inhibitors of dna methyltransferase (dnmt) and histone deacetylases (hdacs) have grew an intensive investigation, and many of these agents are currently being tested in a clinical trial, while some of them have been approved for the use by the authorities. since mirnas can act as tumor suppressors or oncogenes, the mirna mimics and molecules targeted at mirnas (antimirs) have been designed to treat some of the diseases. much naturally occurring nutrition were discovered to alter the epigenetic states of cells. the nutrition, including polyphenol, flavonoid compounds, and cruciferous vegetables possess multiple beneficial effects, and some can simultaneously change the dna methylation, histone modifications and expression of microrna (mirna). this review mainly summarizes the information of epigenetic agents of dnmts and hdacs inhibitors, mirna mimics and antimirs, as well as the natural nutrition. in addition, some future perspectives related to the epigenetic therapy are also included.”
Campos, E. I., Stafford, J. M., & Reinberg, D.. (2014). Epigenetic inheritance: Histone bookmarks across generations. Trends in Cell Biology
Plain numerical DOI: 10.1016/j.tcb.2014.08.004
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“Multiple circuitries ensure that cells respond correctly to the environmental cues within defined cellular programs. there is increasing evidence suggesting that cellular memory for these adaptive processes can be passed on through cell divisions and generations. however, the mechanisms by which this epigenetic information is transferred remain elusive, largely because it requires that such memory survive through gross chromatin remodeling events during dna replication, mitosis, meiosis, and developmental reprogramming. elucidating the processes by which epigenetic information survives and is transmitted is a central challenge in biology. in this review, we consider recent advances in understanding mechanisms of epigenetic inheritance with a focus on histone segregation at the replication fork, and how an epigenetic memory may get passed through the paternal lineage.”
Manjrekar, J.. (2017). Epigenetic inheritance, prions and evolution. Journal of Genetics
Plain numerical DOI: 10.1007/s12041-017-0798-3
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“The field of epigenetics has grown explosively in the past two decades or so. as currently defined, epigenetics deals with heritable, metastable and usually reversible changes that do not involve alterations in dna sequence, but alter the way that information encoded in dna is utilized. the bulk of current research in epigenetics concerns itself with mitotically inherited epigenetic processes underlying development or responses to environmental cues (as well as the role of mis-regulation or dys-regulation of such processes in disease and ageing), i.e., epigenetic changes occurring within individuals. however, a steadily growing body of evidence indicates that epigenetic changes may also sometimes be transmitted from parents to progeny, meiotically in sexually reproducing organisms or mitotically in asexually reproducing ones. such transgenerational epigenetic inheritance (tei) raises obvious questions about a possible evolutionary role for epigenetic ‘lamarckian’ mechanisms in evolution, particularly when epigenetic modifications are induced by environmental cues. in this review i attempt a brief overview of the periodically reviewed and debated ‘classical’ tei phenomena and their possible implications for evolution. the review then focusses on a less-discussed, unique kind of protein-only epigenetic inheritance mediated by prions. much remains to be learnt about the mechanisms, persistence and effects of tei. the jury is still out on their evolutionary significance and how these phenomena should be incorporated into evolutionary theory, but the growing weight of evidence indicates that likely evolutionary roles for these processes need to be seriously explored.”
Ornoy, A., Becker, M., Weinstein-Fudim, L., & Ergaz, Z.. (2020). S-adenosine methionine (SAME) and valproic acid (VPA) as epigenetic modulators: Special emphasis on their interactions affecting nervous tissue during pregnancy. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms21103721
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“S-adenosylmethionine (same) is involved in many transmethylation reactions in most living organisms and is also required in the synthesis of several substances such as monoamine neurotransmitters and the n-methyl-d-aspartate (nmda) receptor. due to its important role as an epigenetic modulator, we discuss in some length the process of dna methylation and demethylation and the critical periods of epigenetic modifications in the embryo, fetus, and thereafter. we also discuss the effects of same deficiency and the attempts to use same for therapeutic purposes such as the treatment of major depressive disorder, alzheimer disease, and other neuropsychiatric disorders. same is an approved food additive and as such is also used during pregnancy. yet, there seems to scanty data on the possible effects of same on the developing embryo and fetus. valproic acid (vpa) is a well-tolerated and effective antiepileptic drug that is also used as a mood stabilizer. due to its high teratogenicity, it is contraindicated in pregnancy. a major mechanism of its action is histone deacetylase inhibition, and therefore, it acts as an epigenetic modulator, mainly on the brain. this prompted clinical trials using vpa for additional indications i.e., treating degenerative brain disease such as alzheimer disease, dementia, hiv, and even cancer. therefore, we discuss the possible effects of vpa and same on the conceptus and early postnatally, during periods of susceptibility to epigenetic modifications. vpa is also used as an inducer of autistic-like behavior in rodents and was found by us to modify gene expression when administered during the first postnatal week but not when administered to the pregnant dams on day 12 of gestation. in contrast, same modified gene expression when administered on day 12 of pregnancy but not postnatally. if administered together, vpa prevented the changes in gene expression induced by prenatal same administration, and same prevented the gene expression changes and autistic-like behavior induced by early postnatal vpa. it is concluded that both vpa and same are powerful epigenetic modifiers with antagonistic actions on the brain that will probably be used in the future more extensively for the treatment of a variety of epigenetic diseases of the nervous system.”
Aslani, S., Jafari, N., Javan, M. R., Karami, J., Ahmadi, M., & Jafarnejad, M.. (2017). Epigenetic Modifications and Therapy in Multiple Sclerosis. NeuroMolecular Medicine
Plain numerical DOI: 10.1007/s12017-016-8422-x
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“Breakthroughs in genetic studies, like whole human genome sequencing and genome-wide association studies (gwas), have richened our knowledge of etiopathology of autoimmune diseases (aid) through discovery of genetic patterns. nonetheless, the precise etiology of autoimmune diseases remains largely unknown. the lack of complete concordance of autoimmune disease in identical twins suggests that non-genetic factors also play a major role in determining disease susceptibility. although there is no certain definition, epigenetics has been known as heritable alterations in gene function without changes in the nucleotide sequence. dna methylation, histone modifications, and microrna-associated gene expression suppression are the central mechanisms for epigenetic regulations. multiple sclerosis (ms) is a disorder of the central nervous system (cns), characterized by both inflammatory and neurodegenerative features. although studies on epigenetic alterations in ms only began in the past decade, a mounting number of surveys suggest that epigenetic changes may be involved in the initiation and development of ms, probably through bridging the effects of environmental risk factors to genetics. arming with clear understanding of epigenetic dysregulations underpins development of epigenetic therapies. identifying agents inhibiting the enzymes controlling epigenetic modifications, particularly dna methyltransferases and histone deacetylases, will be promising therapeutic tool toward ms. in the article underway, it is aimed to go through the recent progresses, attempting to disclose how epigenetics associates with the pathogenesis of ms and how can be used as therapeutic approach.”
Shi, W., Chen, X., Gao, L., Xu, C. Y., Ou, X., Bossdorf, O., … Geng, Y.. (2019). Transient stability of epigenetic population differentiation in a clonal invader. Frontiers in Plant Science
Plain numerical DOI: 10.3389/fpls.2018.01851
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“Epigenetic variation may play an important role in how plants cope with novel environments. while significant epigenetic differences among plants from contrasting habitats have often been observed in the field, the stability of these differences remains little understood. here, we combined field monitoring with a multi-generation common garden approach to study the dynamics of dna methylation variation in invasive chinese populations of the clonal alligator weed (alternanthera philoxeroides). using aflp and msap markers, we found little variation in dna sequence but substantial epigenetic population differentiation. in the field, these differences remained stable across multiple years, whereas in a common environment they were maintained at first but then progressively eroded. however, some epigenetic differentiation remained even after 10 asexual generations. our data indicate that epigenetic variation in alligator weed most likely results from a combination of environmental induction and spontaneous epimutation, and that much of it is neither rapidly reversible (phenotypic plasticity) nor long-term stable, but instead displays an intermediate level of stability. such transient epigenetic stability could be a beneficial mechanism in novel and heterogeneous environments, particularly in a genetically impoverished invader.”
Gräff, J., & Mansuy, I. M.. (2008). Epigenetic codes in cognition and behaviour. Behavioural Brain Research
Plain numerical DOI: 10.1016/j.bbr.2008.01.021
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“The epigenetic marking of chromatin provides a ubiquitous means for cells to shape and maintain their identity, and to react to environmental stimuli via specific remodeling. such an epigenetic code of the core components of chromatin, dna and histone proteins, can thus be stable but is also highly dynamic. in the nervous system, epigenetic codes are critical for basic cellular processes such as synaptic plasticity, and for complex behaviours such as learning and memory. at the same time, epigenetic marks can be stably transmitted through mitosis and meiosis, and thereby underlie non-genomic transgenerational inheritance of behavioural traits. in this review, we describe recent findings on the role and mechanisms of epigenetic codes in the brain, and discuss their implication in synaptic plasticity, cognitive functions and psychiatric disorders. we provide examples of transgenerational inheritance of epigenetic marks that affect simple morphological traits or complex processes such as disease susceptibility, and point to the potential implication of epigenetic codes in medicine and evolution. © 2008 elsevier b.v. all rights reserved.”
Ou, X. H., Zhu, C. C., & Sun, S. C.. (2019). Effects of obesity and diabetes on the epigenetic modification of mammalian gametes. Journal of Cellular Physiology
Plain numerical DOI: 10.1002/jcp.27847
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“Obesity and diabetes are closely associated with numerous reproductive disorders, including termination of ovulation, irregular menstruation, low fertility, abortion, and risky pregnancy, which are now regarded as global health problems. paternal/maternal obesity and diabetes can also be transmitted to the subsequent generation via gametes, suggesting the association of epigenetic inheritance with obesity and diabetes, particularly for its effects on offspring. recent studies indicate that both obesity and diabetes change dna and histone methylation levels, histone acetylation, and noncoding rnas such as micrornas (mirnas) in oocytes and sperm. several important genes, such as ppar-α, igf2, h19, fyn, stella, sirt3, sirt6, and peg3 as well as mirnas, such as let-7c, reportedly participate in the regulation of epigenetic modifications in mammalian gametes. this review summarizes the recent progress that links obesity/diabetes and reproductive disorders from the perspective of gamete epigenetic modifications.”
Uller, T., English, S., & Pen, I.. (2015). When is incomplete epigenetic resetting in germ cells favoured by natural selection?. Proceedings of the Royal Society B: Biological Sciences
Plain numerical DOI: 10.1098/rspb.2015.0682
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“Resetting of epigenetic marks, such as dna methylation, in germ cells or early embryos is not always complete. epigenetic states may therefore persist, decay or accumulate across generations. in spite of mounting empirical evidence for incomplete resetting, it is currently poorly understood whether it simply reflects stochastic noise or plays an adaptive role in phenotype determination. here, we use a simple model to show that incomplete resetting can be adaptive in heterogeneous environments. transmission of acquired epigenetic states prevents mismatched phenotypes when the environment changes infrequently relative to generation time and when maternal and environ- mental cues are unreliable. we discuss how these results may help to interpret the emerging data on transgenerational epigenetic inheritance in plants and animals.”
Horvath, S., & Raj, K.. (2018). DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nature Reviews Genetics
Plain numerical DOI: 10.1038/s41576-018-0004-3
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“Identifying and validating molecular targets of interventions that extend the human health span and lifespan has been difficult, as most clinical biomarkers are not sufficiently representative of the fundamental mechanisms of ageing to serve as their indicators. in a recent breakthrough, biomarkers of ageing based on dna methylation data have enabled accurate age estimates for any tissue across the entire life course. these ‘epigenetic clocks’ link developmental and maintenance processes to biological ageing, giving rise to a unified theory of life course. epigenetic biomarkers may help to address long-standing questions in many fields, including the central question: why do we age?”
Garcia-Martinez, L., Zhang, Y., Nakata, Y., Chan, H. L., & Morey, L.. (2021). Epigenetic mechanisms in breast cancer therapy and resistance. Nature Communications
Plain numerical DOI: 10.1038/s41467-021-22024-3
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“The majority of breast cancers express the estrogen receptor (erα) and agents targeting this pathway represent the main treatment modality. endocrine therapy has proven successful in the treatment of hormone-responsive breast cancer since its early adoption in the 1940s as an ablative therapy. unfortunately, therapeutic resistance arises, leading to disease recurrence and relapse. recent studies increased our understanding in how changes to the chromatin landscape and deregulation of epigenetic factors orchestrate the resistant phenotype. here, we will discuss how the epigenome is an integral determinant in hormone therapy response and why epigenetic factors are promising targets for overcoming clinical resistance.”
Steiger, H., & Booij, L.. (2020). Eating Disorders, Heredity and Environmental Activation: Getting Epigenetic Concepts into Practice. Journal of Clinical Medicine
Plain numerical DOI: 10.3390/jcm9051332
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“Epigenetic mechanisms are believed to link environmental exposures to alterations in gene expression, and in so doing, to provide a physical substrate for the activation of hereditary potentials by life experiences. in keeping with this idea, accumulating data suggest that epigenetic processes are implicated in eating-disorder (ed) etiology. this paper reviews literature on putative links between epigenetic factors and eds, and examines ways in which epigenetic programming of gene expression could account for gene-environment interactions acting in the eds. the paper also presents evidence suggesting that epigenetic processes link malnutrition and life stresses (gestational, perinatal, childhood, and adult) to risk of ed development. drawing from empirical evidence and clinical experience, we propose that an epigenetically informed understanding of ed etiology can benefit patients, caregivers, and clinicians alike, in the sense that the perspective can reduce judgmental or blameful attitudes on the part of clinicians and caregivers, and increase self-acceptance and optimism about recovery on the part of those affected.”
Rinaldi, L., & Benitah, S. A.. (2015). Epigenetic regulation of adult stem cell function. FEBS Journal
Plain numerical DOI: 10.1111/febs.12946
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“Understanding the cellular and molecular mechanisms that specify cell lineages throughout development, and that maintain tissue homeostasis during adulthood, is paramount towards our understanding of why we age or develop pathologies such as cancer. epigenetic mechanisms ensure that genetically identical cells acquire different fates during embryonic development and are therefore essential for the proper progression of development. how they do so is still a matter of intense investigation, but there is sufficient evidence indicating that they act in a concerted manner with inductive signals and tissue-specific transcription factors to promote and stabilize fate changes along the three germ layers during development. in consequence, it is generally hypothesized that epigenetic mechanisms are also required for the continuous maintenance of cell fate during adulthood. however, in vivo models in which different epigenetic factors have been depleted in different tissues do not show overt changes in cell lineage, thus not strongly supporting this view. instead, the function of some of these factors appears to be primarily associated with tissue functionality, and a strong causal relationship has been established between their misregulation and a diseased state. in this review, we summarize our current knowledge of the role of epigenetic factors in adult stem cell function and tissue homeostasis. epigenetic mechanisms ensure that lineages are acquired during development. it is therefore hypothesized that they also maintain cell fates during adulthood. however, perturbation of epigenetic factors in adult tissues affects homeostasis instead of eliciting overt changes in cell identity. here, we summarize current knowledge of the role of epigenetic factors in adult stem cells and homeostasis.”
Liu, M., Zhou, J., Chen, Z., & Cheng, A. S. L.. (2017). Understanding the epigenetic regulation of tumours and their microenvironments: opportunities and problems for epigenetic therapy. Journal of Pathology
Plain numerical DOI: 10.1002/path.4832
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“The tumour microenvironment plays an instrumental role in cancer development, progression and treatment response/resistance. accumulating evidence is underscoring the fundamental importance of epigenetic regulation in tumour immune evasion. following many pioneering discoveries demonstrating malignant transformation through epigenetic anomalies (‘epimutations’), there is also a growing emphasis on elucidating aberrant epigenetic mechanisms that reprogramme the milieu of tumour-associated immune and stromal cells towards an immunosuppressive state. pharmacological inhibition of dna methylation and histone modifications can augment the efficiency of immune checkpoint blockage, and unleash anti-tumour t-cell responses. however, these non-specific agents also represent a ‘double-edged sword’, as they can also reactivate gene transcription of checkpoint molecules, interrupting immune surveillance programmes. by understanding the impact of epigenetic control on the tumour microenvironment, rational combinatorial epigenetic and checkpoint blockage therapies have the potential to harness the immune system for the treatment of cancer. copyright © 2016 pathological society of great britain and ireland. published by john wiley & sons, ltd.”
Belzil, V. V., Katzman, R. B., & Petrucelli, L.. (2016). ALS and FTD: an epigenetic perspective. Acta Neuropathologica
Plain numerical DOI: 10.1007/s00401-016-1587-4
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“Amyotrophic lateral sclerosis (als) and frontotemporal dementia (ftd) are two fatal neurodegenerative diseases seen in comorbidity in up to 50 % of cases. despite tremendous efforts over the last two decades, no biomarkers or effective therapeutics have been identified to prevent, decelerate, or stop neuronal death in patients. while the identification of multiple mutations in more than two dozen genes elucidated the involvement of several mechanisms in the pathogenesis of both diseases, identifying the hexanucleotide repeat expansion in c9orf72, the most common genetic abnormality in als and ftd, opened the door to the discovery of several novel pathogenic biological routes, including chromatin remodeling and transcriptome alteration. epigenetic processes regulate dna replication and repair, rna transcription, and chromatin conformation, which in turn further dictate transcriptional regulation and protein translation. transcriptional and post-transcriptional epigenetic regulation is mediated by enzymes and chromatin-modifying complexes that control dna methylation, histone modifications, and rna editing. while the alteration of dna methylation and histone modification has recently been reported in als and ftd, the assessment of epigenetic involvement in both diseases is still at an early stage, and the involvement of multiple epigenetic players still needs to be evaluated. as the epigenome serves as a way to alter genetic information not only during aging, but also following environmental signals, epigenetic mechanisms might play a central role in initiating als and ftd, especially for sporadic cases. here, we provide a review of what is currently known about altered epigenetic processes in both als and ftd and discuss potential therapeutic strategies targeting epigenetic mechanisms. as approximately 85 % of als and ftd cases are still genetically unexplained, epigenetic therapeutics explored for other diseases might represent a profitable direction for the field.”
Wouters, B. J., & Delwel, R.. (2016). Epigenetics and approaches to targeted epigenetic therapy in acute myeloid leukemia. Blood
Plain numerical DOI: 10.1182/blood-2015-07-604512
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“Acute myeloid leukemia (aml) is the most common type of acute leukemia in adults. aml is a heterogeneous malignancy characterized by distinct genetic abnormalities. recent discoveries have highlighted an additional important role of dysregulated epigenetic mechanisms in the pathogenesis of the disease. in contrast to genetic changes, epigenetic modifications are frequently reversible, which provides opportunities for targeted treatment using specific inhibitors. in this review, we will provide an overview of the current state of epigenetics and epigenetic therapy in aml and will describe perspectives on how to identify promising new approaches for epigenetic targeted treatment.”
Li, T., Mao, C., Wang, X., Shi, Y., & Tao, Y.. (2020). Epigenetic crosstalk between hypoxia and tumor driven by HIF regulation. Journal of Experimental and Clinical Cancer Research
Plain numerical DOI: 10.1186/s13046-020-01733-5
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“Hypoxia is the major influence factor in physiological and pathological courses which are mainly mediated by hypoxia-inducible factors (hifs) in response to low oxygen tensions within solid tumors. under normoxia, hif signaling pathway is inhibited due to hif-α subunits degradation. however, in hypoxic conditions, hif-α is activated and stabilized, and hif target genes are successively activated, resulting in a series of tumour-specific activities. the activation of hifs, including hif-1α, hif-2α and hif-3α, subsequently induce downstream target genes which leads to series of responses, the resulting abnormal processes or metabolites in turn affect hifs stability. given its functions in tumors progression, hifs have been regarded as therapeutic targets for improved treatment efficacy. epigenetics refers to alterations in gene expression that are stable between cell divisions, and sometimes between generations, but do not involve changes in the underlying dna sequence of the organism. and with the development of research, epigenetic regulation has been found to play an important role in the development of tumors, which providing accumulating basic or clinical evidences for tumor treatments. here, given how little has been reported about the overall association between hypoxic tumors and epigenetics, we made a more systematic review from epigenetic perspective in hope of helping others better understand hypoxia or hif pathway, and providing more established and potential therapeutic strategies in tumors to facilitate epigenetic studies of tumors.”
Campos, E. I., Stafford, J. M., & Reinberg, D.. (2014). Epigenetic inheritance: Histone bookmarks across generations. Trends in Cell Biology
Plain numerical DOI: 10.1016/j.tcb.2014.08.004
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“Multiple circuitries ensure that cells respond correctly to the environmental cues within defined cellular programs. there is increasing evidence suggesting that cellular memory for these adaptive processes can be passed on through cell divisions and generations. however, the mechanisms by which this epigenetic information is transferred remain elusive, largely because it requires that such memory survive through gross chromatin remodeling events during dna replication, mitosis, meiosis, and developmental reprogramming. elucidating the processes by which epigenetic information survives and is transmitted is a central challenge in biology. in this review, we consider recent advances in understanding mechanisms of epigenetic inheritance with a focus on histone segregation at the replication fork, and how an epigenetic memory may get passed through the paternal lineage.”
Shea, N., Pen, I., & Uller, T.. (2011). Three epigenetic information channels and their different roles in evolution. Journal of Evolutionary Biology
Plain numerical DOI: 10.1111/j.1420-9101.2011.02235.x
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“There is increasing evidence for epigenetically mediated transgenerational inheritance across taxa. however, the evolutionary implications of such alternative mechanisms of inheritance remain unclear. herein, we show that epigenetic mechanisms can serve two fundamentally different functions in transgenerational inheritance: (i) selection-based effects, which carry adaptive information in virtue of selection over many generations of reliable transmission; and (ii) detection-based effects, which are a transgenerational form of adaptive phenotypic plasticity. the two functions interact differently with a third form of epigenetic information transmission, namely information about cell state transmitted for somatic cell heredity in multicellular organisms. selection-based epigenetic information is more likely to conflict with somatic cell inheritance than is detection-based epigenetic information. consequently, the evolutionary implications of epigenetic mechanisms are different for unicellular and multicellular organisms, which underscores the conceptual and empirical importance of distinguishing between these two different forms of transgenerational epigenetic effect. © 2011 the authors. journal of evolutionary biology © 2011 european society for evolutionary biology.”
Van, M. V., Fujimori, T., & Bintu, L.. (2021). Nanobody-mediated control of gene expression and epigenetic memory. Nature Communications
Plain numerical DOI: 10.1038/s41467-020-20757-1
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“Targeting chromatin regulators to specific genomic locations for gene control is emerging as a powerful method in basic research and synthetic biology. however, many chromatin regulators are large, making them difficult to deliver and combine in mammalian cells. here, we develop a strategy for gene control using small nanobodies that bind and recruit endogenous chromatin regulators to a gene. we show that an antigfp nanobody can be used to simultaneously visualize gfp-tagged chromatin regulators and control gene expression, and that nanobodies against hp1 and dnmt1 can silence a reporter gene. moreover, combining nanobodies together or with other regulators, such as dnmt3a or krab, can enhance silencing speed and epigenetic memory. finally, we use the slow silencing speed and high memory of antidnmt1 to build a signal duration timer and recorder. these results set the basis for using nanobodies against chromatin regulators for controlling gene expression and epigenetic memory.”
Manjrekar, J.. (2017). Epigenetic inheritance, prions and evolution. Journal of Genetics
Plain numerical DOI: 10.1007/s12041-017-0798-3
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“The field of epigenetics has grown explosively in the past two decades or so. as currently defined, epigenetics deals with heritable, metastable and usually reversible changes that do not involve alterations in dna sequence, but alter the way that information encoded in dna is utilized. the bulk of current research in epigenetics concerns itself with mitotically inherited epigenetic processes underlying development or responses to environmental cues (as well as the role of mis-regulation or dys-regulation of such processes in disease and ageing), i.e., epigenetic changes occurring within individuals. however, a steadily growing body of evidence indicates that epigenetic changes may also sometimes be transmitted from parents to progeny, meiotically in sexually reproducing organisms or mitotically in asexually reproducing ones. such transgenerational epigenetic inheritance (tei) raises obvious questions about a possible evolutionary role for epigenetic ‘lamarckian’ mechanisms in evolution, particularly when epigenetic modifications are induced by environmental cues. in this review i attempt a brief overview of the periodically reviewed and debated ‘classical’ tei phenomena and their possible implications for evolution. the review then focusses on a less-discussed, unique kind of protein-only epigenetic inheritance mediated by prions. much remains to be learnt about the mechanisms, persistence and effects of tei. the jury is still out on their evolutionary significance and how these phenomena should be incorporated into evolutionary theory, but the growing weight of evidence indicates that likely evolutionary roles for these processes need to be seriously explored.”
Bar, S., & Benvenisty, N.. (2019). Epigenetic aberrations in human pluripotent stem cells. The EMBO Journal
Plain numerical DOI: 10.15252/embj.2018101033
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“Human pluripotent stem cells (hpscs) are being increasingly utilized worldwide in investigating human development, and modeling and discovering therapies for a wide range of diseases as well as a source for cellular therapy. yet, since the first isolation of human embryonic stem cells (hescs) 20 years ago, followed by the successful reprogramming of human-induced pluripotent stem cells (hipscs) 10 years later, various studies shed light on abnormalities that sometimes accumulate in these cells in vitro whereas genetic aberrations are well documented, epigenetic alterations are not as thoroughly discussed. in this review, we highlight frequent epigenetic aberrations found in hpscs, including alterations in dna methylation patterns, parental imprinting, and x chromosome inactivation. we discuss the potential origins of these abnormalities in hescs and hipscs, survey the different methods for detecting them, and elaborate on their potential consequences for the different utilities of hpscs.”
Ladd-Acosta, C.. (2015). Epigenetic Signatures as Biomarkers of Exposure. Current Environmental Health Reports
Plain numerical DOI: 10.1007/s40572-015-0051-2
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“To advance our knowledge of the influence of environmental exposures on human health and disease, robust studies are needed. however, for many exposures, robust studies are not feasible due to limitations with current ascertainment methods and/or study designs. epigenetics, the study of mitotically heritable, reversible information that regulates critical cell processes, has gained much attention because it offers a potential mechanism to explain how exposures can influence cell states. therefore, most studies have focused on epigenetics as a mechanism for disease. however, emerging evidence also suggests that epigenetic marks may also serve as biomarkers of exposure. here, we highlight findings showing that the epigenome is labile to the environment and that these exposure-associated changes show long-term stability, are specific, are detectable in accessible tissues, can predict exposure status, and can be practically implemented, thus supporting the potential for epigenetic patterns to serve as robust measures of environmental exposure.”
Montgomery, M., & Srinivasan, A.. (2019). Epigenetic Gene Regulation by Dietary Compounds in Cancer Prevention. Advances in Nutrition
Plain numerical DOI: 10.1093/advances/nmz046
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“Traditionally, cancer has been viewed as a set of diseases that are driven by the accumulation of genetic mutations, but we now understand that disruptions in epigenetic regulatory mechanisms are prevalent in cancer as well. unlike genetic mutations, however, epigenetic alterations are reversible, making them desirable therapeutic targets. the potential for diet, and bioactive dietary components, to target epigenetic pathways in cancer is now widely appreciated, but our understanding of how to utilize these compounds for effective chemopreventive strategies in humans is in its infancy. this review provides a brief overview of epigenetic regulation and the clinical applications of epigenetics in cancer. it then describes the capacity for dietary components to contribute to epigenetic regulation, with a focus on the efficacy of dietary epigenetic regulators as secondary cancer prevention strategies in humans. lastly, it discusses the necessary precautions and challenges that will need to be overcome before the chemopreventive power of dietary-based intervention strategies can be fully harnessed.”
Kim, J. K., Samaranayake, M., & Pradhan, S.. (2009). Epigenetic mechanisms in mammals. Cellular and Molecular Life Sciences
Plain numerical DOI: 10.1007/s00018-008-8432-4
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“DNA and histone methylation are linked and subjected to mitotic inheritance in mammals. yet how methylation is propagated and maintained between successive cell divisions is not fully understood. a series of enzyme families that can add methylation marks to cytosine nucleobases, and lysine and arginine amino acid residues has been discovered. apart from methyltransferases, there are also histone modification enzymes and accessory proteins, which can facilitate and/or target epigenetic marks. several lysine and arginine demethylases have been discovered recently, and the presence of an active dna demethylase is speculated in mammalian cells. a mammalian methyl dna binding protein mbd2 and de novo dna methyltransferase dnmt3a and dnmt3b are shown experimentally to possess dna demethylase activity. thus, complex mammalian epigenetic mechanisms appear to be dynamic yet reversible along with a well-choreographed set of events that take place during mammalian development. © 2008 birkhäuser verlag.”
Ashe, A., Colot, V., & Oldroyd, B. P.. (2021). How does epigenetics influence the course of evolution?. Philosophical Transactions of the Royal Society B: Biological Sciences
Plain numerical DOI: 10.1098/rstb.2020.0111
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“Epigenetics is the study of changes in gene activity that can be transmitted through cell divisions but cannot be explained by changes in the dna sequence. epigenetic mechanisms are central to gene regulation, phenotypic plasticity, development and the preservation of genome integrity. epigenetic mechanisms are often held to make a minor contribution to evolutionary change because epigenetic states are typically erased and reset at every generation, and are therefore, not heritable. nonetheless, there is growing appreciation that epigenetic variation makes direct and indirect contributions to evolutionary processes. first, some epigenetic states are transmitted intergenerationally and affect the phenotype of offspring. moreover, bona fide heritable ‘epialleles’ exist and are quite common in plants. such epialleles could, therefore, be subject to natural selection in the same way as conventional dna sequence-based alleles. second, epigenetic variation enhances phenotypic plasticity and phenotypic variance and thus can modulate the effect of natural selection on sequence-based genetic variation. third, given that phenotypic plasticity is central to the adaptability of organisms, epigenetic mechanisms that generate plasticity and acclimation are important to consider in evolutionary theory. fourth, some genes are under selection to be ‘imprinted’ identifying the sex of the parent from which they were derived, leading to parent-of-origin-dependent gene expression and effects. these effects can generate hybrid disfunction and contribute to speciation. finally, epigenetic processes, particularly dna methylation, contribute directly to dna sequence evolution, because they act as mutagens on the one hand and modulate genome stability on the other by keeping transposable elements in check. this article is part of the theme issue ‘how does epigenetics influence the course of evolution?’”
Ashapkin, V. V., Kutueva, L. I., & Vanyushin, B. F.. (2017). Aging as an Epigenetic Phenomenon. Current Genomics
Plain numerical DOI: 10.2174/1389202918666170412112130
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“© 2017 bentham science publishers. introduction: hypermethylation of genes associated with promoter cpg islands, and hypomethylation of cpg poor genes, repeat sequences, transposable elements and intergenic genome sections occur during aging in mammals. methylation levels of certain cpg sites display strict correlation to age and could be used as ‘epigenetic clock’ to predict biological age. multi-substrate deacetylases sirt1 and sirt6 affect aging via locus-specific modulations of chromatin structure and activity of multiple regulatory proteins involved in aging. random errors in dna methylation and other epigenetic marks during aging increase the transcriptional noise, and thus lead to enhanced phenotypic variation between cells of the same tissue. such variation could cause progressive organ dysfunction observed in aged individuals. multiple experimental data show that induction of nf-κb regulated gene sets occurs in various tissues of aged mammals. upregulation of multiple mirnas occurs at mid age leading to downregulation of enzymes and regulatory proteins involved in basic cellular functions, such as dna repair, oxidative phosphorylation, intermediate metabolism, and others. conclusion: strong evidence shows that all epigenetic systems contribute to the lifespan control in various organisms. similar to other cell systems, epigenome is prone to gradual degradation due to the genome damage, stressful agents, and other aging factors. but unlike mutations and other kinds of the genome damage, age-related epigenetic changes could be fully or partially reversed to a ‘young’ state.”
Singh, R., Chandel, S., Dey, D., Ghosh, A., Roy, S., Ravichandiran, V., & Ghosh, D.. (2020). Epigenetic modification and therapeutic targets of diabetes mellitus. Bioscience Reports
Plain numerical DOI: 10.1042/BSR20202160
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“The prevalence of diabetes and its related complications are increasing significantly globally. collected evidence suggested that several genetic and environmental factors contribute to diabetes mellitus. associated complications such as retinopathy, neuropathy, nephropathy and other cardiovascular complications are a direct result of diabetes. epigenetic factors include deoxyribonucleic acid (dna) methylation and histone post-translational modifications. these factors are directly related with pathological factors such as oxidative stress, generation of inflammatory mediators and hyperglycemia. these result in altered gene expression and targets cells in the pathology of diabetes mellitus without specific changes in a dna sequence. environmental factors and malnutrition are equally responsible for epigenetic states. accumulated evidence suggested that environmental stimuli alter the gene expression that result in epigenetic changes in chromatin. recent studies proposed that epigenetics may include the occurrence of ‘metabolic memory’ found in animal studies. further study into epigenetic mechanism might give us new vision into the pathogenesis of diabetes mellitus and related complication thus leading to the discovery of new therapeutic targets. in this review, we discuss the possible epigenetic changes and mechanism that happen in diabetes mellitus type 1 and type 2 separately. we highlight the important epigenetic and non-epigenetic therapeutic targets involved in the management of diabetes and associated complications.”
Andersen, E., Altlntaş, A., Andersson-Hall, U., Holmäng, A., & Barrès, R.. (2019). Environmental factors influence the epigenetic signature of newborns from mothers with gestational diabetes. Epigenomics
Plain numerical DOI: 10.2217/epi-2019-0055
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“Aim: to investigate the degree by which epigenetic signatures in children from mothers with gestational diabetes mellitus (gdm) are influenced by environmental factors. methods: we profiled the dna methylation signature of blood from lean, obese and gdm mothers and their respective newborns. results: dna methylation profiles of mothers showed high similarity across groups, while newborns from gdm mothers showed a marked distinct epigenetic profile compared with newborns of both lean and obese mothers. analysis of variance in dna methylation levels between newborns showed higher variance in the gdm group. conclusion: our results suggest that environmental factors, rather than direct transmission of epigenetic marks from the mother, are involved in establishing the epigenetic signature associated with gdm.”
Trejo Banos, D., McCartney, D. L., Patxot, M., Anchieri, L., Battram, T., Christiansen, C., … Robinson, M. R.. (2020). Bayesian reassessment of the epigenetic architecture of complex traits. Nature Communications
Plain numerical DOI: 10.1038/s41467-020-16520-1
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“Linking epigenetic marks to clinical outcomes improves insight into molecular processes, disease prediction, and therapeutic target identification. here, a statistical approach is presented to infer the epigenetic architecture of complex disease, determine the variation captured by epigenetic effects, and estimate phenotype-epigenetic probe associations jointly. implicitly adjusting for probe correlations, data structure (cell-count or relatedness), and single-nucleotide polymorphism (snp) marker effects, improves association estimates and in 9,448 individuals, 75.7% (95% ci 71.70–79.3) of body mass index (bmi) variation and 45.6% (95% ci 37.3–51.9) of cigarette consumption variation was captured by whole blood methylation array data. pathway-linked probes of blood cholesterol, lipid transport and sterol metabolism for bmi, and xenobiotic stimuli response for smoking, showed >1.5 times larger associations with >95% posterior inclusion probability. prediction accuracy improved by 28.7% for bmi and 10.2% for smoking over a lasso model, with age-, and tissue-specificity, implying associations are a phenotypic consequence rather than causal.”
Kim, M., & Costello, J.. (2017). DNA methylation: An epigenetic mark of cellular memory. Experimental and Molecular Medicine
Plain numerical DOI: 10.1038/emm.2017.10
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“DNA methylation is a stable epigenetic mark that can be inherited through multiple cell divisions. during development and cell differentiation, dna methylation is dynamic, but some dna methylation patterns may be retained as a form of epigenetic memory. dna methylation profiles can be useful for the lineage classification and quality control of stem cells such as embryonic stem cells, induced pluripotent cells and mesenchymal stem cells. during cancer initiation and progression, genomewide and gene-specific dna methylation changes occur as a consequence of mutated or deregulated chromatin regulators. early aberrant dna methylation states occurring during transformation appear to be retained during tumor evolution. similarly, dna methylation differences among different regions of a tumor reflect the history of cancer cells and their response to the tumor microenvironment. therefore, dna methylation can be a useful molecular marker for cancer diagnosis and drug treatment.”
Di Domenico, A., Wiedmer, T., Marinoni, I., & Perren, A.. (2017). Genetic and epigenetic drivers of neuroendocrine tumours (NET). Endocrine-Related Cancer
Plain numerical DOI: 10.1530/ERC-17-0012
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“Neuroendocrine tumours (net) of the gastrointestinal tract and the lung are a rare and heterogeneous group of tumours. the molecular characterization and the clinical classification of these tumours have been evolving slowly and show differences according to organs of origin. novel technologies such as next-generation sequencing revealed new molecular aspects of net over the last years. notably, whole-exome/genome sequencing (wes/wgs) approaches underlined the very low mutation rate of well-differentiated net of all organs compared to other malignancies, while the engagement of epigenetic changes in driving net evolution is emerging. indeed, mutations in genes encoding for proteins directly involved in chromatin remodelling, such as daxx and atrx are a frequent event in net. epigenetic changes are reversible and targetable; therefore, an attractive target for treatment. the discovery of the mechanisms underlying the epigenetic changes and the implication on gene and mirna expression in the different subgroups of net may represent a crucial change in the diagnosis of this disease, reveal new therapy targets and identify predictive markers. molecular profiles derived from omics data including dna mutation, methylation, gene and mirna expression have already shown promising results in distinguishing clinically and molecularly different subtypes of net. in this review, we recapitulate the major genetic and epigenetic characteristics of pancreatic, lung and small intestinal net and the affected pathways. we also discuss potential epigenetic mechanisms leading to net development.”
Akbari, M., & Hassan-Zadeh, V.. (2020). The inflammatory effect of epigenetic factors and modifications in type 2 diabetes. Inflammopharmacology
Plain numerical DOI: 10.1007/s10787-019-00663-9
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“Inflammation has a central role in the etiology of type 2 diabetes (t2d) and its complications. both genetic and epigenetic factors have been implicated in the development of t2d-associated inflammation. epigenetic mechanisms regulate the function of several components of the immune system. diabetic conditions trigger aberrant epigenetic alterations that contribute to the progression of insulin resistance and β-cell dysfunction by induction of inflammatory responses. thus, targeting epigenetic factors and modifications, as one of the underlying causes of inflammation, could lead to the development of novel immune-based strategies for the treatment of t2d. the aim of this review is to provide an overview of the epigenetic mechanisms involved in the propagation and perpetuation of chronic inflammation in t2d. we also discuss the possible anti-inflammatory approaches that target epigenetic factors for the treatment of t2d.”
Slatkin, M.. (2009). Epigenetic inheritance and the missing heritability problem. Genetics
Plain numerical DOI: 10.1534/genetics.109.102798
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“Epigenetic phenomena, and in particular heritable epigenetic changes, or transgenerational effects, are the subject of much discussion in the current literature. this article presents a model of transgenerational epigenetic inheritance and explores the effect of epigenetic inheritance on the risk and recurrence risk of a complex disease. the model assumes that epigenetic modifications of the genome are gained and lost at specified rates and that each modification contributes multiplicatively to disease risk. the potentially high rate of loss of epigenetic modifications causes the probability of identity in state in close relatives to be smaller than is implied by their relatedness. as a consequence, the recurrence risk to close relatives is reduced. although epigenetic modifications may contribute substantially to average risk, they will not contribute much to recurrence risk and heritability unless they persist on average for many generations. if they do persist for long times, they are equivalent to mutations and hence are likely to be in linkage disequilibrium with snps surveyed in genomewide association studies. thus epigenetic modifications are a potential solution to the problem of missing causality of complex diseases but not to the problem of missing heritability. the model highlights the need for empirical estimates of the persistence times of heritable epialleles. copyright © 2009 by the genetics society of america.”
Blacker, C. J., Frye, M. A., Morava, E., Kozicz, T., & Veldic, M.. (2019). A review of epigenetics of PTSD in comorbid psychiatric conditions. Genes
Plain numerical DOI: 10.3390/genes10020140
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“Post-traumatic stress disorder (ptsd) is an acquired psychiatric disorder with functionally impairing physiological and psychological symptoms following a traumatic exposure. genetic, epigenetic, and environmental factors act together to determine both an individual’s susceptibility to ptsd and its clinical phenotype. in this literature review, we briefly review the candidate genes that have been implicated in the development and severity of the ptsd phenotype. we discuss the importance of the epigenetic regulation of these candidate genes. we review the general epigenetic mechanisms that are currently understood, with examples of each in the ptsd phenotype. our focus then turns to studies that have examined ptsd in the context of comorbid psychiatric disorders or associated social and behavioral stressors. we examine the epigenetic variation in cases or models of ptsd with comorbid depressive disorders, anxiety disorders, psychotic disorders, and substance use disorders. we reviewed the literature that has explored epigenetic regulation in ptsd in adverse childhood experiences and suicide phenotypes. finally, we review some of the information available from studies of the transgenerational transmission of epigenetic variation in maternal cases of ptsd. we discuss areas pertinent for future study to further elucidate the complex interactions between epigenetic modifications and this complex psychiatric disorder.”
Glastad, K. M., Graham, R. J., Ju, L., Roessler, J., Brady, C. M., & Berger, S. L.. (2020). Epigenetic Regulator CoREST Controls Social Behavior in Ants. Molecular Cell
Plain numerical DOI: 10.1016/j.molcel.2019.10.012
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“Glastad et al. find that epigenetic regulation is pivotal in mediating programming and reprogramming of worker ant behavior. the conserved neuronal co-repressor corest, working with histone deacetylation, is vital in establishing foraging behavior via binding to and repressing genes that degrade jh, a behaviorally mportant hormone promoting foraging.”
Eckersley-Maslin, M. A.. (2020). Keeping your options open: insights from Dppa2/4 into how epigenetic priming factors promote cell plasticity. Biochemical Society Transactions
Plain numerical DOI: 10.1042/BST20200873
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“The concept of cellular plasticity is particularly apt in early embryonic development, where there is a tug-of-war between the stability and flexibility of cell identity. this balance is controlled in part through epigenetic mechanisms. epigenetic plasticity dictates how malleable cells are to change by adjusting the potential to initiate new transcriptional programmes. the higher the plasticity of a cell, the more readily it can adapt and change its identity in response to external stimuli such as differentiation cues. epigenetic plasticity is regulated in part through the action of epigenetic priming factors which establish this permissive epigenetic landscape at genomic regulatory elements to enable future transcriptional changes. recent studies on the dna binding proteins developmental pluripotency associated 2 and 4 (dppa2/4) support their roles as epigenetic priming factors in facilitating cell fate transitions. here, using dppa2/4 as a case study, the concept of epigenetic plasticity and molecular mechanism of epigenetic priming factors will be explored. understanding how epigenetic priming factors function is key not only to improve our understanding of the tight control of development, but also to give insights into how this goes awry in diseases of cell identity, such as cancer.”
Akerberg, B. N., & Pu, W. T.. (2020). Genetic and epigenetic control of heart development. Cold Spring Harbor Perspectives in Biology
Plain numerical DOI: 10.1101/cshperspect.a036756
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“A transcriptional program implemented by transcription factors and epigenetic regulators governs cardiac development and disease. mutations in these factors are important causes of congenital heart disease. here, we review selected recent advances in our understanding of the transcriptional and epigenetic control of heart development, including determinants of cardiac transcription factor chromatin occupancy, the gene regulatory network that regulates atrial septation, the chromatin landscape and cardiac gene regulation, and the role of brg/ brahma-associated factor (baf), nucleosome remodeling and histone deacetylation (nurd), and polycomb epigenetic regulatory complexes in heart development.”
Loison, L.. (2021). Epigenetic inheritance and evolution: A historian’s perspective. Philosophical Transactions of the Royal Society B: Biological Sciences
Plain numerical DOI: 10.1098/rstb.2020.0120
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“The aim of this article is to put the growing interest in epigenetics in the field of evolutionary theory into a historical context. first, i assess the view that epigenetic inheritance could be seen as vindicating a revival of (neo)lamarckism. drawing on jablonka’s and lamb’s considerable output, i identify several differences between modern epigenetics and what lamarckism was in the history of science. even if lamarckism is not back, epigenetic inheritance might be appealing for evolutionary biologists because it could potentiate two neglected mechanisms: the baldwin effect and genetic assimilation. second, i go back to the first ideas about the baldwin effect developed in the late nineteenth century to show that the efficiency of this mechanism was already linked with a form of non-genetic inheritance. the opposition to all forms of non-genetic inheritance that prevailed at the time of the rise of the modern synthesis helps to explain why the baldwin effect was understood as an insignificant mechanism during the second half of the twentieth century. based on this historical reconstruction, in §4, i examine what modern epigenetics can bring to the picture and under what conditions epigenetic inheritance might be seen as strengthening the causal relationship between adaptability and adaptation. throughout i support the view that the baldwin effect and genetic assimilation, even if they are quite close, should not be conflated, and that drawing a line between these concepts is helpful in order to better understand where epigenetic inheritance might endorse a new causal role. this article is part of the theme issue ‘how does epigenetics influence the course of evolution?’”
Park, J. H., Kim, S. H., Lee, M. S., & Kim, M. S.. (2017). Epigenetic modification by dietary factors: Implications in metabolic syndrome. Molecular Aspects of Medicine
Plain numerical DOI: 10.1016/j.mam.2017.01.008
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“Dietary factors play a role in normal biological processes and are involved in the regulation of pathological progression over a lifetime. evidence has emerged indicating that dietary factor-dependent epigenetic modifications can significantly affect genome stability and the expression of mrna and proteins, which are involved in metabolic dysfunction. since metabolic syndrome is a progressive phenotype characterized by insulin resistance, obesity, hypertension, dyslipidemia, or type 2 diabetes, gene-diet interactions are important processes involved in the initiation of particular symptoms of metabolic syndrome and their progression. some epigenetic risk markers can be initiated or reversed by diet and environmental factors. in this review, we discuss recent advances in our understanding of the interactions between dietary factors and epigenetic changes in metabolic syndrome. we discuss the contribution of nutritional factors in transgenerational inheritance of epigenetic markers and summarize the current knowledge of epigenetic modifications by dietary bioactive components in metabolic diseases. the intake of dietary components that regulate epigenetic modifications can provide significant health effects and, as an epigenetic diet, may prevent various pathological processes in the development of metabolic disease.”
Cutter DiPiazza, A. R., Taneja, N., Dhakshnamoorthy, J., Wheeler, D., Holla, S., & Grewal, S. I. S.. (2021). Spreading and epigenetic inheritance of heterochromatin require a critical density of histone H3 lysine 9 tri-methylation. Proceedings of the National Academy of Sciences of the United States of America
Plain numerical DOI: 10.1073/pnas.2100699118
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“Heterochromatin assembly requires methylation of histone h3 lysine 9 (h3k9me) and serves as a paradigm for understanding the importance of histone modifications in epigenetic genome control. heterochromatin is nucleated at specific genomic sites and spreads across extended chromosomal domains to promote gene silencing. moreover, heterochromatic structures can be epigenetically inherited in a self-templating manner, which is critical for stable gene repression. the spreading and inheritance of heterochromatin are believed to be dependent on preexisting h3k9 tri-methylation (h3k9me3), which is recognized by the histone methyltransferase clr4/suv39h via its chromodomain, to promote further deposition of h3k9me. however, the process involving the coupling of the ‘read’ and ‘write’ capabilities of histone methyltransferases is poorly understood. from an unbiased genetic screen, we characterize a dominant-negative mutation in histone h3 (h3g13d) that impairs the propagation of endogenous and ectopic heterochromatin domains in the fission yeast genome. h3g13dblocks methylation of h3k9 by the clr4/suv39h methyltransferase and acts in a dosage-dependentmanner to interfere with the spreading and maintenance of heterochromatin. our analyses show that the incorporation of unmethylatable histone h3g13dinto chromatin decreases h3k9me3 density and thereby compromises the read-write capability of clr4/suv39h. consistently, enhancing the affinity of clr4/suv39h for methylated h3k9 is sufficient to overcome the defects in heterochromatin assembly caused by h3g13d. ourwork directly implicates methylated histones in the transmission of epigenetic memory and shows that a critical density threshold of h3k9me3 is required to promote epigenetic inheritance of heterochromatin through the read-write mechanism.”
Schlesinger, S., & Meshorer, E.. (2019). Open Chromatin, Epigenetic Plasticity, and Nuclear Organization in Pluripotency. Developmental Cell
Plain numerical DOI: 10.1016/j.devcel.2019.01.003
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“Pluripotent embryonic stem cells are considered to have open and accessible chromatin relative to differentiated cells. schlesinger and meshorer review chromatin and epigenetic features in 2i- versus serum-grown conditions to come to a clearer picture of the genuine characteristics of pluripotency as opposed to artifacts of culture condition.”
Heinbockel, T., & Csoka, A. B.. (2018). Epigenetic effects of drugs of abuse. International Journal of Environmental Research and Public Health
Plain numerical DOI: 10.3390/ijerph15102098
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“Drug addiction affects a large extent of young people and disadvantaged populations. drugs of abuse impede brain circuits or affect the functionality of brain circuits and interfere with bodily functions. cannabinoids (∆9-tetrahydrocannabinol) form key constituents of marijuana derived from the cannabis plant. marijuana is a frequently used illegal drug in the usa. here, we review the effects of cannabinoids at the epigenetic level and the potential role of these epigenetic effects in health and disease. epigenetics is the study of alterations in gene expression that are transmitted across generations and take place without an alteration in dna sequence, but are due to modulation of chromatin associated factors by environmental effects. epigenetics is now known to offer an extra mechanism of control over transcription and how genes are expressed. insights from research at the genetic and epigenetic level potentially provide venues that allow the translation of the biology of abused drugs to new means of how to treat marijuana substance use disorder or other addictions using pharmacotherapeutic tools.”
Kim, S., & Kaang, B. K.. (2017). Epigenetic regulation and chromatin remodeling in learning and memory. Experimental and Molecular Medicine
Plain numerical DOI: 10.1038/emm.2016.140
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“Understanding the underlying mechanisms of memory formation and maintenance has been a major goal in the field of neuroscience. memory formation and maintenance are tightly controlled complex processes. among the various processes occurring at different levels, gene expression regulation is especially crucial for proper memory processing, as some genes need to be activated while some genes must be suppressed. epigenetic regulation of the genome involves processes such as dna methylation and histone post-translational modifications. these processes edit genomic properties or the interactions between the genome and histone cores. they then induce structural changes in the chromatin and lead to transcriptional changes of different genes. recent studies have focused on the concept of chromatin remodeling, which consists of 3d structural changes in chromatin in relation to gene regulation, and is an important process in learning and memory. in this review, we will introduce three major epigenetic processes involved in memory regulation: dna methylation, histone methylation and histone acetylation. we will also discuss general mechanisms of long-term memory storage and relate the epigenetic control of learning and memory to chromatin remodeling. finally, we will discuss how epigenetic mechanisms can contribute to the pathologies of neurological disorders and cause memory-related symptoms.”
Olova, N., Simpson, D. J., Marioni, R. E., & Chandra, T.. (2019). Partial reprogramming induces a steady decline in epigenetic age before loss of somatic identity. Aging Cell
Plain numerical DOI: 10.1111/acel.12877
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“Induced pluripotent stem cells (ipscs), with their unlimited regenerative capacity, carry the promise for tissue replacement to counter age-related decline. however, attempts to realize in vivo ipsc have invariably resulted in the formation of teratomas. partial reprogramming in prematurely aged mice has shown promising results in alleviating age-related symptoms without teratoma formation. does partial reprogramming lead to rejuvenation (i.e., ‘younger’ cells), rather than dedifferentiation, which bears the risk of cancer? here, we analyse the dynamics of cellular age during human ipsc reprogramming and find that partial reprogramming leads to a reduction in the epigenetic age of cells. we also find that the loss of somatic gene expression and epigenetic age follows different kinetics, suggesting that they can be uncoupled and there could be a safe window where rejuvenation can be achieved with a minimized risk of cancer.”
Youngson, N. A., & Morris, M. J.. (2013). What obesity research tells us about epigenetic mechanisms. Philosophical Transactions of the Royal Society B: Biological Sciences
Plain numerical DOI: 10.1098/rstb.2011.0337
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“The pathophysiology of obesity is extremely complex and is associated with extensive gene expression changes in tissues throughout the body. this situation, combined with the fact that all gene expression changes are thought to have associated epigenetic changes, means that the links between obesity and epigenetics will undoubtedly be vast. much progress in identifying epigenetic changes induced by (or inducing) obesity has already been made, with candidate and genome-wide approaches. these discoveries will aid the clinician through increasing our understanding of the inheritance, development and treatment of obesity. however, they are also of great value for epigenetic researchers, as they have revealed mechanisms of environmental interactions with epigenetics that can produce or perpetuate a disease state. here, we will review the evidence for four mechanisms through which epigenetics contributes to obesity: as downstream effectors of environmental signals; through abnormal global epigenetic state driving obesogenic expression patterns; through facilitating developmental programming and through transgenerational epigenetic inheritance. © 2012 the author(s) published by the royal society. all rights reserved.”
Burggren, W.. (2016). Epigenetic inheritance and its role in evolutionary biology: Re-evaluation and new perspectives. Biology
Plain numerical DOI: 10.3390/biology5020024
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“Epigenetics increasingly occupies a pivotal position in our understanding of inheritance, natural selection and, perhaps, even evolution. a survey of the pubmed database, however, reveals that the great majority (>93%) of epigenetic papers have an intra-, rather than an inter-generational focus, primarily on mechanisms and disease. approximately ~1% of epigenetic papers even mention the nexus of epigenetics, natural selection and evolution. yet, when environments are dynamic (e.g., climate change effects), there may be an ‘epigenetic advantage’ to phenotypic switching by epigenetic inheritance, rather than by gene mutation. an epigenetically-inherited trait can arise simultaneously in many individuals, as opposed to a single individual with a gene mutation. moreover, a transient epigenetically-modified phenotype can be quickly ‘sunsetted’, with individuals reverting to the original phenotype. thus, epigenetic phenotype switching is dynamic and temporary and can help bridge periods of environmental stress. epigenetic inheritance likely contributes to evolution both directly and indirectly. while there is as yet incomplete evidence of direct permanent incorporation of a complex epigenetic phenotype into the genome, doubtlessly, the presence of epigenetic markers and the phenotypes they create (which may sort quite separately from the genotype within a population) will influence natural selection and, so, drive the collective genotype of a population.”
Gapp, K., & Bohacek, J.. (2018). Epigenetic germline inheritance in mammals: looking to the past to understand the future. Genes, Brain and Behavior
Plain numerical DOI: 10.1111/gbb.12407
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“Life experiences can induce epigenetic changes in mammalian germ cells, which can influence the developmental trajectory of the offspring and impact health and disease across generations. while this concept of epigenetic germline inheritance has long been met with skepticism, evidence in support of this route of information transfer is now overwhelming, and some key mechanisms underlying germline transmission of acquired information are emerging. this review focuses specifically on sperm rnas as causal vectors of inheritance. we examine how they might become altered in the germline, and how different classes of sperm rnas might interact with other epimodifications in germ cells or in the zygote. we integrate the latest findings with earlier pioneering work in this field, point out major questions and challenges, and suggest how new experiments could address them.”
Yang, H. J., Koh, E., Sung, M. K., & Kang, H.. (2021). Changes induced by mind–body intervention including epigenetic marks and its effects on diabetes. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms22031317
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“Studies have evidenced that epigenetic marks associated with type 2 diabetes (t2d) can be inherited from parents or acquired through fetal and early-life events, as well as through lifelong environments or lifestyles, which can increase the risk of diabetes in adulthood. however, epigenetic modifications are reversible, and can be altered through proper intervention, thus mitigating the risk factors of t2d. mind–body intervention (mbi) refers to interventions like meditation, yoga, and qigong, which deal with both physical and mental well-being. mbi not only induces psychological changes, such as alleviation of depression, anxiety, and stress, but also physiological changes like parasympathetic activation, lower cortisol secretion, reduced inflammation, and aging rate de-lay, which are all risk factors for t2d. notably, mbi has been reported to reduce blood glucose in patients with t2d. herein, based on recent findings, we review the effects of mbi on diabetes and the mechanisms involved, including epigenetic modifications.”
Peng, Q., Weng, K., Li, S., Xu, R., Wang, Y., & Wu, Y.. (2021). A Perspective of Epigenetic Regulation in Radiotherapy. Frontiers in Cell and Developmental Biology
Plain numerical DOI: 10.3389/fcell.2021.624312
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“Radiation therapy (rt) has been employed as a tumoricidal modality for more than 100 years and on 470,000 patients each year in the united states. the ionizing radiation causes genetic changes and results in cell death. however, since the biological mechanism of radiation remains unclear, there is a pressing need to understand this mechanism to improve the killing effect on tumors and reduce the side effects on normal cells. dna break and epigenetic remodeling can be induced by radiotherapy. hence the modulation of histone modification enzymes may tune the radiosensitivity of cancer cells. for instance, histone deacetylase (hdac) inhibitors sensitize irradiated cancer cells by amplifying the dna damage signaling and inhibiting double-strand dna break repair to influence the irradiated cells’ survival. however, the combination of epigenetic drugs and radiotherapy has only been evaluated in several ongoing clinical trials for limited cancer types, partly due to a lack of knowledge on the potential mechanisms on how radiation induces epigenetic regulation and chromatin remodeling. here, we review recent advances of radiotherapy and radiotherapy-induced epigenetic remodeling and introduce related technologies for epigenetic monitoring. particularly, we exploit the application of fluorescence resonance energy transfer (fret) biosensors to visualize dynamic epigenetic regulations in single living cells and tissue upon radiotherapy and drug treatment. we aim to bridge fret biosensor, epigenetics, and radiotherapy, providing a perspective of using fret to assess epigenetics and provide guidance for radiotherapy to improve cancer treatment. in the end, we discuss the feasibility of a combination of epigenetic drugs and radiotherapy as new approaches for cancer therapeutics.”
Hoffman, G. E., Hoffman, G. E., Hoffman, G. E., Bendl, J., Bendl, J., Bendl, J., … Roussos, P.. (2020). Decorate: Differential epigenetic correlation test. Bioinformatics
Plain numerical DOI: 10.1093/bioinformatics/btaa067
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“Motivation: identifying correlated epigenetic features and finding differences in correlation between individuals with disease compared to controls can give novel insight into disease biology. this framework has been successful in analysis of gene expression data, but application to epigenetic data has been limited by the computational cost, lack of scalable software and lack of robust statistical tests. results: decorate, differential epigenetic correlation test, identifies correlated epigenetic features and finds clusters of features that are differentially correlated between two or more subsets of the data. the software scales to genome-wide datasets of epigenetic assays on hundreds of individuals. we apply decorate to four large-scale datasets of dna methylation, atac-seq and histone modification chip-seq.”
Cariati, F., Carbone, L., Conforti, A., Bagnulo, F., Peluso, S. R., Carotenuto, C., … Strina, I.. (2020). Bisphenol A-Induced Epigenetic Changes and Its Effects on the Male Reproductive System. Frontiers in Endocrinology
Plain numerical DOI: 10.3389/fendo.2020.00453
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“Bisphenol a (bpa) is a widespread chemical agent which can exert detrimental effects on the male reproductive system. exposure to bpa has been shown to induce several epigenetic modifications in both animal and human cells. specifically, bpa could not only modify the methylation pattern of multiple genes encoding proteins related to reproductive physiology but also directly influence the genes responsible for dna methylation. bpa effects include hormonal alterations, microscopic and macroscopic alteration of male reproductive organs, and inheritable epigenetic changes involving human reproduction. bpa exposure was also linked to prostate cancer. this review aims to show the current scenario of bpa-induced epigenetic changes and its effects on the male reproductive system. possible strategies to counter the toxic effect of bpa were also addressed.”
Brazel, A. J., & Vernimmen, D.. (2016). The complexity of epigenetic diseases. Journal of Pathology
Plain numerical DOI: 10.1002/path.4647
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“Over the past 30 years, a plethora of pathogenic mutations affecting enhancer regions and epigenetic regulators have been identified. coupled with more recent genome-wide association studies (gwas) and epigenome-wide association studies (ewas) implicating major roles for regulatory mutations in disease, it is clear that epigenetic mechanisms represent important biomarkers for disease development and perhaps even therapeutic targets. here, we discuss the diversity of disease-causing mutations in enhancers and epigenetic regulators, with a particular focus on cancer.”
Sharma, U.. (2019). Paternal contributions to offspring health: Role of sperm small rnas in intergenerational transmission of epigenetic information. Frontiers in Cell and Developmental Biology
Plain numerical DOI: 10.3389/fcell.2019.00215
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“The most fundamental process for the perpetuation of a species is the transfer of information from parent to offspring. although genomic dna contributes to the majority of the inheritance, it is now clear that epigenetic information-information beyond the underlying dna sequence-is also passed on to future generations. however, the mechanism and extent of such inheritance are not well-understood. here, i review some of the concepts, evidence, and mechanisms of intergenerational epigenetic inheritance via sperm small rnas. recent studies provide evidence that mature sperm are highly abundant in small non-coding rnas. these rnas are modulated by paternal environmental conditions and potentially delivered to the zygote at fertilization, where they can regulate early embryonic development. intriguingly, sperm small rna payload undergoes dramatic changes during testicular and post-testicular maturation, making the mature sperm epigenome highly unique and distinct from testicular germ cells. i explore the mechanism of sperm small rna remodeling during post-testicular maturation in the epididymis, and the potential role of this reprograming in intergenerational epigenetic inheritance.”
Arrowsmith, C. H., Bountra, C., Fish, P. V., Lee, K., & Schapira, M.. (2012). Epigenetic protein families: A new frontier for drug discovery. Nature Reviews Drug Discovery
Plain numerical DOI: 10.1038/nrd3674
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“Epigenetic regulation of gene expression is a dynamic and reversible process that establishes normal cellular phenotypes but also contributes to human diseases. at the molecular level, epigenetic regulation involves hierarchical covalent modification of dna and the proteins that package dna, such as histones. here, we review the key protein families that mediate epigenetic signalling through the acetylation and methylation of histones, including histone deacetylases, protein methyltransferases, lysine demethylases, bromodomain-containing proteins and proteins that bind to methylated histones. these protein families are emerging as druggable classes of enzymes and druggable classes of proteing-protein interaction domains. in this article, we discuss the known links with disease, basic molecular mechanisms of action and recent progress in the pharmacological modulation of each class of proteins. © 2012 macmillan publishers limited. all rights reserved.”
Chen, J., Clinton, M., Qi, G., Wang, D., Liu, F., & Qing Fu, Z.. (2020). Reprogramming and remodeling: Transcriptional and epigenetic regulation of salicylic acid-mediated plant defense. Journal of Experimental Botany
Plain numerical DOI: 10.1093/jxb/eraa072
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“As a plant hormone, salicylic acid (sa) plays essential roles in plant defense against biotrophic and hemibiotrophic pathogens. significant progress has been made in understanding the sa biosynthesis pathways and sa-mediated defense signaling networks in the past two decades. plant defense responses involve rapid and massive transcriptional reprogramming upon the recognition of pathogens. plant transcription factors and their co-regulators are critical players in establishing a transcription regulatory network and boosting plant immunity. a multitude of transcription factors and epigenetic regulators have been discovered, and their roles in sa-mediated defense responses have been reported. however, our understanding of plant transcriptional networks is still limited. as such, novel genomic tools and bioinformatic techniques will be necessary if we are to fully understand the mechanisms behind plant immunity. here, we discuss current knowledge, provide an update on the sa biosynthesis pathway, and describe the transcriptional and epigenetic regulation of sa-mediated plant immune responses.”
Yen, C. Y., Huang, H. W., Shu, C. W., Hou, M. F., Yuan, S. S. F., Wang, H. R., … Chang, H. W.. (2016). DNA methylation, histone acetylation and methylation of epigenetic modifications as a therapeutic approach for cancers. Cancer Letters
Plain numerical DOI: 10.1016/j.canlet.2016.01.036
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“Epigenetic modifications play important roles in regulating carcinogenesis, and specific epigenetic modifications have emerged as potential tumor markers. herein, we summarize several types of epigenetic modifications, explore the role played by epigenetic modifications in gene regulation, and describe the patterns of epigenetic modifications in cancers. since epigenetic modifications have been reported to regulate the warburg effect in cancers, the roles of epigenetic modifications in sugar metabolism are discussed. in addition, oxidative stress may play an important role in carcinogenesis, and the role of oxidative stress and epigenetic modification in carcinogenesis is addressed. we also discuss the role of epigenetic modifications as therapeutic targets. finally, the synergistic effects of the combined treatment of epigenetic regulator and anticancer drugs for cancer therapy are described.”
Blasiak, J., Chojnacki, J., Pawlowska, E., Szczepanska, J., & Chojnacki, C.. (2020). Nutrition in cancer therapy in the elderly—an epigenetic connection?. Nutrients
Plain numerical DOI: 10.3390/nu12113366
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“The continuous increase in life expectancy results in a steady increase of cancer risk, which consequently increases the population of older adults with cancer. older adults have their age-related nutritional needs and often suffer from comorbidities that may affect cancer therapy. they frequently are malnourished and present advanced-stage cancer. therefore, this group of patients requires a special multidisciplinary approach to optimize their therapy and increase quality of life impaired by aging, cancer, and the side effects of therapy. evaluation strategies, taking advantage of comprehensive geriatric assessment tools, including the comprehensive geriatric assessment (cga), can help individualize treatment. as epigenetics, an emerging element of the regulation of gene expression, is involved in both aging and cancer and the epigenetic profile can be modulated by the diet, it seems to be a candidate to assist with planning a nutritional intervention in elderly populations with cancer. in this review, we present problems associated with the diet and nutrition in the elderly undergoing active cancer therapy and provide some information on epigenetic aspects of aging and cancer transformation. nutritional interventions modulating the epigenetic profile, including caloric restriction and basal diet with modifications (elimination diet, supplementary diet) are discussed as the ways to improve the efficacy of cancer therapy and maintain the quality of life of older adults with cancer.”
Kim, S., & Kaang, B. K.. (2017). Epigenetic regulation and chromatin remodeling in learning and memory. Experimental and Molecular Medicine
Plain numerical DOI: 10.1038/emm.2016.140
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“Understanding the underlying mechanisms of memory formation and maintenance has been a major goal in the field of neuroscience. memory formation and maintenance are tightly controlled complex processes. among the various processes occurring at different levels, gene expression regulation is especially crucial for proper memory processing, as some genes need to be activated while some genes must be suppressed. epigenetic regulation of the genome involves processes such as dna methylation and histone post-translational modifications. these processes edit genomic properties or the interactions between the genome and histone cores. they then induce structural changes in the chromatin and lead to transcriptional changes of different genes. recent studies have focused on the concept of chromatin remodeling, which consists of 3d structural changes in chromatin in relation to gene regulation, and is an important process in learning and memory. in this review, we will introduce three major epigenetic processes involved in memory regulation: dna methylation, histone methylation and histone acetylation. we will also discuss general mechanisms of long-term memory storage and relate the epigenetic control of learning and memory to chromatin remodeling. finally, we will discuss how epigenetic mechanisms can contribute to the pathologies of neurological disorders and cause memory-related symptoms.”
Zubrzycka, A., Zubrzycki, M., Perdas, E., & Zubrzycka, M.. (2020). Genetic, Epigenetic, and Steroidogenic Modulation Mechanisms in Endometriosis. Journal of Clinical Medicine
Plain numerical DOI: 10.3390/jcm9051309
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“Endometriosis is a chronic gynecological disease, affecting up to 10% of reproductive-age women. the exact cause of the disease is unknown; however, it is a heritable condition affected by multiple genetic, epigenetic, and environmental factors. previous studies reported variations in the epigenetic patterns of numerous genes known to be involved in the aberrant modulation of cell cycle steroidogenesis, abnormal hormonal, immune and inflammatory status in endometriosis, apoptosis, adhesion, angiogenesis, proliferation, immune and inflammatory processes, response to hypoxia, steroidogenic pathway and hormone signaling are involved in the pathogenesis of endometriosis. accumulating evidence suggest that various epigenetic aberrations may contribute to the pathogenesis of endometriosis. among them, dna methyltransferases, histone deacetylators, and non-coding micrornas demonstrate differential expression within endometriotic lesions and in the endometrium of patients with endometriosis. it has been indicated that the identification of epigenetic differences within the dna or histone proteins may contribute to the discovery of a useful prognostic biomarker, which could aid in the future earlier detection, timely diagnosis, and initiation of a new approach to the treatment of endometriosis, as well as inform us about the effectiveness of treatment and the stage of the disease. as the etiology of endometriosis is highly complex and still far from being fully elucidated, the presented review focuses on different approaches to identify the genetic and epigenetic links of endometriosis and its pathogenesis.”
Li, T., Mao, C., Wang, X., Shi, Y., & Tao, Y.. (2020). Epigenetic crosstalk between hypoxia and tumor driven by HIF regulation. Journal of Experimental and Clinical Cancer Research
Plain numerical DOI: 10.1186/s13046-020-01733-5
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“Hypoxia is the major influence factor in physiological and pathological courses which are mainly mediated by hypoxia-inducible factors (hifs) in response to low oxygen tensions within solid tumors. under normoxia, hif signaling pathway is inhibited due to hif-α subunits degradation. however, in hypoxic conditions, hif-α is activated and stabilized, and hif target genes are successively activated, resulting in a series of tumour-specific activities. the activation of hifs, including hif-1α, hif-2α and hif-3α, subsequently induce downstream target genes which leads to series of responses, the resulting abnormal processes or metabolites in turn affect hifs stability. given its functions in tumors progression, hifs have been regarded as therapeutic targets for improved treatment efficacy. epigenetics refers to alterations in gene expression that are stable between cell divisions, and sometimes between generations, but do not involve changes in the underlying dna sequence of the organism. and with the development of research, epigenetic regulation has been found to play an important role in the development of tumors, which providing accumulating basic or clinical evidences for tumor treatments. here, given how little has been reported about the overall association between hypoxic tumors and epigenetics, we made a more systematic review from epigenetic perspective in hope of helping others better understand hypoxia or hif pathway, and providing more established and potential therapeutic strategies in tumors to facilitate epigenetic studies of tumors.”
Akbari, M., & Hassan-Zadeh, V.. (2020). The inflammatory effect of epigenetic factors and modifications in type 2 diabetes. Inflammopharmacology
Plain numerical DOI: 10.1007/s10787-019-00663-9
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“Inflammation has a central role in the etiology of type 2 diabetes (t2d) and its complications. both genetic and epigenetic factors have been implicated in the development of t2d-associated inflammation. epigenetic mechanisms regulate the function of several components of the immune system. diabetic conditions trigger aberrant epigenetic alterations that contribute to the progression of insulin resistance and β-cell dysfunction by induction of inflammatory responses. thus, targeting epigenetic factors and modifications, as one of the underlying causes of inflammation, could lead to the development of novel immune-based strategies for the treatment of t2d. the aim of this review is to provide an overview of the epigenetic mechanisms involved in the propagation and perpetuation of chronic inflammation in t2d. we also discuss the possible anti-inflammatory approaches that target epigenetic factors for the treatment of t2d.”
Hoffman, G. E., Hoffman, G. E., Hoffman, G. E., Bendl, J., Bendl, J., Bendl, J., … Roussos, P.. (2020). Decorate: Differential epigenetic correlation test. Bioinformatics
Plain numerical DOI: 10.1093/bioinformatics/btaa067
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“Motivation: identifying correlated epigenetic features and finding differences in correlation between individuals with disease compared to controls can give novel insight into disease biology. this framework has been successful in analysis of gene expression data, but application to epigenetic data has been limited by the computational cost, lack of scalable software and lack of robust statistical tests. results: decorate, differential epigenetic correlation test, identifies correlated epigenetic features and finds clusters of features that are differentially correlated between two or more subsets of the data. the software scales to genome-wide datasets of epigenetic assays on hundreds of individuals. we apply decorate to four large-scale datasets of dna methylation, atac-seq and histone modification chip-seq.”
Nestler, E. J., Peña, C. J., Kundakovic, M., Mitchell, A., & Akbarian, S.. (2016). Epigenetic Basis of Mental Illness. Neuroscientist
Plain numerical DOI: 10.1177/1073858415608147
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“Psychiatric disorders are complex multifactorial illnesses involving chronic alterations in neural circuit structure and function as well as likely abnormalities in glial cells. while genetic factors are important in the etiology of most mental disorders, the relatively high rates of discordance among identical twins, particularly for depression and other stress-related syndromes, clearly indicate the importance of additional mechanisms. environmental factors such as stress are known to play a role in the onset of these illnesses. exposure to such environmental insults induces stable changes in gene expression, neural circuit function, and ultimately behavior, and these maladaptations appear distinct between developmental versus adult exposures. increasing evidence indicates that these sustained abnormalities are maintained by epigenetic modifications in specific brain regions. indeed, transcriptional dysregulation and the aberrant epigenetic regulation that underlies this dysregulation is a unifying theme in psychiatric disorders. here, we provide a progress report of epigenetic studies of the three major psychiatric syndromes, depression, schizophrenia, and bipolar disorder. we review the literature derived from animal models of these disorders as well as from studies of postmortem brain tissue from human patients. while epigenetic studies of mental illness remain at early stages, understanding how environmental factors recruit the epigenetic machinery within specific brain regions to cause lasting changes in disease susceptibility and pathophysiology is revealing new insight into the etiology and treatment of these conditions.”
Jurkowski, T. P., Ravichandran, M., & Stepper, P.. (2015). Synthetic epigenetics—towards intelligent control of epigenetic states and cell identity. Clinical Epigenetics
Plain numerical DOI: 10.1186/s13148-015-0044-x
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“Epigenetics is currently one of the hottest topics in basic and biomedical research. however, to date, most of the studies have been descriptive in nature, designed to investigate static distribution of various epigenetic modifications in cells. even though tremendous amount of information has been collected, we are still far from the complete understanding of epigenetic processes, their dynamics or even their direct effects on local chromatin and we still do not comprehend whether these epigenetic states are the cause or the consequence of the transcriptional profile of the cell. in this review, we try to define the concept of synthetic epigenetics and outline the available genome targeting technologies, which are used for locus-specific editing of epigenetic signals. we report early success stories and the lessons we have learned from them, and provide a guide for their application. finally, we discuss existing limitations of the available technologies and indicate possible areas for further development.”
Lee, D. Y., & Chiu, J. J.. (2019). Atherosclerosis and flow: Roles of epigenetic modulation in vascular endothelium. Journal of Biomedical Science
Plain numerical DOI: 10.1186/s12929-019-0551-8
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“Background: endothelial cell (ec) dysfunctions, including turnover enrichment, gap junction disruption, inflammation, and oxidation, play vital roles in the initiation of vascular disorders and atherosclerosis. hemodynamic forces, i.e., atherprotective pulsatile (ps) and pro-atherogenic oscillatory shear stress (os), can activate mechanotransduction to modulate ec function and dysfunction. this review summarizes current studies aiming to elucidate the roles of epigenetic factors, i.e., histone deacetylases (hdacs), non-coding rnas, and dna methyltransferases (dnmts), in mechanotransduction to modulate hemodynamics-regulated ec function and dysfunction. main body of the abstract: os enhances the expression and nuclear accumulation of class i and class ii hdacs to induce ec dysfunction, i.e., proliferation, oxidation, and inflammation, whereas ps induces phosphorylation-dependent nuclear export of class ii hdacs to inhibit ec dysfunction. ps induces overexpression of the class iii hdac sirt1 to enhance nitric oxide (no) production and prevent ec dysfunction. in addition, hemodynamic forces modulate the expression and acetylation of transcription factors, i.e., retinoic acid receptor α and krüppel-like factor-2, to transcriptionally regulate the expression of micrornas (mirs). os-modulated mirs, which stimulate proliferative, pro-inflammatory, and oxidative signaling, promote ec dysfunction, whereas ps-regulated mirs, which induce anti-proliferative, anti-inflammatory, and anti-oxidative signaling, inhibit ec dysfunction. ps also modulates the expression of long non-coding rnas to influence ec function. i.e., turnover, aligmant, and migration. on the other hand, os enhances the expression of dnmt-1 and -3a to induce ec dysfunction, i.e., proliferation, inflammation, and no repression. conclusion: overall, epigenetic factors play vital roles in modulating hemodynamic-directed ec dysfunction and vascular disorders, i.e., atherosclerosis. understanding the detailed mechanisms through which epigenetic factors regulate hemodynamics-directed ec dysfunction and vascular disorders can help us to elucidate the pathogenic mechanisms of atherosclerosis and develop potential therapeutic strategies for atherosclerosis treatment.”
Yen, C. Y., Huang, H. W., Shu, C. W., Hou, M. F., Yuan, S. S. F., Wang, H. R., … Chang, H. W.. (2016). DNA methylation, histone acetylation and methylation of epigenetic modifications as a therapeutic approach for cancers. Cancer Letters
Plain numerical DOI: 10.1016/j.canlet.2016.01.036
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“Epigenetic modifications play important roles in regulating carcinogenesis, and specific epigenetic modifications have emerged as potential tumor markers. herein, we summarize several types of epigenetic modifications, explore the role played by epigenetic modifications in gene regulation, and describe the patterns of epigenetic modifications in cancers. since epigenetic modifications have been reported to regulate the warburg effect in cancers, the roles of epigenetic modifications in sugar metabolism are discussed. in addition, oxidative stress may play an important role in carcinogenesis, and the role of oxidative stress and epigenetic modification in carcinogenesis is addressed. we also discuss the role of epigenetic modifications as therapeutic targets. finally, the synergistic effects of the combined treatment of epigenetic regulator and anticancer drugs for cancer therapy are described.”
Heinbockel, T., & Csoka, A. B.. (2018). Epigenetic effects of drugs of abuse. International Journal of Environmental Research and Public Health
Plain numerical DOI: 10.3390/ijerph15102098
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“Drug addiction affects a large extent of young people and disadvantaged populations. drugs of abuse impede brain circuits or affect the functionality of brain circuits and interfere with bodily functions. cannabinoids (∆9-tetrahydrocannabinol) form key constituents of marijuana derived from the cannabis plant. marijuana is a frequently used illegal drug in the usa. here, we review the effects of cannabinoids at the epigenetic level and the potential role of these epigenetic effects in health and disease. epigenetics is the study of alterations in gene expression that are transmitted across generations and take place without an alteration in dna sequence, but are due to modulation of chromatin associated factors by environmental effects. epigenetics is now known to offer an extra mechanism of control over transcription and how genes are expressed. insights from research at the genetic and epigenetic level potentially provide venues that allow the translation of the biology of abused drugs to new means of how to treat marijuana substance use disorder or other addictions using pharmacotherapeutic tools.”
Zhao, W., Qi, X., Liu, L., Liu, Z., Ma, S., & Wu, J.. (2020). Epigenetic Regulation of m6A Modifications in Human Cancer. Molecular Therapy – Nucleic Acids
Plain numerical DOI: 10.1016/j.omtn.2019.11.022
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“N6-methyladenosine (m6a) is the most prevalent internal rna modification, especially within eukaryotic messenger rnas (mrnas). m6a modifications of rna regulate splicing, translocation, stability, and translation into proteins. m6a modifications are catalyzed by rna methyltransferases, such as mettl3, mettl14, and wtap (writers); the modifications are removed by the demethylases fat mass and obesity-associated protein (fto) and alkbh5 (alkb homolog 5) (erasers); and the modifications are recognized by m6a-binding proteins, such as ythdf domain-containing proteins and igf2bps (readers). abnormal changes in the m6a levels of these genes are closely related to tumor occurrence and development. in this paper, we review the role of m6a in human cancer and summarize its prospective applications in cancer.”
Mangum, K. D., & Farber, M. A.. (2020). Genetic and epigenetic regulation of abdominal aortic aneurysms. Clinical Genetics
Plain numerical DOI: 10.1111/cge.13705
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“Abdominal aortic aneurysms (aaas) are focal dilations of the aorta that develop from degenerative changes in the media and adventitia of the vessel. ruptured aaas have a mortality of up to 85%, thus it is important to identify patients with aaa at increased risk for rupture who would benefit from increased surveillance and/or surgical repair. although the exact genetic and epigenetic mechanisms regulating aaa formation are not completely understood, mendelian cases of aaa, which result from pathologic variants in a single gene, have helped provide a basic understanding of aaa pathophysiology. more recently, genome wide associated studies (gwas) have identified additional variants, termed single nucleotide polymorphisms, in humans that may be associated with aaas. while some variants may be associated with aaas and play causal roles in aneurysm pathogenesis, it should be emphasized that the majority of snps do not actually cause disease. in addition to gwas, other studies have uncovered epigenetic causes of disease that regulate expression of genes known to be important in aaa pathogenesis. this review describes many of these genetic and epigenetic contributors of aaas, which altogether provide a deeper insight into aaa pathogenesis.”
Coetzee, N., von Grüning, H., Opperman, D., van der Watt, M., Reader, J., & Birkholtz, L. M.. (2020). Epigenetic inhibitors target multiple stages of Plasmodium falciparum parasites. Scientific Reports
Plain numerical DOI: 10.1038/s41598-020-59298-4
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“The epigenome of the malaria parasite, plasmodium falciparum, is associated with regulation of various essential processes in the parasite including control of proliferation during asexual development as well as control of sexual differentiation. the unusual nature of the epigenome has prompted investigations into the potential to target epigenetic modulators with novel chemotypes. here, we explored the diversity within a library of 95 compounds, active against various epigenetic modifiers in cancerous cells, for activity against multiple stages of p. falciparum development. we show that p. falciparum is differentially susceptible to epigenetic perturbation during both asexual and sexual development, with early stage gametocytes particularly sensitive to epi-drugs targeting both histone and non-histone epigenetic modifiers. moreover, 5 compounds targeting histone acetylation and methylation show potent multistage activity against asexual parasites, early and late stage gametocytes, with transmission-blocking potential. overall, these results warrant further examination of the potential antimalarial properties of these hit compounds.”
Sarkar, S., Horn, G., Moulton, K., Oza, A., Byler, S., Kokolus, S., & Longacre, M.. (2013). Cancer development, progression, and therapy: An epigenetic overview. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms141021087
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“Carcinogenesis involves uncontrolled cell growth, which follows the activation of oncogenes and/or the deactivation of tumor suppression genes. metastasis requires down-regulation of cell adhesion receptors necessary for tissue-specific, cell-cell attachment, as well as up-regulation of receptors that enhance cell motility. epigenetic changes, including histone modifications, dna methylation, and dna hydroxymethylation, can modify these characteristics. targets for these epigenetic changes include signaling pathways that regulate apoptosis and autophagy, as well as microrna. we propose that predisposed normal cells convert to cancer progenitor cells that, after growing, undergo an epithelial-mesenchymal transition. this process, which is partially under epigenetic control, can create a metastatic form of both progenitor and full-fledged cancer cells, after which metastasis to a distant location may occur. identification of epigenetic regulatory mechanisms has provided potential therapeutic avenues. in particular, epigenetic drugs appear to potentiate the action of traditional therapeutics, often by demethylating and re-expressing tumor suppressor genes to inhibit tumorigenesis. epigenetic drugs may inhibit both the formation and growth of cancer progenitor cells, thus reducing the recurrence of cancer. adopting epigenetic alteration as a new hallmark of cancer is a logical and necessary step that will further encourage the development of novel epigenetic biomarkers and therapeutics. © 2013 by the authors; licensee mdpi, basel, switzerland.”
Yuan, J., Chang, S. Y., Yin, S. G., Liu, Z. Y., Cheng, X., Liu, X. J., … Cai, S. Q.. (2020). Two conserved epigenetic regulators prevent healthy ageing. Nature
Plain numerical DOI: 10.1038/s41586-020-2037-y
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“It has long been assumed that lifespan and healthspan correlate strongly, yet the two can be clearly dissociated1–6. although there has been a global increase in human life expectancy, increasing longevity is rarely accompanied by an extended healthspan4,7. thus, understanding the origin of healthy behaviours in old people remains an important and challenging task. here we report a conserved epigenetic mechanism underlying healthy ageing. through genome-wide rna-interference-based screening of genes that regulate behavioural deterioration in ageing caenorhabditis elegans, we identify 59 genes as potential modulators of the rate of age-related behavioural deterioration. among these modulators, we found that a neuronal epigenetic reader, baz-2, and a neuronal histone 3 lysine 9 methyltransferase, set-6, accelerate behavioural deterioration in c. elegans by reducing mitochondrial function, repressing the expression of nuclear-encoded mitochondrial proteins. this mechanism is conserved in cultured mouse neurons and human cells. examination of human databases8,9 shows that expression of the human orthologues of these c. elegans regulators, baz2b and ehmt1, in the frontal cortex increases with age and correlates positively with the progression of alzheimer’s disease. furthermore, ablation of baz2b, the mouse orthologue of baz-2, attenuates age-dependent body-weight gain and prevents cognitive decline in ageing mice. thus our genome-wide rna-interference screen in c. elegans has unravelled conserved epigenetic negative regulators of ageing, suggesting possible ways to achieve healthy ageing.”
Chen, Y. S., Lian, W. S., Kuo, C. W., Ke, H. J., Wang, S. Y., Kuo, P. C., … Wang, F. S.. (2020). Epigenetic regulation of skeletal tissue integrity and osteoporosis development. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms21144923
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“Bone turnover is sophisticatedly balanced by a dynamic coupling of bone formation and resorption at various rates. the orchestration of this continuous remodeling of the skeleton further affects other skeletal tissues through organ crosstalk. chronic excessive bone resorption compromises bone mass and its porous microstructure as well as proper biomechanics. this accelerates the development of osteoporotic disorders, a leading cause of skeletal degeneration-associated disability and premature death. bone-forming cells play important roles in maintaining bone deposit and osteoclastic resorption. a poor organelle machinery, such as mitochondrial dysfunction, endoplasmic reticulum stress, and defective autophagy, etc., dysregulates growth factor secretion, mineralization matrix production, or osteoclast-regulatory capacity in osteoblastic cells. a plethora of epigenetic pathways regulate bone formation, skeletal integrity, and the development of osteoporosis. micrornas inhibit protein translation by binding the 3′-untranslated region of mrnas or promote translation through post-transcriptional pathways. dna methylation and post-translational modification of histones alter the chromatin structure, hindering histone enrichment in promoter regions. microrna-processing enzymes and dna as well as histone modification enzymes catalyze these modifying reactions. gain and loss of these epigenetic modifiers in bone-forming cells affect their epigenetic landscapes, influencing bone homeostasis, microarchitectural integrity, and osteoporotic changes. this article conveys productive insights into biological roles of dna methylation, microrna, and histone modification and highlights their interactions during skeletal development and bone loss under physiological and pathological conditions.”
Hoare, J., Stein, D. J., Heany, S. J., Fouche, J. P., Phillips, N., Er, S., … Levine, A. J.. (2020). Accelerated epigenetic aging in adolescents from low-income households is associated with altered development of brain structures. Metabolic Brain Disease
Plain numerical DOI: 10.1007/s11011-020-00589-0
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“The relationship between cognitive performance, macro and microstructural brain anatomy and accelerated aging as measured by a highly accurate epigenetic biomarker of aging known as the epigenetic clock in healthy adolescents has not been studied. healthy adolescents enrolled in the cape town adolescent antiretroviral cohort study were studied cross sectionally. the illumina infinium methylation epic array was used to generate dna methylation data from the blood samples of 44 adolescents aged 9 to 12 years old. the epigenetic clock software and method was used to estimate two measures, epigenetic age acceleration residual (aar) and extrinsic epigenetic age acceleration (eeaa). each participant underwent neurocognitive testing, t1 structural magnetic resonance imaging (mri), and diffusion tensor imaging (dti). correlation tests were run between the two epigenetic aging measures and 10 cognitive functioning domains, to assess for differences in cognitive performance as epigenetic aging increases. in order to investigate the associations of epigenetic age acceleration on brain structure, we developed stepwise multiple regression models in r (version 3.4.3, 2017) including grey and white matter volumes, cortical thickness, and cortical surface area, as well as dti measures of white matter microstructural integrity. in addition to negatively affecting two cognitive domains, visual memory (p =.026) and visual spatial acuity (p =.02), epigenetic age acceleration was associated with alterations of brain volumes, cortical thickness, cortical surface areas and abnormalities in neuronal microstructure in a range of regions. stress was a significant predictor (p =.029) of aar. understanding the drivers of epigenetic age acceleration in adolescents could lead to valuable insights into the development of neurocognitive impairment in adolescents.”
Lin, Y. Te, & Wu, K. J.. (2020). Epigenetic regulation of epithelial-mesenchymal transition: Focusing on hypoxia and TGF-β signaling. Journal of Biomedical Science
Plain numerical DOI: 10.1186/s12929-020-00632-3
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“Epithelial-mesenchymal transition (emt) is an important process triggered during cancer metastasis. regulation of emt is mostly initiated by outside signalling, including tgf-β, growth factors, notch ligand, wnt, and hypoxia. many signalling pathways have been delineated to explain the molecular mechanisms of emt. in this review, we will focus on the epigenetic regulation of two critical emt signalling pathways: hypoxia and tgf-β. for hypoxia, hypoxia-induced emt is mediated by the interplay between chromatin modifiers histone deacetylase 3 (hdac3) and wdr5 coupled with the presence of histone 3 lysine 4 acetylation (h3k4ac) mark that labels the promoter regions of various traditional emt marker genes (e.g. cdh1, vim). recently identified new hypoxia-induced emt markers belong to transcription factors (e.g. smo, gli1) that mediate emt themselves. for tgf-β-induced, global chromatin changes, removal of a histone variant (h2a.z), and new chromatin modifiers (e.g. utx, rad21, prmt5, rbbp5, etc) are identified to be crucial for the regulation of both emt transcription factors (emt-tfs) and emt markers (emt-ms). the epigenetic mechanisms utilized in these two pathways may serve as good model systems for other signalling pathways and also provide new potential therapeutic targets.”
Fujimoto, R., Sasaki, T., Ishikawa, R., Osabe, K., Kawanabe, T., & Dennis, E. S.. (2012). Molecular mechanisms of epigenetic variation in plants. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms13089900
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“Natural variation is defined as the phenotypic variation caused by spontaneous mutations. in general, mutations are associated with changes of nucleotide sequence, and many mutations in genes that can cause changes in plant development have been identified. epigenetic change, which does not involve alteration to the nucleotide sequence, can also cause changes in gene activity by changing the structure of chromatin through dna methylation or histone modifications. now there is evidence based on induced or spontaneous mutants that epigenetic changes can cause altering plant phenotypes. epigenetic changes have occurred frequently in plants, and some are heritable or metastable causing variation in epigenetic status within or between species. therefore, heritable epigenetic variation as well as genetic variation has the potential to drive natural variation. © 2012 by the authors; licensee mdpi, basel, switzerland.”
Shin, J. E., & Cho, Y.. (2017). Epigenetic regulation of axon regeneration after neural injury. Molecules and Cells
Plain numerical DOI: 10.14348/molcells.2017.2311
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“When peripheral axons are damaged, neuronal injury signaling pathways induce transcriptional changes that support axon regeneration and consequent functional recovery. the recent development of bioinformatics techniques has allowed for the identification of many of the regeneration-associated genes that are regulated by neural injury, yet it remains unclear how global changes in transcriptome are coordinated. in this article, we review recent studies on the epigenetic mechanisms orchestrating changes in gene expression in response to nerve injury. we highlight the importance of epigenetic mechanisms in discriminating efficient axon regeneration in the peripheral nervous system and very limited axon regrowth in the central nervous system and discuss the therapeutic potential of targeting epigenetic regulators to improve neural recovery.”
Hoeksema, M. A., & De Winther, M. P. J.. (2016). Epigenetic Regulation of Monocyte and Macrophage Function. Antioxidants and Redox Signaling
Plain numerical DOI: 10.1089/ars.2016.6695
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“Significance: monocytes and macrophages are key players in tissue homeostasis and immune responses. epigenetic processes tightly regulate cellular functioning in health and disease. recent advances: recent technical developments have allowed detailed characterizations of the transcriptional circuitry underlying monocyte and macrophage regulation. upon differentiation and activation, enhancers are selected by lineage-determining and signal-dependent transcription factors. enhancers are shown to be very dynamic and activation of these enhancers underlies the differences in gene transcription between monocytes and macrophages and their subtypes. critical issues: it has been shown that epigenetic enzymes regulate the functioning of these cells and targeting of epigenetic enzymes has been proven to be a valuable tool to dampen inflammatory responses. we give a comprehensive overview of recent developments and understanding of the epigenetic pathways that control monocyte and macrophage function and of the epigenetic enzymes involved in monocyte and macrophage differentiation and activation. future directions: the key challenges in the upcoming years will be to study epigenetic changes in human disease and to better understand how epigenetic pathways control the inflammatory repertoire in disease.”
Gapp, K., & Bohacek, J.. (2018). Epigenetic germline inheritance in mammals: looking to the past to understand the future. Genes, Brain and Behavior
Plain numerical DOI: 10.1111/gbb.12407
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“Life experiences can induce epigenetic changes in mammalian germ cells, which can influence the developmental trajectory of the offspring and impact health and disease across generations. while this concept of epigenetic germline inheritance has long been met with skepticism, evidence in support of this route of information transfer is now overwhelming, and some key mechanisms underlying germline transmission of acquired information are emerging. this review focuses specifically on sperm rnas as causal vectors of inheritance. we examine how they might become altered in the germline, and how different classes of sperm rnas might interact with other epimodifications in germ cells or in the zygote. we integrate the latest findings with earlier pioneering work in this field, point out major questions and challenges, and suggest how new experiments could address them.”
Gowda, C., Song, C., Ding, Y., Iyer, S., Dhanyamraju, P. K., McGrath, M., … Dovat, S.. (2020). Cellular signaling and epigenetic regulation of gene expression in leukemia. Advances in Biological Regulation
Plain numerical DOI: 10.1016/j.jbior.2019.100665
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“Alterations in normal regulation of gene expression is one of the key features of hematopoietic malignancies. in order to gain insight into the mechanisms that regulate gene expression in these diseases, we dissected the role of the ikaros protein in leukemia. ikaros is a dna-binding, zinc finger protein that functions as a transcriptional regulator and a tumor suppressor in leukemia. the use of chip-seq, rna-seq, and atac-seq—coupled with functional experiments—revealed that ikaros regulates both the global epigenomic landscape and epigenetic signature at promoter regions of its target genes. casein kinase ii (ck2), an oncogenic kinase that is overexpressed in leukemia, directly phosphorylates ikaros at multiple, evolutionarily-conserved residues. phosphorylation of ikaros impairs the protein’s ability to regulate both the transcription of its target genes and global epigenetic landscape in leukemia. treatment of leukemia cells with a specific inhibitor of ck2 restores ikaros function, resulting in cytotoxicity of leukemia cells. here, we review the mechanisms through which the ck2-ikaros signaling axis regulates the global epigenomic landscape and expression of genes that control cellular proliferation in leukemia.”
Zhang, G., & Pradhan, S.. (2014). Mammalian epigenetic mechanisms. IUBMB Life
Plain numerical DOI: 10.1002/iub.1264
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“The mammalian genome is packaged into chromatin that is further compacted into three-dimensional structures consisting of distinct functional domains. the higher order structure of chromatin is in part dictated by enzymatic dna methylation and histone modifications to establish epigenetic layers controlling gene expression and cellular functions, without altering the underlying dna sequences. apart from dna and histone modifications, non-coding rnas can also regulate the dynamics of the mammalian gene expression and various physiological functions including cell division, differentiation, and apoptosis. aberrant epigenetic signatures are associated with abnormal developmental processes and diseases such as cancer. in this review, we will discuss the different layers of epigenetic regulation, including writer enzymes for dna methylation, histone modifications, non-coding rna, and chromatin conformation. we will highlight the combinatorial role of these structural and chemical modifications along with their partners in various cellular processes in mammalian cells. we will also address the cis and trans interacting ‘reader’ proteins that recognize these modifications and ‘eraser’ enzymes that remove these marks. furthermore, an attempt will be made to discuss the interplay between various epigenetic writers, readers, and erasures in the establishment of mammalian epigenetic mechanisms. © 2014 iubmb life.”
Hillyar, C., Rallis, K. S., & Varghese, J.. (2020). Advances in Epigenetic Cancer Therapeutics. Cureus
Plain numerical DOI: 10.7759/cureus.11725
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“Cancer has traditionally been hailed a genetic disease, dictated by successive genetic aberrations which alter gene expression. yet, recent advances in molecular sequencing technologies, enabling the characterisation of cancer patient phenotypes on a large scale, have highlighted epigenetic changes as a hallmark of cancer. epigenetic modifications, including dna methylation and demethylation and histone modifications, have been found to play a key role in the pathogenesis of a wide variety of cancers through the regulation of chromatin state, gene expression and other nuclear events. targeting epigenetic aberrations offers remarkable promise as a potential anti-cancer therapy given the reversible nature of epigenetic changes. hence, epigenetic therapy has emerged as a rapidly advancing field of cancer research. a plethora of epigenetic therapies which inhibit enzymes of post-translational histone modifications, so-called ‘writers’, ‘erasers’ and ‘readers’, have been developed, with several epigenetic inhibitor agents approved for use in routine clinical practice. epigenetic therapeutics inhibit the methylation or demethylation and acetylation or deacetylation of dna and histone proteins. their targets include writers (dna methyltransferases [dnmt], histone acetyltransferases [hat] and histone deacetylases [hdac]) and erasers (histone demethylases [hdm] and histone methylases [hmt]). with new epigenetic mechanisms increasingly being elucidated, a vast array of targets and therapeutics have been brought to the fore. this review discusses recent advances in cancer epigenetics with a focus on molecular targets and mechanisms of action of epigenetic cancer therapeutics.”
Leung, C., Angers, B., & Bergeron, P.. (2020). Epigenetic anticipation for food and reproduction. Environmental Epigenetics
Plain numerical DOI: 10.1093/eep/dvz026
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“Physiological changes in anticipation of cyclic environmental events are common for the persistence of populations in fluctuating environments (e.g. seasons). however, dealing with sporadic resources such as the intermittent production of seed masting trees may be challenging unless reliable cues also make them predictable. to be adaptive, the anticipation of such episodic events would have to trigger the corresponding physiological response. epigenetic modifications could result in such physiological anticipatory responses to future changes. the eastern chipmunk (tamias striatus) is known to adjust its reproductive activity to match juvenile weaning with peak seed availability of masting trees, which are essential for their survival. we therefore expected that epigenetic changes would be linked to spring reproductive initiation in anticipation for beech seed availability in fall. we correlated the variation of dna methylation profiles of 114 adult chipmunks captured in may with beech seeds abundance in september, over 4 years, for three distinct populations, as well as individuals sampled twice during reproductive and non-reproductive years. the significant correlation between spring epigenetic variation and the amount of food in the fall confirmed the phenotypic flexibility of individuals according to environmental fluctuations. altogether, these results underlined the key role of epigenetic processes in anticipatory responses enabling organisms to persist in fluctuating environments.”
Boccellino, M., Vanacore, D., Zappavigna, S., Cavaliere, C., Rossetti, S., D’Aniello, C., … Facchini, G.. (2017). Testicular cancer from diagnosis to epigenetic factors. Oncotarget
Plain numerical DOI: 10.18632/oncotarget.20992
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“Testicular cancer (tc) is one of the most common neoplasms that occurs in male and includes germ cell tumors (gct), sex cord-gonadal stromal tumors and secondary testicular tumors. diagnosis of tc involves the evaluation of serum tumor markers alpha-fetoprotein, human chorionic gonadotropin and lactate dehydrogenase, but clinically several types of immunohistochemical markers are more useful and more sensitive in gct, but not in teratoma. these new biomarkers are genes expressed in primordial germ cells/gonocytes and embryonic pluripotency-related cells but not in normal adult germ cells and they include plap, oct3/4 (pou5f1), nanog, sox2, rex1, ap-2γ (tfap2c) and lin28. gene expression in gct is regulated, at least in part, by dna and histone modifications, and the epigenetic profile of these tumours is characterised by genome-wide demethylation. there are different epigenetic modifications in tg-subtypes that reflect the normal developmental switch in primordial germ cells from an under- to normally methylated genome. the main purpose of this review is to illustrate the findings of recent investigations in the classification of male genital organs, the discoveries in the use of prognostic and diagnostic markers and the epigenetic aberrations mainly affecting the patterns of dna methylation/histone modifications of genes (especially tumor suppressors) and micrornas (mirnas).”
Cao, J., & Yan, Q.. (2020). Cancer Epigenetics, Tumor Immunity, and Immunotherapy. Trends in Cancer
Plain numerical DOI: 10.1016/j.trecan.2020.02.003
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“Epigenetic mechanisms, including dna methylation, histone post-translational modifications, and chromatin structure regulation, are critical for the interactions between tumor and immune cells. emerging evidence shows that tumors commonly hijack various epigenetic mechanisms to escape immune restriction. as a result, the pharmaceutical modulation of epigenetic regulators, including ‘writers’, ‘readers’, ‘erasers’, and ‘remodelers’, is able to normalize the impaired immunosurveillance and/or trigger antitumor immune responses. thus, epigenetic targeting agents are attractive immunomodulatory drugs and will have major impacts on immuno-oncology. here, we discuss epigenetic regulators of the cancer–immunity cycle and current advances in developing epigenetic therapies to boost anticancer immune responses, either alone or in combination with current immunotherapies.”
Beltra, J. C., Manne, S., Abdel-Hakeem, M. S., Kurachi, M., Giles, J. R., Chen, Z., … Wherry, E. J.. (2020). Developmental Relationships of Four Exhausted CD8+ T Cell Subsets Reveals Underlying Transcriptional and Epigenetic Landscape Control Mechanisms. Immunity
Plain numerical DOI: 10.1016/j.immuni.2020.04.014
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“CD8+ t cell exhaustion is a major barrier to current anti-cancer immunotherapies. despite this, the developmental biology of exhausted cd8+ t cells (tex) remains poorly defined, restraining improvement of strategies aimed at ‘re-invigorating’ tex cells. here, we defined a four-cell-stage developmental framework for tex cells. two tcf1+ progenitor subsets were identified, one tissue restricted and quiescent and one more blood accessible, that gradually lost tcf1 as it divided and converted to a third intermediate tex subset. this intermediate subset re-engaged some effector biology and increased upon pd-l1 blockade but ultimately converted into a fourth, terminally exhausted subset. by using transcriptional and epigenetic analyses, we identified the control mechanisms underlying subset transitions and defined a key interplay between tcf1, t-bet, and tox in the process. these data reveal a four-stage developmental hierarchy for tex cells and define the molecular, transcriptional, and epigenetic mechanisms that could provide opportunities to improve cancer immunotherapy. beltra et al. define a hierarchical developmental pathway for cd8+ t cell exhaustion, revealing four stages and multistep transcriptional and epigenetic dynamics underlying subset transitions and subset-associated biological changes.”
Amenyah, S. D., Ward, M., Strain, J. J., McNulty, H., Hughes, C. F., Dollin, C., … Lees-Murdock, D. J.. (2020). Nutritional epigenomics and age-related disease. Current Developments in Nutrition
Plain numerical DOI: 10.1093/CDN/NZAA097
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“Recent advances in epigenetic research have enabled the development of epigenetic clocks, which have greatly enhanced our ability to investigate molecular processes that contribute to aging and age-related disease. these biomarkers offer the potential to measure the effect of environmental exposures linked to dynamic changes in dna methylation, including nutrients, as factors in age-related disease. they also offer a compelling insight into how imbalances in the supply of nutrients, particularly b-vitamins, or polymorphisms in regulatory enzymes involved in 1-carbon metabolism, the key pathway that supplies methyl groups for epigenetic reactions, may influence epigenetic age and interindividual disease susceptibility. evidence from recent studies is critically reviewed, focusing on the significant contribution of the epigenetic clock to nutritional epigenomics and its impact on health outcomes and age-related disease. further longitudinal studies and randomized nutritional interventions are required to advance the field. curr dev nutr 2020;4:nzaa097.”
Tian, F.-Y., & Marsit, C. J.. (2018). Environmentally Induced Epigenetic Plasticity in Development: Epigenetic Toxicity and Epigenetic Adaptation. Current Epidemiology Reports
Plain numerical DOI: 10.1007/s40471-018-0175-7
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“PURPOSE of review: epigenetic processes represent important mechanisms underlying developmental plasticity in response to environmental exposures. the current review discusses three classes of environmentally-induced epigenetic changes reflecting two aspects of that plasticity, toxicity effects as well as adaptation in the process of development. recent findings: due to innate resilience, epigenetic changes caused by environmental exposures may not always lead impairments but may allow the organisms to achieve positive developmental outcomes through appropriate adaptation and a buffering response. thus, some epigenetic adaptive responses to an immediate stimulus or exposure early in life would be expected to have a survival advantage but these same responses may also result in adverse developmental outcomes as they persists into later life stage. although accumulating literature has identified environmentally induced epigenetic changes and linked them to health outcomes, we currently face challenges in the interpretation of the functional impact of their epigenetic plasticity. summary: current environmental epigenetic research suggest that epigenetic processes may serve as a mechanism for resilience, and that they can be considered in terms of their impact on toxicity as a negative outcome, but also on adaptation for improved survival or health. this review encourages epigenetic environmental studies to move deeper inside into the functional meaning of epigenetic plasticity in the development.”
De Almeida, D. C., Ferreira, M. R. P., Franzen, J., Weidner, C. I., Frobel, J., Zenke, M., … Wagner, W.. (2016). Epigenetic Classification of Human Mesenchymal Stromal Cells. Stem Cell Reports
Plain numerical DOI: 10.1016/j.stemcr.2016.01.003
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“Standardization of mesenchymal stromal cells (mscs) is hampered by the lack of a precise definition for these cell preparations; for example, there are no molecular markers to discern mscs and fibroblasts. in this study, we followed the hypothesis that specific dna methylation (dnam) patterns can assist classification of mscs. we utilized 190 dnam profiles to address the impact of tissue of origin, donor age, replicative senescence, and serum supplements on the epigenetic makeup. based on this, we elaborated a simple epigenetic signature based on two cpg sites to classify mscs and fibroblasts, referred to as the epi-msc-score. another two-cpg signature can distinguish between mscs from bone marrow and adipose tissue, referred to as the epi-tissue-score. these assays were validated by site-specific pyrosequencing analysis in 34 primary cell preparations. furthermore, even individual subclones of mscs were correctly classified by our epigenetic signatures. in summary, we propose an alternative concept to use dnam patterns for molecular definition of cell preparations, and our epigenetic scores facilitate robust and cost-effective quality control of msc cultures.”
Garcia-Martinez, L., Zhang, Y., Nakata, Y., Chan, H. L., & Morey, L.. (2021). Epigenetic mechanisms in breast cancer therapy and resistance. Nature Communications
Plain numerical DOI: 10.1038/s41467-021-22024-3
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“The majority of breast cancers express the estrogen receptor (erα) and agents targeting this pathway represent the main treatment modality. endocrine therapy has proven successful in the treatment of hormone-responsive breast cancer since its early adoption in the 1940s as an ablative therapy. unfortunately, therapeutic resistance arises, leading to disease recurrence and relapse. recent studies increased our understanding in how changes to the chromatin landscape and deregulation of epigenetic factors orchestrate the resistant phenotype. here, we will discuss how the epigenome is an integral determinant in hormone therapy response and why epigenetic factors are promising targets for overcoming clinical resistance.”
Lameirinhas, A., Miranda-Gonçalves, V., Henrique, R., & Jerónimo, C.. (2019). The complex interplay between metabolic reprogramming and epigenetic alterations in renal cell carcinoma. Genes
Plain numerical DOI: 10.3390/genes10040264
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“Renal cell carcinoma (rcc) is the most common malignancy affecting the kidney. current therapies are mostly curative for localized disease, but do not completely preclude recurrence and metastization. thus, it is imperative to develop new therapeutic strategies based on rcc biological properties. presently, metabolic reprograming and epigenetic alterations are recognized cancer hallmarks and their interactions are still in its infancy concerning rcc. in this review, we explore rcc biology, highlighting genetic and epigenetic alterations that contribute to metabolic deregulation of tumor cells, including high glycolytic phenotype (warburg effect). moreover, we critically discuss available data concerning epigenetic enzymes’ regulation by aberrant metabolite accumulation and their consequences in rcc emergence and progression. finally, we emphasize the clinical relevance of uncovering novel therapeutic targets based on epigenetic reprograming by metabolic features to improve treatment and survival of rcc patients.”
Dupras, C., Beck, S., Rothstein, M. A., Berner, A., Saulnier, K. M., Pinkesz, M., … Joly, Y.. (2019). Potential (mis)use of epigenetic age estimators by private companies and public agencies: Human rights law should provide ethical guidance. Environmental Epigenetics
Plain numerical DOI: 10.1093/eep/dvz018
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“Over the past decade, researchers in epigenetics have developed testing methods to predict the chronological and biological age of individuals based on levels of dna methylation at combinations of cpg sites in specific cell types. these epigenetic age and aging estimators, also referred to as ‘epigenetic clocks’, represent a promising avenue to better understand the biological pathways underlying the development of aging-associated disorders, and imagine biomedical and/or social interventions to prevent, reverse, or alleviate them. epigenetic clock technologies aimed at testing for epigenetic age of different cell types also provide an opportunity to investigate how environmental stressors, social adversity, and unhealthy lifestyle can contribute to such disorders through epigenetic aging acceleration. in addition to their potential clinical and public health applications, epigenetic age and aging estimators may be used for non-medical purposes, such as insurance and forensic sciences. in this article, we present and discuss a set of potential ethical, legal, and social implications of non-medical uses of epigenetic clocks. we highlight concerns related to actuarial and moral fairness, free and informed consent, data governance and the protection of privacy, equity and non-discrimination principles, identification and surveillance, the moral liability of criminals, as well as scientific validity, test accuracy, and interpretation of test results. we argue that a human rights framework should guide further discussions about these important and timely questions.”
Raeisossadati, R., Ferrari, M. F. R., Kihara, A. H., AlDiri, I., & Gross, J. M.. (2021). Epigenetic regulation of retinal development. Epigenetics and Chromatin
Plain numerical DOI: 10.1186/s13072-021-00384-w
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“In the developing vertebrate retina, retinal progenitor cells (rpcs) proliferate and give rise to terminally differentiated neurons with exquisite spatio-temporal precision. lineage commitment, fate determination and terminal differentiation are controlled by intricate crosstalk between the genome and epigenome. indeed, epigenetic regulation plays pivotal roles in numerous cell fate specification and differentiation events in the retina. moreover, aberrant chromatin structure can contribute to developmental disorders and retinal pathologies. in this review, we highlight recent advances in our understanding of epigenetic regulation in the retina. we also provide insight into several aspects of epigenetic-related regulation that should be investigated in future studies of retinal development and disease. importantly, focusing on these mechanisms could contribute to the development of novel treatment strategies targeting a variety of retinal disorders.”
Giorgio, M., Dellino, I. G., Gambino, V., Roda, N., & Pelicci, P. G.. (2020). On the epigenetic role of guanosine oxidation. Redox Biology
Plain numerical DOI: 10.1016/j.redox.2019.101398
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“Chemical modifications of dna and rna regulate genome functions or trigger mutagenesis resulting in aging or cancer. oxidations of macromolecules, including dna, are common reactions in biological systems and often part of regulatory circuits rather than accidental events. dna alterations are particularly relevant since the unique role of nuclear and mitochondrial genome is coding enduring and inheritable information. therefore, an alteration in dna may represent a relevant problem given its transmission to daughter cells. at the same time, the regulation of gene expression allows cells to continuously adapt to the environmental changes that occur throughout the life of the organism to ultimately maintain cellular homeostasis. here we review the multiple ways that lead to dna oxidation and the regulation of mechanisms activated by cells to repair this damage. moreover, we present the recent evidence suggesting that dna damage caused by physiological metabolism acts as epigenetic signal for regulation of gene expression. in particular, the predisposition of guanine to oxidation might reflect an adaptation to improve the genome plasticity to redox changes.”
Barros, S. P., Fahimipour, F., Tarran, R., Kim, S., Scarel-Caminaga, R. M., Justice, A., & North, K.. (2020). Epigenetic reprogramming in periodontal disease: Dynamic crosstalk with potential impact in oncogenesis. Periodontology 2000
Plain numerical DOI: 10.1111/prd.12322
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“Periodontitis is a chronic multifactorial inflammatory disease associated with microbial dysbiosis and characterized by progressive destruction of the periodontal tissues. such chronic infectious inflammatory disease is recognized as a major public health problem worldwide with measurable impact in systemic health. it has become evident that the periodontal disease phenotypes are not only determined by the microbiome effect, but the extent of the tissue response is also driven by the host genome and epigenome patterns responding to various environmental exposures. more recently there is mounting evidence indicating that epigenetic reprogramming in response to combined intrinsic and environmental exposures, might be particularly relevant due its plasticity and potential application towards precision health. the complex epigenetic crosstalk is reflected in the prognosis and progress of periodontal diseases and may also lead to a favorable landscape for cancer development. this review discusses epigenomics modifications focusing on the role of dna methylation and pathways linking microbial infection and inflammatory pathways, which are also associated with carcinogenesis. there is a more clear vision whereas ‘omics’ technologies applied to unveil relevant epigenetic factors could play a significant role in the treatment of periodontal disease in a personalized mode, evidencing that public health approach should coexist with precision individualized treatment.”
Bar, S., & Benvenisty, N.. (2019). Epigenetic aberrations in human pluripotent stem cells. The EMBO Journal
Plain numerical DOI: 10.15252/embj.2018101033
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“Human pluripotent stem cells (hpscs) are being increasingly utilized worldwide in investigating human development, and modeling and discovering therapies for a wide range of diseases as well as a source for cellular therapy. yet, since the first isolation of human embryonic stem cells (hescs) 20 years ago, followed by the successful reprogramming of human-induced pluripotent stem cells (hipscs) 10 years later, various studies shed light on abnormalities that sometimes accumulate in these cells in vitro whereas genetic aberrations are well documented, epigenetic alterations are not as thoroughly discussed. in this review, we highlight frequent epigenetic aberrations found in hpscs, including alterations in dna methylation patterns, parental imprinting, and x chromosome inactivation. we discuss the potential origins of these abnormalities in hescs and hipscs, survey the different methods for detecting them, and elaborate on their potential consequences for the different utilities of hpscs.”
Ahmadi, M., Gharibi, T., Dolati, S., Rostamzadeh, D., Aslani, S., Baradaran, B., … Yousefi, M.. (2017). Epigenetic modifications and epigenetic based medication implementations of autoimmune diseases. Biomedicine and Pharmacotherapy
Plain numerical DOI: 10.1016/j.biopha.2016.12.072
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“Recent genome-wide association studies have documented a number of genetic variants to explain mechanisms underlying autoimmune diseases. however, the precise etiology of autoimmune diseases remains largely unknown. epigenetic mechanisms like alterations in the post-translational modification of histones and dna methylation may potentially cause a breakdown of immune tolerance and the perpetuation of autoreactive responses. recently, several studies both in experimental models and clinical settings proposed that the epigenome may hold the key to a better understanding of autoimmunity initiation and perpetuation. more specifically, data support the impact of epigenetic changes in autoimmune diseases, in some cases based on mechanistical observations. epigenetic therapy already being employed in hematopoietic malignancies may also be associated with beneficial effects in autoimmune diseases. in this review, we will discuss on what we know and expect about the treatment of autoimmune disease based on epigenetic aberrations.”
Bauch, C., Boonekamp, J. J., Korsten, P., Mulder, E., & Verhulst, S.. (2019). Epigenetic inheritance of telomere length in wild birds. PLoS Genetics
Plain numerical DOI: 10.1371/journal.pgen.1007827
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“Telomere length (tl) predicts health and survival across taxa. variation in tl between individuals is thought to be largely of genetic origin, but telomere inheritance is unusual, because zygotes already express a tl phenotype, the tl of the parental gametes. offspring tl changes with paternal age in many species including humans, presumably through age-related tl changes in sperm, suggesting an epigenetic inheritance mechanism. however, present evidence is based on cross-sectional analyses, and age at reproduction is confounded with between-father variation in tl. furthermore, the quantitative importance of epigenetic tl inheritance is unknown. using longitudinal data of free-living jackdaws corvus monedula, we show that erythrocyte tl of subsequent offspring decreases with parental age within individual fathers, but not mothers. by cross-fostering eggs, we confirmed the paternal age effect to be independent of paternal age dependent care. epigenetic inheritance accounted for a minimum of 34% of the variance in offspring tl that was explained by paternal tl. this is a minimum estimate, because it ignores the epigenetic component in paternal tl variation and sperm tl heterogeneity within ejaculates. our results indicate an important epigenetic component in the heritability of tl with potential consequences for offspring fitness prospects.”
Nannini, D. R., Joyce, B. T., Zheng, Y., Gao, T., Liu, L., Yoon, G., … Hou, L.. (2019). Epigenetic age acceleration and metabolic syndrome in the coronary artery risk development in young adults study. Clinical Epigenetics
Plain numerical DOI: 10.1186/s13148-019-0767-1
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“Background: the metabolic syndrome (mets) is a collection of metabolic disturbances that can lead to various cardiovascular diseases. previous studies have shown a more adverse metabolic risk profile is associated with more advanced biological aging. the associations between epigenetic biomarkers of age with mets, however, are not well understood. we therefore investigated the associations between epigenetic age acceleration and mets severity score and incident mets. results: a subset of study participants with available whole blood at examination years 15 and 20 from the coronary artery risk development in young adults study underwent epigenomic profiling using the illumina methylationepic beadchip (~ 850,000 sites). intrinsic and extrinsic epigenetic age acceleration (ieaa and eeaa) were calculated from dna methylation levels. the mets severity score was positively associated with ieaa at years 15 (p = 0.016) and 20 (p = 0.016) and eeaa at year 20 (p = 0.040) in cross-sectional analysis. ieaa at year 20 was significantly associated with incident mets at year 30 (or = 1.05 [95% ci 1.01, 1.10], p = 0.028). conclusions: to our knowledge, this is the first report of the longitudinal association between epigenetic age acceleration and mets. these findings suggest that a higher mets severity score is associated with accelerated epigenetic aging and such aging may play a role in the development of metabolic disorders, potentially serving as a useful biomarker of and early detection tool for future mets.”
Schmidl, C., Delacher, M., Huehn, J., & Feuerer, M.. (2018). Epigenetic mechanisms regulating T-cell responses. Journal of Allergy and Clinical Immunology
Plain numerical DOI: 10.1016/j.jaci.2018.07.014
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“During the last decade, advances in sequencing technologies allowed production of a wealth of information on epigenetic modifications in t cells. epigenome maps, in combination with mechanistic studies, have demonstrated that t cells undergo extensive epigenome remodeling in response to signals, which has a strong effect on phenotypic stability and function of lymphocytes. in this review we focus on dna methylation, histone modifications, and chromatin structure as important epigenetic mechanisms involved in controlling t-cell responses. in particular, we discuss epigenetic processes in light of the development, activation, and differentiation of cd4+ t helper (th), regulatory t, and cd8+ t cells. as central aspects of the adaptive immune system, we review mechanisms that ensure molecular memory, stability, plasticity, and exhaustion of t cells. we further discuss the effect of the tissue environment on imprinting t-cell epigenomes with potential implications for immunotherapy.”
Wang, T., Ma, J., Hogan, A. N., Fong, S., Licon, K., Tsui, B., … Ideker, T.. (2020). Quantitative Translation of Dog-to-Human Aging by Conserved Remodeling of the DNA Methylome. Cell Systems
Plain numerical DOI: 10.1016/j.cels.2020.06.006
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“All mammals progress through similar physiological stages throughout life, from early development to puberty, aging, and death. yet, the extent to which this conserved physiology reflects underlying genomic events is unclear. here, we map the common methylation changes experienced by mammalian genomes as they age, focusing on comparison of humans with dogs, an emerging model of aging. using oligo-capture sequencing, we characterize methylomes of 104 labrador retrievers spanning a 16-year age range, achieving >150× coverage within mammalian syntenic blocks. comparison with human methylomes reveals a nonlinear relationship that translates dog-to-human years and aligns the timing of major physiological milestones between the two species, with extension to mice. conserved changes center on developmental gene networks, which are sufficient to translate age and the effects of anti-aging interventions across multiple mammals. these results establish methylation not only as a diagnostic age readout but also as a cross-species translator of physiological aging milestones. wang et al. create an oligo-capture system to characterize the canine dna methylome, targeting syntenic regions of the genome conserved across all mammals. cross-species comparisons reveal a nonlinear epigenetic signature that aligns the progression of life events in dogs, humans, and mice. this conserved signature occurs primarily in modules of developmental genes, leading the team to create a conserved epigenetic clock model of aging that can be trained and operated across different species.”
Haarhaus, M., Gilham, D., Kulikowski, E., Magnusson, P., & Kalantar-Zadeh, K.. (2020). Pharmacologic epigenetic modulators of alkaline phosphatase in chronic kidney disease. Current Opinion in Nephrology and Hypertension
Plain numerical DOI: 10.1097/MNH.0000000000000570
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“Purpose of reviewin chronic kidney disease (ckd), disturbance of several metabolic regulatory mechanisms cause premature ageing, accelerated cardiovascular disease (cvd), and mortality. single-target interventions have repeatedly failed to improve the prognosis for ckd patients. epigenetic interventions have the potential to modulate several pathogenetic processes simultaneously. alkaline phosphatase (alp) is a robust predictor of cvd and all-cause mortality and implicated in pathogenic processes associated with cvd in ckd.recent findingsin experimental studies, epigenetic modulation of alp by micrornas or bromodomain and extraterminal (bet) protein inhibition has shown promising results for the treatment of cvd and other chronic metabolic diseases. the bet inhibitor apabetalone is currently being evaluated for cardiovascular risk reduction in a phase iii clinical study in high-risk cvd patients, including patients with ckd (clinicaltrials.gov identifier: nct02586155). phase ii studies demonstrate an alp-lowering potential of apabetalone, which was associated with improved cardiovascular and renal outcomes.summaryalp is a predictor of cvd and mortality in ckd. epigenetic modulation of alp has the potential to affect several pathogenetic processes in ckd and thereby improve cardiovascular outcome.”
Lu, Z., Zou, J., Li, S., Topper, M. J., Tao, Y., Zhang, H., … Brock, M. V.. (2020). Epigenetic therapy inhibits metastases by disrupting premetastatic niches. Nature
Plain numerical DOI: 10.1038/s41586-020-2054-x
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“Cancer recurrence after surgery remains an unresolved clinical problem1–3. myeloid cells derived from bone marrow contribute to the formation of the premetastatic microenvironment, which is required for disseminating tumour cells to engraft distant sites4–6. there are currently no effective interventions that prevent the formation of the premetastatic microenvironment6,7. here we show that, after surgical removal of primary lung, breast and oesophageal cancers, low-dose adjuvant epigenetic therapy disrupts the premetastatic microenvironment and inhibits both the formation and growth of lung metastases through its selective effect on myeloid-derived suppressor cells (mdscs). in mouse models of pulmonary metastases, mdscs are key factors in the formation of the premetastatic microenvironment after resection of primary tumours. adjuvant epigenetic therapy that uses low-dose dna methyltransferase and histone deacetylase inhibitors, 5-azacytidine and entinostat, disrupts the premetastatic niche by inhibiting the trafficking of mdscs through the downregulation of ccr2 and cxcr2, and by promoting mdsc differentiation into a more-interstitial macrophage-like phenotype. a decreased accumulation of mdscs in the premetastatic lung produces longer periods of disease-free survival and increased overall survival, compared with chemotherapy. our data demonstrate that, even after removal of the primary tumour, mdscs contribute to the development of premetastatic niches and settlement of residual tumour cells. a combination of low-dose adjuvant epigenetic modifiers that disrupts this premetastatic microenvironment and inhibits metastases may permit an adjuvant approach to cancer therapy.”
Phan, A. T., Goldrath, A. W., & Glass, C. K.. (2017). Metabolic and Epigenetic Coordination of T Cell and Macrophage Immunity. Immunity
Plain numerical DOI: 10.1016/j.immuni.2017.04.016
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“Recognition of pathogens by innate and adaptive immune cells instructs rapid alterations of cellular processes to promote effective resolution of infection. to accommodate increased bioenergetic and biosynthetic demands, metabolic pathways are harnessed to maximize proliferation and effector molecule production. in parallel, activation initiates context-specific gene-expression programs that drive effector functions and cell fates that correlate with changes in epigenetic landscapes. many chromatin- and dna-modifying enzymes make use of substrates and cofactors that are intermediates of metabolic pathways, providing potential cross talk between metabolism and epigenetic regulation of gene expression. in this review, we discuss recent studies of t cells and macrophages supporting a role for metabolic activity in integrating environmental signals with activation-induced gene-expression programs through modulation of the epigenome and speculate as to how this may influence context-specific macrophage and t cell responses to infection.”
Cole, J., Morris, P., Dickman, M. J., & Dockrell, D. H.. (2016). The therapeutic potential of epigenetic manipulation during infectious diseases. Pharmacology and Therapeutics
Plain numerical DOI: 10.1016/j.pharmthera.2016.07.013
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“Epigenetic modifications are increasingly recognized as playing an important role in the pathogenesis of infectious diseases. they represent a critical mechanism regulating transcriptional profiles in the immune system that contributes to the cell-type and stimulus specificity of the transcriptional response. recent data highlight how epigenetic changes impact macrophage functional responses and polarization, influencing the innate immune system through macrophage tolerance and training. in this review we will explore how post-translational modifications of histone tails influence immune function to specific infectious diseases. we will describe how these may influence outcome, highlighting examples derived from responses to acute bacterial pathogens, models of sepsis, maintenance of viral latency and hiv infection. we will discuss how emerging classes of pharmacological agents, developed for use in oncology and other settings, have been applied to models of infectious diseases and their potential to modulate key aspects of the immune response to bacterial infection and hiv therapy.”
Blasiak, J., Chojnacki, J., Pawlowska, E., Szczepanska, J., & Chojnacki, C.. (2020). Nutrition in cancer therapy in the elderly—an epigenetic connection?. Nutrients
Plain numerical DOI: 10.3390/nu12113366
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“The continuous increase in life expectancy results in a steady increase of cancer risk, which consequently increases the population of older adults with cancer. older adults have their age-related nutritional needs and often suffer from comorbidities that may affect cancer therapy. they frequently are malnourished and present advanced-stage cancer. therefore, this group of patients requires a special multidisciplinary approach to optimize their therapy and increase quality of life impaired by aging, cancer, and the side effects of therapy. evaluation strategies, taking advantage of comprehensive geriatric assessment tools, including the comprehensive geriatric assessment (cga), can help individualize treatment. as epigenetics, an emerging element of the regulation of gene expression, is involved in both aging and cancer and the epigenetic profile can be modulated by the diet, it seems to be a candidate to assist with planning a nutritional intervention in elderly populations with cancer. in this review, we present problems associated with the diet and nutrition in the elderly undergoing active cancer therapy and provide some information on epigenetic aspects of aging and cancer transformation. nutritional interventions modulating the epigenetic profile, including caloric restriction and basal diet with modifications (elimination diet, supplementary diet) are discussed as the ways to improve the efficacy of cancer therapy and maintain the quality of life of older adults with cancer.”
Horvath, S., Erhart, W., Brosch, M., Ammerpohl, O., Von Schönfels, W., Ahrens, M., … Hampe, J.. (2014). Obesity accelerates epigenetic aging of human liver. Proceedings of the National Academy of Sciences of the United States of America
Plain numerical DOI: 10.1073/pnas.1412759111
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“Because of the dearth of biomarkers of aging, it has been difficult to test the hypothesis that obesity increases tissue age. here we use a novel epigenetic biomarker of aging (referred to as an ‘epigenetic clock’) to study the relationship between high body mass index (bmi) and the dna methylation ages of human blood, liver, muscle, and adipose tissue. a significant correlation between bmi and epigenetic age acceleration could only be observed for liver (r = 0.42, p = 6.8 × 10-4 in dataset 1 and r = 0.42, p = 1.2 × 10-4 in dataset 2). on average, epigenetic age increased by 3.3 y for each 10 bmi units. the detected age acceleration in liver is not associated with the nonalcoholic fatty liver disease activity score or any of its component traits after adjustment for bmi. the 279 genes that are underexpressed in older liver samples are highly enriched (1.2 × 10-9) with nuclear mitochondrial genes that play a role in oxidative phosphorylation and electron transport. the epigenetic age acceleration, which is not reversible in the short term after rapid weight loss induced by bariatric surgery, may play a role in liver-related comorbidities of obesity, such as insulin resistance and liver cancer.”
Teschendorff, A. E.. (2020). A comparison of epigenetic mitotic-like clocks for cancer risk prediction. Genome Medicine
Plain numerical DOI: 10.1186/s13073-020-00752-3
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“Background: dna methylation changes that accrue in the stem cell pool of an adult tissue in line with the cumulative number of cell divisions may contribute to the observed variation in cancer risk among tissues and individuals. thus, the construction of epigenetic ‘mitotic’clocks that can measure the lifetime number of stem cell divisions is of paramount interest. methods: building upon a dynamic model of dna methylation gain in unmethylated cpg-rich regions, we here derive a novel mitotic clock (‘epitoc2’) that can directly estimate the cumulative number of stem cell divisions in a tissue. we compare epitoc2 to a different mitotic model, based on hypomethylation at solo-wcgw sites (‘Hypoclock’), in terms of their ability to measure mitotic age of normal adult tissues and predict cancer risk. results: using epitoc2, we estimate the intrinsic stem cell division rate for different normal tissue types, demonstrating excellent agreement (pearson correlation = 0.92, r 2 = 0.85, p = 3e-6) with those derived from experiment. in contrast, hypoclock’s estimates do not (pearson correlation = 0.30, r 2 = 0.09, p = 0.29). we validate these results in independent datasets profiling normal adult tissue types. while both epitoc2 and hypoclock correctly predict an increased mitotic rate in cancer, epitoc2 is more robust and significantly better at discriminating preneoplastic lesions characterized by chronic inflammation, a major driver of tissue turnover and cancer risk. our data suggest that dna methylation loss at solo-wcgws is significant only when cells are under high replicative stress and that epitoc2 is a better mitotic age and cancer risk prediction model for normal adult tissues. conclusions: these results have profound implications for our understanding of epigenetic clocks and for developing cancer risk prediction or early detection assays. we propose that measurement of dnam at the 163 epitoc2 cpgs in adult pre-neoplastic lesions, and potentially in serum cell-free dna, could provide the basis for building feasible pre-diagnostic or cancer risk assays. epitoc2 is freely available from https://doi.org/10.5281/zenodo.2632938”
Katsuyama, T., & Paro, R.. (2011). Epigenetic reprogramming during tissue regeneration. FEBS Letters
Plain numerical DOI: 10.1016/j.febslet.2011.05.010
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“Epigenetic control of gene regulation is fundamental to the maintenance of cellular identities during all stages of metazoan life. tissue regeneration involves cellular reprogramming processes, like dedifferentiation, re-differentiation, and trans-differentiation. hence, in these processes epigenetic maintenance of gene expression programs requires a resetting through mechanisms that we are only beginning to understand. here we summarize the current status of these studies, in particular regarding the role of epigenetic mechanisms of cellular reprogramming during tissue regeneration. © 2011 federation of european biochemical societies. published by elsevier b.v. all rights reserved.”
Gibson, J., Russ, T. C., Clarke, T. K., Howard, D. M., Hillary, R. F., Evans, K. L., … Marioni, R. E.. (2019). A meta-analysis of genome-wide association studies of epigenetic age acceleration. PLoS Genetics
Plain numerical DOI: 10.1371/journal.pgen.1008104
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“‘Epigenetic age acceleration’ is a valuable biomarker of ageing, predictive of morbidity and mortality, but for which the underlying biological mechanisms are not well established. two commonly used measures, derived from dna methylation, are horvath-based (horvath-eaa) and hannum-based (hannum-eaa) epigenetic age acceleration. we conducted genome-wide association studies of horvath-eaa and hannum-eaa in 13,493 unrelated individuals of european ancestry, to elucidate genetic determinants of differential epigenetic ageing. we identified ten independent snps associated with horvath-eaa, five of which are novel. we also report 21 horvath-eaa-associated genes including several involved in metabolism (nhlrc, tpmt) and immune system pathways (trim59, edaradd). gwas of hannum-eaa identified one associated variant (rs1005277), and implicated 12 genes including several involved in innate immune system pathways (ube2d3, manba, trim46), with metabolic functions (ube2d3, manba), or linked to lifespan regulation (cisd2). both measures had nominal inverse genetic correlations with father’s age at death, a rough proxy for lifespan. nominally significant genetic correlations between hannum-eaa and lifestyle factors including smoking behaviours and education support the hypothesis that hannum-based epigenetic ageing is sensitive to variations in environment, whereas horvath-eaa is a more stable cellular ageing process. we identified novel snps and genes associated with epigenetic age acceleration, and highlighted differences in the genetic architecture of horvath-based and hannum-based epigenetic ageing measures. understanding the biological mechanisms underlying individual differences in the rate of epigenetic ageing could help explain different trajectories of age-related decline.”
Wójcikowska, B., Wójcik, A. M., & Gaj, M. D.. (2020). Epigenetic regulation of auxin-induced somatic embryogenesis in plants. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms21072307
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“Somatic embryogenesis (se) that is induced in plant explants in response to auxin treatment is closely associated with an extensive genetic reprogramming of the cell transcriptome. the significant modulation of the gene transcription profiles during se induction results from the epigenetic factors that fine-tune the gene expression towards embryogenic development. among these factors, microrna molecules (mirnas) contribute to the post-transcriptional regulation of gene expression. in the past few years, several mirnas that regulate the se-involved transcription factors (tfs) have been identified, and most of them were involved in the auxin-related processes, including auxin metabolism and signaling. in addition to mirnas, chemical modifications of dna and chromatin, in particular the methylation of dna and histones and histone acetylation, have been shown to shape the se transcriptomes. in response to auxin, these epigenetic modifications regulate the chromatin structure, and hence essentially contribute to the control of gene expression during se induction. in this paper, we describe the current state of knowledge with regard to the se epigenome. the complex interactions within and between the epigenetic factors, the key se tfs that have been revealed, and the relationships between the se epigenome and auxin-related processes such as auxin perception, metabolism, and signaling are highlighted.”
Dyke, S. O. M., Saulnier, K. M., Dupras, C., Webster, A. P., Maschke, K., Rothstein, M., … Joly, Y.. (2019). Points-to-consider on the return of results in epigenetic research. Genome Medicine
Plain numerical DOI: 10.1186/s13073-019-0646-6
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“As epigenetic studies become more common and lead to new insights into health and disease, the return of individual epigenetic results to research participants, in particular in large-scale epigenomic studies, will be of growing importance. members of the international human epigenome consortium (ihec) bioethics workgroup considered the potential ethical, legal, and social issues (elsi) involved in returning epigenetic research results and incidental findings in order to produce a set of ‘Points-to-consider’ (p-t-c) for the epigenetics research community. these p-t-c draw on existing guidance on the return of genetic research results, while also integrating the ihec bioethics workgroup’s elsi research on and discussion of the issues associated with epigenetic data as well as the experience of a return of results pilot study by the personal genome project uk (pgp-uk). major challenges include how to determine the clinical validity and actionability of epigenetic results, and considerations related to environmental exposures and epigenetic marks, including circumstances warranting the sharing of results with family members and third parties. interdisciplinary collaboration and good public communication regarding epigenetic risk will be important to advance the return of results framework for epigenetic science.”
Chen, Y., Zander, R., Khatun, A., Schauder, D. M., & Cui, W.. (2018). Transcriptional and Epigenetic Regulation of Effector and Memory CD8 T Cell Differentiation. Frontiers in Immunology
Plain numerical DOI: 10.3389/fimmu.2018.02826
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“Immune protection and lasting memory are accomplished through the generation of phenotypically and functionally distinct cd8 t cell subsets. understanding how these effector and memory t cells are formed is the first step in eventually manipulating the immune system for therapeutic benefit. in this review, we will summarize the current understanding of cd8 t cell differentiation upon acute infection, with a focus on the transcriptional and epigenetic regulation of cell fate decision and memory formation. moreover, we will highlight the importance of high throughput sequencing approaches and single cell technologies in providing insight into genome-wide investigations and the heterogeneity of individual cd8 t cells.”
Cheng, Z., & Almeida, F. A.. (2014). Mitochondrial alteration in type 2 diabetes and obesity: An epigenetic link. Cell Cycle
Plain numerical DOI: 10.4161/cc.28189
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“The growing epidemic of type 2 diabetes mellitus (t2dm) and obesity is largely attributed to the current lifestyle of over-consumption and physical inactivity. as the primary platform controlling metabolic and energy homeostasis, mitochondria show aberrant changes in t2dm and obese subjects. while the underlying mechanism is under extensive investigation, epigenetic regulation is now emerging to play an important role in mitochondrial biogenesis, function, and dynamics. in line with lifestyle modifications preventing mitochondrial alterations and metabolic disorders, exercise has been shown to change dna methylation of the promoter of pgc1α to favor gene expression responsible for mitochondrial biogenesis and function. in this article we discuss the epigenetic mechanism of mitochondrial alteration in t2dm and obesity, and the effects of lifestyle on epigenetic regulation. future studies designed to further explore and integrate the epigenetic mechanisms with lifestyle modification may lead to interdisciplinary interventions and novel preventive options for mitochondrial alteration and metabolic disorders. © 2014 landes bioscience.”
Rathod, A., Duan, J., Zhang, H., Holloway, J. W., Ewart, S., Arshad, S. H., & Karmaus, W.. (2020). Interweaving Between Genetic and Epigenetic Studies on Childhood Asthma. Epigenetics Insights
Plain numerical DOI: 10.1177/2516865720923395
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“The cause and underlying mechanisms that contribute to asthma pathogenesis are not well known. both genome- and epigenome-wide association studies have identified genes associated with asthma risk. it is unknown to what extent genes identified in these two types of studies overlap. based on existing literature and the disgenet database, we extracted overlapping genes identified in genetic and epigenetic studies of childhood asthma. through analyses of variance, we assessed whether dna methylation (dnam) at 5′-c-phosphate-g-3′ (cpgs) on the overlapping genes was associated with neighboring single-nucleotide polymorphisms (snps) within 1m base pairs (bps) and with low linkage disequilibrium (r2 < 0.2) in the childhood asthma-related genes. in total, 285 genes from genetic studies and 226 genes from epigenetic studies were shown to be associated with asthma risk, of which six overlap. of the six genes, 79 cpgs and 8229 unique neighboring snps (1m bps) were included in methylation quantitative loci (methqtl) assessment analyses. we tested the association of dnam at each of the 79 cpg sites with its neighboring snps. after adjusting for multiple testing by controlling the false discovery rate to 0.05 when testing methqtl for each cpg site, we found statistically significant associations in three genes with their neighboring snps and identified 34 unique methqtls. the rather limited overlap in genes between genetic and epigenetic studies on asthma and the absence of methqtl in some of the overlapping genes highlight a need to jointly, rather than independently, examine genetic and epigenetic effects on asthma risk to improve our understanding of the underlying mechanisms of asthma.”
Hagihara, Y., Yoshimatsu, Y., Mikami, Y., Takada, Y., Mizuno, S., & Kanai, T.. (2019). Epigenetic regulation of T helper cells and intestinal pathogenicity. Seminars in Immunopathology
Plain numerical DOI: 10.1007/s00281-019-00732-9
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“Inflammatory bowel diseases (ibds) are characterized by relapsing and remitting chronic intestinal inflammation. previous studies have demonstrated the contributions of genetic background, environmental factors (food, microbiota, use of antibiotics), and host immunity in the development of ibds. more than 200 genes have been shown to influence ibd susceptibility, most of which are involved in immunity. the vertebrate immune system comprises a complex network of innate and adaptive immune cells that protect the host from infection and cancer. dysregulation of the mutualistic relationship between the immune system and the gut environment results in ibd. considering the fundamental role of epigenetic regulation in immune cells, epigenetic mechanisms, particularly in t helper (th) cells, may play a major role in the complex regulation of mucosal immunity. epigenetic regulation and dysregulation of th cells are involved in the maintenance of intestinal homeostasis and its breakdown in ibd.”
Kang, J. G., Park, J. S., Ko, J. H., & Kim, Y. S.. (2019). Regulation of gene expression by altered promoter methylation using a CRISPR/Cas9-mediated epigenetic editing system. Scientific Reports
Plain numerical DOI: 10.1038/s41598-019-48130-3
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“Despite the increased interest in epigenetic research, its progress has been hampered by a lack of satisfactory tools to control epigenetic factors in specific genomic regions. until now, many attempts to manipulate dna methylation have been made using drugs but these drugs are not target-specific and have global effects on the whole genome. however, due to new genome editing technologies, potential epigenetic factors can now possibly be regulated in a site-specific manner. here, we demonstrate the utility of crispr/cas9 to modulate methylation at specific cpg sites and to elicit gene expression. we targeted the murine oct4 gene which is transcriptionally locked due to hypermethylation at the promoter region in nih3t3 cells. to induce site-specific demethylation at the oct4 promoter region and its gene expression, we used the crispr/cas9 knock-in and crispr/dcas9-tet1 systems. using these two approaches, we induced site-specific demethylation at the oct4 promoter and confirmed the up-regulation of oct4 expression. furthermore, we confirmed that the synergistic effect of dna demethylation and other epigenetic regulations increased the expression of oct4 significantly. based on our research, we suggest that our proven epigenetic editing methods can selectively modulate epigenetic factors such as dna methylation and have promise for various applications in epigenetics.”
Torres-Berrío, A., Issler, O., Parise, E. M., & Nestler, E. J.. (2019). Unraveling the epigenetic landscape of depression: Focus on early life stress. Dialogues in Clinical Neuroscience
Plain numerical DOI: 10.31887/DCNS.2019.21.4/enestler
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“Depression is a devastating psychiatric disorder caused by a combination of genetic predisposition and life events, mainly exposure to stress. early life stress (els) in particular is known to ‘scar’ the brain, leading to an increased susceptibility to developing depression later in life via epigenetic mechanisms. epigenetic processes lead to changes in gene expression that are not due to changes in dna sequence, but achieved via modulation of chromatin modifications, dna methylation, and noncoding rnas. here we review common epigenetic mechanisms including the enzymes that take part in reading, writing, and erasing specific epigenetic marks. we then describe recent developments in understanding how els leads to changes in the epigenome that are manifested in increased susceptibility to depression-like abnormalities in animal models. we conclude with highlighting the need for future studies that will potentially enable the utilisation of the understanding of epigenetic changes linked to els for the development of much-needed novel therapeutic strategies and biomarker discovery.”
Lau, C. M., Adams, N. M., Geary, C. D., Weizman, O. El, Rapp, M., Pritykin, Y., … Sun, J. C.. (2018). Epigenetic control of innate and adaptive immune memory. Nature Immunology
Plain numerical DOI: 10.1038/s41590-018-0176-1
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“Clonal expansion and immunological memory are hallmark features of the mammalian adaptive immune response and essential for prolonged host control of pathogens. recent work demonstrates that natural killer (nk) cells of the innate immune system also exhibit these adaptive traits during infection. here we demonstrate that differentiating and ‘memory’ nk cells possess distinct chromatin accessibility states and that their epigenetic profiles reveal a ‘poised’ regulatory program at the memory stage. furthermore, we elucidate how individual stat transcription factors differentially control epigenetic and transcriptional states early during infection. finally, concurrent chromatin profiling of the canonical cd8+ t cell response against the same infection demonstrated parallel and distinct epigenetic signatures defining nk cells and cd8+ t cells. overall, our study reveals the dynamic nature of epigenetic modifications during the generation of innate and adaptive lymphocyte memory.”
Apprato, G., Fiz, C., Fusano, I., Bergandi, L., & Silvagno, F.. (2020). Natural epigenetic modulators of vitamin D receptor. Applied Sciences (Switzerland)
Plain numerical DOI: 10.3390/APP10124096
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“Vitamin d plays an important role in every tissue due to its differentiating properties and the control of calcium homeostasis. the reversion of the epigenetic repression of the vitamin d receptor (vdr) could lead to an increased sensitivity of the cells to the beneficial activity of the hormone and could be exploited in many vitamin d-resistant diseases. in this study we analyzed the effects of three natural epigenetic modulators: sulforaphane, curcumin, and the products of the fermentative activity of probiotics. sulforaphane and curcumin are inhibitors of the dna methyltransferases (dnmt) and of the histone deacetylases (hdac); it has been demonstrated that sulforaphane and curcumin increase vdr expression in intestinal epithelial cells and in a human liver cancer cell line, respectively. the anti-inflammatory properties associated with the probiotic administration in vivo can be linked to the increased activity of intestinal vdr. butyrate, an inhibitor of hdac and a known modulator of vdr expression, is the candidate byproduct of fermentation by gut microbiome that could mediate the enhanced expression of vdr triggered by probiotics in vivo. many other natural compounds wait to be investigated and recognized as epigenetic modulators of vdr, thus opening promising therapeutic avenues for many diseases by natural means.”
Cubiles, M. D., Barroso, S., Vaquero-Sedas, M. I., Enguix, A., Aguilera, A., & Vega-Palas, M. A.. (2018). Epigenetic features of human telomeres. Nucleic Acids Research
Plain numerical DOI: 10.1093/nar/gky006
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“Although subtelomeric regions in humans are heterochromatic, the epigenetic nature of human telomeres remains controversial. this controversy might have been influenced by the confounding effect of subtelomeric regions and interstitial telomeric sequences (itss) on telomeric chromatin structure analyses. in addition, different human cell lines might carry diverse epigenetic marks at telomeres. we have developed a reliable procedure to study the chromatin structure of human telomeres independently of subtelomeres and itss. this procedure is based on the statistical analysis of multiple chip-seq experiments. we have found that human telomeres are not enriched in the heterochromatic h3k9me3 mark in most of the common laboratory cell lines, including embryonic stem cells. instead, they are labeled with h4k20me1 and h3k27ac, which might be established by p300. these results together with previously published data argue that subtelomeric heterochromatin might control human telomere functions. interestingly, u2os cells that exhibit alternative lengthening of telomeres have heterochromatic levels of h3k9me3 in their telomeres.”
Nestler, E. J., & Lüscher, C.. (2019). The Molecular Basis of Drug Addiction: Linking Epigenetic to Synaptic and Circuit Mechanisms. Neuron
Plain numerical DOI: 10.1016/j.neuron.2019.01.016
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“Here, nestler and lüscher link addiction circuits to epigenetic mechanisms that are engaged by drug exposure or reflect life experience. these molecular alterations may not only explain the basis of drug-evoked synaptic plasticity, but may also help understand individual addiction vulnerability.”
Tiwari, P. K.. (2020). Epigenetic Biomarkers in Gallbladder Cancer. Trends in Cancer
Plain numerical DOI: 10.1016/j.trecan.2020.03.003
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“Gallbladder cancer (gbc) is associated with various nongenetic and genetic factors. lack of specific and sensitive diagnostic markers has significantly impacted the mortality of this disease. here we discuss the recent discovery of epigenetic changes that show great promise as diagnostic biomarkers as well as potential therapeutic targets for gbc.”
Wang, X., & Bhandari, R. K.. (2019). DNA methylation dynamics during epigenetic reprogramming of medaka embryo. Epigenetics
Plain numerical DOI: 10.1080/15592294.2019.1605816
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“Post-fertilization epigenome reprogramming erases epigenetic marks transmitted through gametes and establishes new marks during mid-blastula stages. the mouse embryo undergoes dynamic dna methylation reprogramming after fertilization, while in zebrafish, the paternal dna methylation pattern is maintained throughout the early embryogenesis and the maternal genome is reprogrammed in a pattern similar to that of sperm during the mid-blastula transition. here, we show dna methylation dynamics in medaka embryos, the biomedical model fish, during epigenetic reprogramming of embryonic genome. the sperm genome was hypermethylated and the oocyte genome hypomethylated prior to fertilization. after fertilization, the methylation marks of sperm genome were erased within the first cell cycle and embryonic genome remained hypomethylated from the zygote until 16-cell stage. the dna methylation level gradually increased from 16-cell stage through the gastrula. the 5-hydroxymethylation (5hmc) levels showed an opposite pattern to dna methylation (5-mc). the mrna levels for dna methyltransferase (dnmt) 1 remained high in oocytes and maintained the same level through late blastula stage and was reduced thereafter. dnmt3bb.1 mrna levels increased prior to remethylation. the mrna levels for ten-eleven translocation methylcytosine dioxygenases (tet2 & tet3) were detected in sperm and embryos at cleavage stages, whereas tet1 and tet3 mrnas decreased during gastrulation. the pattern of genome methylation in medaka was identical to mammalian genome methylation but not to zebrafish. the present study suggests that a medaka embryo resets its dna methylation pattern by active demethylation and by a gradual remethylation similar to mammals.”
Foley, D. L., Craig, J. M., Morley, R., Olsson, C. J., Dwyer, T., Smith, K., & Saffery, R.. (2009). Prospects for epigenetic epidemiology. American Journal of Epidemiology
Plain numerical DOI: 10.1093/aje/kwn380
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“Epigenetic modification can mediate environmental influences on gene expression and can modulate the disease risk associated with genetic variation. epigenetic analysis therefore holds substantial promise for identifying mechanisms through which genetic and environmental factors jointly contribute to disease risk. the spatial and temporal variance in epigenetic profile is of particular relevance for developmental epidemiology and the study of aging, including the variable age at onset for many common diseases. this review serves as a general introduction to the topic by describing epigenetic mechanisms, with a focus on dna methylation; genetic and environmental factors that influence dna methylation; epigenetic influences on development, aging, and disease; and current methodology for measuring epigenetic profile. methodological considerations for epidemiologic studies that seek to include epigenetic analysis are also discussed. © the author 2009. published by the johns hopkins bloomberg school of public health. all rights reserved.”
Nguyen, H. M., Kim, M., Ralph, P. J., Marín-Guirao, L., Pernice, M., & Procaccini, G.. (2020). Stress Memory in Seagrasses: First Insight Into the Effects of Thermal Priming and the Role of Epigenetic Modifications. Frontiers in Plant Science
Plain numerical DOI: 10.3389/fpls.2020.00494
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“While thermal priming and the relative role of epigenetic modifications have been widely studied in terrestrial plants, their roles remain unexplored in seagrasses so far. here, we experimentally compared the ability of two different functional types of seagrass species, dominant in the southern hemisphere, climax species posidonia australis and pioneer species zostera muelleri, to acquire thermal-stress memory to better survive successive stressful thermal events. to this end, a two-heatwave experimental design was conducted in a mesocosm setup. findings across levels of biological organization including the molecular (gene expression), physiological (photosynthetic performances and pigments content) and organismal (growth) levels provided the first evidence of thermal priming in seagrasses. non-preheated plants suffered a significant reduction in photosynthetic capacity, leaf growth and chlorophyll a content, while preheated plants were able to cope better with the recurrent stressful event. gene expression results demonstrated significant regulation of methylation-related genes in response to thermal stress, suggesting that epigenetic modifications could play a central role in seagrass thermal stress memory. in addition, we revealed some interspecific differences in thermal responses between the two different functional types of seagrass species. these results provide the first insights into thermal priming and relative epigenetic modifications in seagrasses paving the way for more comprehensive forecasting and management of thermal stress in these marine foundation species in an era of rapid environmental change.”
Renault, S., Genty, M., Gabori, A., Boisneau, C., Esnault, C., Dugé De Bernonville, T., & Augé-Gouillou, C.. (2019). The epigenetic regulation of HsMar1, a human DNA transposon. BMC Genetics
Plain numerical DOI: 10.1186/s12863-019-0719-y
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“Background: both classes of transposable elements (dna and rna) are tightly regulated at the transcriptional level leading to the inactivation of transposition via epigenetic mechanisms. due to the high copies number of these elements, the hypothesis has emerged that their regulation can coordinate a regulatory network of genes. herein, we investigated whether transposition regulation of hsmar1, a human dna transposon, differs in presence or absence of endogenous hsmar1 copies. in the case where hsmar1 transposition is regulated, the number of repetitive dna sequences issued by hsmar1 and distributed in the human genome makes hsmar1 a good candidate to regulate neighboring gene expression by epigenetic mechanisms. results: a recombinant active hsmar1 copy was inserted in hela (human) and cho (hamster) cells and its genomic excision monitored. we show that hsmar1 excision is blocked in hela cells, whereas cho cells are competent to promote hsmar1 excision. we demonstrate that de novo hsmar1 insertions in hela cells (human) undergo rapid silencing by cytosine methylation and apposition of h3k9me3 marks, whereas de novo hsmar1 insertions in cho cells (hamster) are not repressed and enriched in h3k4me3 modifications. the overall analysis of hsmar1 endogenous copies in hela cells indicates that neither full-length endogenous inactive copies nor their inverted terminal repeats seem to be specifically silenced, and are, in contrast, devoid of epigenetic marks. finally, the setmar gene, derived from hsmar1, presents h3k4me3 modifications as expected for a human housekeeping gene. conclusions: our work highlights that de novo and old hsmar1 are not similarly regulated by epigenetic mechanisms. old hsmar1 are generally detected as lacking epigenetic marks, irrespective their localisation relative to the genes. considering the putative existence of a network associating hsmar1 old copies and setmar, two non-mutually exclusive hypotheses are proposed: active and inactive hsmar1 copies are not similarly regulated or/and regulations concern only few loci (and few genes) that cannot be detected at the whole genome level.”
Ecker, S., Pancaldi, V., Valencia, A., Beck, S., & Paul, D. S.. (2018). Epigenetic and Transcriptional Variability Shape Phenotypic Plasticity. BioEssays
Plain numerical DOI: 10.1002/bies.201700148
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“Epigenetic and transcriptional variability contribute to the vast diversity of cellular and organismal phenotypes and are key in human health and disease. in this review, we describe different types, sources, and determinants of epigenetic and transcriptional variability, enabling cells and organisms to adapt and evolve to a changing environment. we highlight the latest research and hypotheses on how chromatin structure and the epigenome influence gene expression variability. further, we provide an overview of challenges in the analysis of biological variability. an improved understanding of the molecular mechanisms underlying epigenetic and transcriptional variability, at both the intra- and inter-individual level, provides great opportunity for disease prevention, better therapeutic approaches, and personalized medicine.”
Guerrero-Bosagna, C., Morisson, M., Liaubet, L., Rodenburg, T. B., De Haas, E. N., Košťál, C. D. S., & Pitel, F.. (2018). Transgenerational epigenetic inheritance in birds. Environmental Epigenetics
Plain numerical DOI: 10.1093/eep/dvy008
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“While it has been shown that epigenetics accounts for a portion of the variability of complex traits linked to interactions with the environment, the real contribution of epigenetics to phenotypic variation remains to be assessed. in recent years, a growing number of studies have revealed that epigenetic modifications can be transmitted across generations in several animal species. numerous studies have demonstrated inter- or multi-generational effects of changing environment in birds, but very few studies have been published showing epigenetic transgenerational inheritance in these species. in this review, we mention work conducted in parent-to-offspring transmission analyses in bird species, with a focus on the impact of early stressors on behaviour. we then present recent advances in transgenerational epigenetics in birds, which involve germline linked non-mendelian inheritance, underline the advantages and drawbacks of working on birds in this field and comment on future directions of transgenerational studies in bird species.”
Fan, S. J., Sun, A. B., & Liu, L.. (2018). Epigenetic modulation during hippocampal development (Review). Biomedical Reports
Plain numerical DOI: 10.3892/br.2018.1160
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“The hippocampus is located in the limbic system and is vital in learning ability, memory formation and emotion regulation, and is associated with depression, epilepsy and mental retardation in an abnormal developmental situation. several factors have been found to modulate the development of the hippocampus, and epigenetic modification have a crucial effect in this progress. the present review summarizes the epigenetic modifications, including dna methylation, histone acetylation, and non-coding rnas, regulating all stages of hippocampal development, focusing on the growth of ammon’s horn and the dentate gyrus in humans and rodents. these modifications may significantly affect hippocampal development and health in addition to cognitive processes.”
Sher, G., Salman, N. A., Khan, A. Q., Prabhu, K. S., Raza, A., Kulinski, M., … Uddin, S.. (2020). Epigenetic and breast cancer therapy: Promising diagnostic and therapeutic applications. Seminars in Cancer Biology
Plain numerical DOI: 10.1016/j.semcancer.2020.08.009
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“The global burden of breast cancer (bc) is increasing significantly. this trend is caused by several factors such as late diagnosis, limited treatment options for certain bc subtypes, drug resistance which all lead to poor clinical outcomes. recent research has reported the role of epigenetic alterations in the mechanism of bc pathogenesis and its hallmarks include drug resistance and stemness features. the understanding of these modifications and their significance in the management of bc carcinogenesis is challenging and requires further attention. nevertheless, it promises to provide novel insight needed for utilizing these alterations as potential diagnostic, prognostic markers, predict treatment efficacy, as well as therapeutic agents. this highlights the importance of continuing research development to further advance the existing knowledge on epigenetics and bc carcinogenesis to overcome the current challenges. hence, this review aims to shed light and discuss the current state of epigenetics research in the diagnosis and management of bc.”
Ross, K. M., Carroll, J. E., Horvath, S., Hobel, C. J., Coussons-Read, M. E., & Dunkel Schetter, C.. (2020). Epigenetic age and pregnancy outcomes: GrimAge acceleration is associated with shorter gestational length and lower birthweight. Clinical Epigenetics
Plain numerical DOI: 10.1186/s13148-020-00909-2
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“Background: advanced biological aging, as measured by epigenetic aging indices, is associated with early mortality and morbidity. associations between maternal epigenetic aging indices in pregnancy and pregnancy outcomes, namely gestational length and birthweight, have not been assessed. the purpose of this study was to examine whether epigenetic age during pregnancy was associated with gestational length and birthweight. results: the sample consisted of 77 women from the los angeles, ca, area enrolled in the healthy babies before birth study. whole blood samples for dna methylation assay were obtained during the second trimester (15.6 ± 2.15 weeks gestation). epigenetic age indices grimage acceleration (grimageaccel), dnam pai-1, dnam adm, and dnam cystatin c were calculated. gestational length and birthweight were obtained from medical chart review. covariates were maternal sociodemographic variables, gestational age at blood sample collection, and pre-pregnancy body mass index. in separate covariate-adjusted linear regression models, higher early second trimester grimageaccel, b(se) = -.171 (.056), p =.004; dnam pai-1, b(se) = – 1.95 × 10-4 (8.5 × 10-5), p =.004; dnam adm, b(se) = -.033 (.011), p =.003; and dnam cystatin c, b(se) = 2.10 × 10-5 (8.0 × 10-5), p =.012, were each associated with shorter gestational length. higher grimageaccel, b(se) = – 75.2 (19.7), p <.001; dnam pai-1, b(se) = -.079(.031), p =.013; dnam adm, b(se) = - 13.8 (3.87), p =.001; and dnam cystatin c, b(se) = -.010 (.003), p =.001, were also associated with lower birthweight, independent of gestational length. discussion: higher maternal prenatal grimageaccel, dnam pai-1, dnam adm, and dnam cystatin c were associated with shorter gestational length and lower birthweight. these findings suggest that biological age, as measured by these epigenetic indices, could indicate risk for adverse pregnancy outcomes.”
Farooqi, A. A., Fuentes-Mattei, E., Fayyaz, S., Raj, P., Goblirsch, M., Poltronieri, P., & Calin, G. A.. (2019). Interplay between epigenetic abnormalities and deregulated expression of microRNAs in cancer. Seminars in Cancer Biology
Plain numerical DOI: 10.1016/j.semcancer.2019.02.003
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“Epigenetic abnormalities and aberrant expression of non-coding rnas are two emerging features of cancer cells, both of which are responsible for deregulated gene expression. in this review, we describe the interplay between the two. specific themes include epigenetic silencing of tumor suppressor mirnas, epigenetic activation of oncogenic mirnas, epigenetic aberrations caused by mirnas, and naturally occurring compounds which modulate mirna expression through epigenetic mechanisms.”
Kamińska, K., Nalejska, E., Kubiak, M., Wojtysiak, J., Żołna, Ł., Kowalewski, J., & Lewandowska, M. A.. (2019). Prognostic and Predictive Epigenetic Biomarkers in Oncology. Molecular Diagnosis and Therapy
Plain numerical DOI: 10.1007/s40291-018-0371-7
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“Epigenetic patterns, such as dna methylation, histone modifications, and non-coding rnas, can be both driver factors and characteristic features of certain malignancies. aberrant dna methylation can lead to silencing of crucial tumor suppressor genes or upregulation of oncogene expression. histone modifications and chromatin spatial organization, which affect transcription, regulation of gene expression, dna repair, and replication, have been associated with multiple tumors. certain micrornas (mirnas), mainly those that silence tumor suppressor genes and occur in a greater number of copies, have also been shown to promote oncogenesis. multiple patterns of these epigenetic factors occur specifically in certain malignancies, which allows their potential use as biomarkers. this review presents examples of tests for each group of epigenetic factors that are currently available or in development for use in early cancer detection, prediction, prognosis, and response to treatment. the availability of blood-based biomarkers is noted, as they allow sampling invasiveness to be reduced and the sampling procedure to be simplified. the article stresses the role of epigenetics as a crucial element of future cancer diagnostics and therapy.”
Slatkin, M.. (2009). Epigenetic inheritance and the missing heritability problem. Genetics
Plain numerical DOI: 10.1534/genetics.109.102798
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“Epigenetic phenomena, and in particular heritable epigenetic changes, or transgenerational effects, are the subject of much discussion in the current literature. this article presents a model of transgenerational epigenetic inheritance and explores the effect of epigenetic inheritance on the risk and recurrence risk of a complex disease. the model assumes that epigenetic modifications of the genome are gained and lost at specified rates and that each modification contributes multiplicatively to disease risk. the potentially high rate of loss of epigenetic modifications causes the probability of identity in state in close relatives to be smaller than is implied by their relatedness. as a consequence, the recurrence risk to close relatives is reduced. although epigenetic modifications may contribute substantially to average risk, they will not contribute much to recurrence risk and heritability unless they persist on average for many generations. if they do persist for long times, they are equivalent to mutations and hence are likely to be in linkage disequilibrium with snps surveyed in genomewide association studies. thus epigenetic modifications are a potential solution to the problem of missing causality of complex diseases but not to the problem of missing heritability. the model highlights the need for empirical estimates of the persistence times of heritable epialleles. copyright © 2009 by the genetics society of america.”
Bhattacharjee, S., & Dashwood, R. H.. (2020). Epigenetic regulation of NRF2/KEAP1 by phytochemicals. Antioxidants
Plain numerical DOI: 10.3390/antiox9090865
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“Epigenetics has provided a new dimension to our understanding of nuclear factor erythroid 2–related factor 2/kelch-like ech-associated protein 1 (human nrf2/keap1 and murine nrf2/keap1) signaling. unlike the genetic changes affecting dna sequence, the reversible nature of epigenetic alterations provides an attractive avenue for cancer interception. thus, targeting epigenetic mechanisms in the corresponding signaling networks represents an enticing strategy for therapeutic intervention with dietary phytochemicals acting at transcriptional, post-transcriptional, and post-translational levels. this regulation involves the interplay of histone modifications and dna methylation states in the human nfe2l2/keap1 and murine nfe2l2/keap1 genes, acetylation of lysine residues in nrf2 and nrf2, interaction with bromodomain and extraterminal domain (bet) acetyl ‘reader’ proteins, and non-coding rnas such as microrna (mirna) and long noncoding rna (lncrna). phytochemicals documented to modulate nrf2 signaling act by reversing hypermethylated states in the cpg islands of nfe2l2 or nfe2l2, via the inhibition of dna methyltransferases (dnmts) and histone deacetylases (hdacs), through the induction of ten-eleven translocation (tet) enzymes, or by inducing mirna to target the 3′-utr of the corresponding mrna transcripts. to date, fewer than twenty phytochemicals have been reported as nrf2 epigenetic modifiers, including curcumin, sulforaphane, resveratrol, reserpine, and ursolic acid. this opens avenues for exploring additional dietary phytochemicals that regulate the human epigenome, and the potential for novel strategies to target nrf2 signaling with a view to beneficial interception of cancer and other chronic diseases.”
Conboy, K., Henshall, D. C., & Brennan, G. P.. (2021). Epigenetic principles underlying epileptogenesis and epilepsy syndromes. Neurobiology of Disease
Plain numerical DOI: 10.1016/j.nbd.2020.105179
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“Epilepsy is a network disorder driven by fundamental changes in the function of the cells which compose these networks. driving this aberrant cellular function are large scale changes in gene expression and gene expression regulation. recent studies have revealed rapid and persistent changes in epigenetic control of gene expression as a critical regulator of the epileptic transcriptome. epigenetic-mediated gene output regulates many aspects of cellular physiology including neuronal structure, neurotransmitter assembly and abundance, protein abundance of ion channels and other critical neuronal processes. thus, understanding the contribution of epigenetic-mediated gene regulation could illuminate novel regulatory mechanisms which may form the basis of novel therapeutic approaches to treat epilepsy. in this review we discuss the effects of epileptogenic brain insults on epigenetic regulation of gene expression, recent efforts to target epigenetic processes to block epileptogenesis and the prospects of an epigenetic-based therapy for epilepsy, and finally we discuss technological advancements which have facilitated the interrogation of the epigenome.”
Patnaik, S., & Anupriya. (2019). Drugs targeting epigenetic modifications and plausible therapeutic strategies against colorectal cancer. Frontiers in Pharmacology
Plain numerical DOI: 10.3389/fphar.2019.00588
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“Genetic variations along with epigenetic modifications of dna are involved in colorectal cancer (crc) development and progression. crc is the fourth leading cause of cancer-related deaths worldwide. initiation and progression of crc is the cumulation of a variety of genetic and epigenetic changes in colonic epithelial cells. colorectal carcinogenesis is associated with epigenetic aberrations including dna methylation, histone modifications, chromatin remodeling, and non-coding rnas. recently, epigenetic modifications have been identified like association of hypermethylated gene claudin11 (cldn11) with metastasis and prognosis of poor survival of crc. dna methylation of genes cmtm3, sstr2, mdf1, ndrg4 and tgfb2 are potential epigenetic biomarkers for the early detection of crc. tumor suppressor candidate 3 (tusc3) mrna expression is silenced by promoter methylation, which promotes epidermal growth factor receptor (egfr) signaling and rescues the crc cells from apoptosis and hence leading to poor survival rate. previous scientific evidences strongly suggest epigenetic modifications that contribute to anticancer drug resistance. recent research studies emphasize development of drugs targeting histone deacetylases (hdacs) and dna methyltransferase inhibitors as an emerging anticancer strategy. this review covers potential epigenetic modification targeting chemotherapeutic drugs and probable implementation for the treatment of crc, which offers a strong rationale to explore therapeutic strategies and provides a basis to develop potent antitumor drugs.”
Dodson, A. E., & Kennedy, S.. (2019). Germ Granules Coordinate RNA-Based Epigenetic Inheritance Pathways. Developmental Cell
Plain numerical DOI: 10.1016/j.devcel.2019.07.025
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“Germ granules are biomolecular condensates that promote germ cell totipotency in animals. in c. elegans, meg-3 and meg-4 function redundantly to assemble germ granules in germline blastomeres. here, we show that meg-3/4 mutant animals exhibit defects in rna interference (rnai) that are transgenerationally disconnected from the meg-3/4 genotype. similar non-mendelian inheritance is associated with other mutations disrupting germ granule formation, indicating that loss of germ granules is the likely cause of the observed disconnects between genotype and phenotype. meg-3/4 animals produce aberrant sirnas that are propagated for ≅10 generations in wild-type descendants of meg-3/4 ancestors. aberrant sirnas inappropriately and heritably silence germline-expressed genes including the rnai gene sid-1, suggesting that transgenerational silencing of sid-1 underlies inherited defects in rnai. we conclude that one function of germ granules is to organize rna-based epigenetic inheritance pathways and that germ granule loss has consequences that persist for many generations. parentally deposited small non-coding rnas direct heritable gene regulation in the c. elegans germline. dodson and kennedy provide evidence that biomolecular condensates known as germ granules spatially organize these small rna-based epigenetic inheritance pathways. disrupting germ granules triggers changes in small-rna-based gene regulation that can be inherited across generations.”
Ling, C., & Rönn, T.. (2019). Epigenetics in Human Obesity and Type 2 Diabetes. Cell Metabolism
Plain numerical DOI: 10.1016/j.cmet.2019.03.009
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“Epigenetic mechanisms control gene activity and the development of an organism. the epigenome includes dna methylation, histone modifications, and rna-mediated processes, and disruption of this balance may cause several pathologies and contribute to obesity and type 2 diabetes (t2d). this review summarizes epigenetic signatures obtained from human tissues of relevance for metabolism—i.e., adipose tissue, skeletal muscle, pancreatic islets, liver, and blood—in relation to obesity and t2d. although this research field is still young, these comprehensive data support not only a role for epigenetics in disease development, but also epigenetic alterations as a response to disease. genetic predisposition, as well as aging, contribute to epigenetic variability, and several environmental factors, including exercise and diet, further interact with the human epigenome. the reversible nature of epigenetic modifications holds promise for future therapeutic strategies in obesity and t2d. epigenetic factors are suggested to contribute to metabolic dysfunctions. in this review, ling and rönn summarize evidence for altered dna methylation, both as a cause and a consequence of human obesity and type 2 diabetes. as epigenetic alterations are dynamic in nature, they may also provide targets for drug development.”
Banik, A., Kandilya, D., Ramya, S., Stünkel, W., Chong, Y. S., & Thameem Dheen, S.. (2017). Maternal factors that induce epigenetic changes contribute to neurological disorders in offspring. Genes
Plain numerical DOI: 10.3390/genes8060150
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“It is well established that the regulation of epigenetic factors, including chromatic reorganization, histone modifications, dna methylation, and mirna regulation, is critical for the normal development and functioning of the human brain. there are a number of maternal factors influencing epigenetic pathways such as lifestyle, including diet, alcohol consumption, and smoking, as well as age and infections (viral or bacterial). genetic and metabolic alterations such as obesity, gestational diabetes mellitus (gdm), and thyroidism alter epigenetic mechanisms, thereby contributing to neurodevelopmental disorders (nds) such as embryonic neural tube defects (ntds), autism, down’s syndrome, rett syndrome, and later onset of neuropsychological deficits. this review comprehensively describes the recent findings in the epigenetic landscape contributing to altered molecular profiles resulting in nds. furthermore, we will discuss potential avenues for future research to identify diagnostic markers and therapeutic epi-drugs to reverse these abnormalities in the brain as epigenetic marks are plastic and reversible in nature.”
Dandri, M.. (2020). Epigenetic modulation in chronic hepatitis B virus infection. Seminars in Immunopathology
Plain numerical DOI: 10.1007/s00281-020-00780-6
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“The human hepatitis b virus (hbv) is a small-enveloped dna virus causing acute and chronic hepatitis. despite the existence of an effective prophylactic vaccine and the strong capacity of approved antiviral drugs to suppress viral replication, chronic hbv infection (chb) continues to be a major health burden worldwide. both the inability of the immune system to resolve chb and the unique replication strategy employed by hbv, which forms a stable viral covalently closed circular dna (cccdna) minichromosome in the hepatocyte nucleus, enable infection persistence. knowledge of the complex network of interactions that hbv engages with its host is still limited but accumulating evidence indicates that epigenetic modifications occurring both on the cccdna and on the host genome in the course of infection are essential to modulate viral activity and likely contribute to pathogenesis and cancer development. thus, a deeper understanding of epigenetic regulatory processes may open new venues to control and eventually cure chb. this review summarizes major findings in hbv epigenetic research, focusing on the epigenetic mechanisms regulating cccdna activity and the modifications determined in infected host cells and tumor liver tissues.”
Zhao, Y., Chen, Y., Jin, M., & Wang, J.. (2021). The crosstalk between m6A RNA methylation and other epigenetic regulators: A novel perspective in epigenetic remodeling. Theranostics
Plain numerical DOI: 10.7150/THNO.54967
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“Epigenetic regulation involves a range of sophisticated processes which contribute to heritable alterations in gene expression without altering dna sequence. regulatory events predominantly include dna methylation, chromatin remodeling, histone modifications, non-coding rnas (ncrnas), and rna modification. as the most prevalent rna modification in eukaryotic cells, n6-methyladenosine (m6a) rna methylation actively participates in the modulation of rna metabolism. notably, accumulating evidence has revealed complicated interrelations occurring between m6a and other well-known epigenetic modifications. their crosstalk conspicuously triggers epigenetic remodeling, further yielding profound impacts on a variety of physiological and pathological processes, especially tumorigenesis. herein, we provide an up-to-date review of this emerging hot area of biological research, summarizing the interplay between m6a rna methylation and other epigenetic regulators, and highlighting their underlying functions in epigenetic reprogramming.”
Li, F., Huang, Q., Luster, T. A., Hu, H., Zhang, H., Ng, W. L., … Wong, K. K.. (2020). In vivo epigenetic crispr screen identifies asf1a as an immunotherapeutic target in kras-mutant lung adenocarcinoma. Cancer Discovery
Plain numerical DOI: 10.1158/2159-8290.CD-19-0780
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“Despite substantial progress in lung cancer immunotherapy, the overall response rate in patients with kras-mutant lung adenocarcinoma (luad) remains low. com-bining standard immunotherapy with adjuvant approaches that enhance adaptive immune responses— such as epigenetic modulation of antitumor immunity—is therefore an attractive strategy. to identify epigenetic regulators of tumor immunity, we constructed an epigenetic-focused single guide rna library and performed an in vivo crispr screen in a krasg12d/trp53−/− luad model. our data showed that loss of the histone chaperone asf1a in tumor cells sensitizes tumors to anti–pd-1 treatment. mechanistic studies revealed that tumor cell–intrinsic asf1a deficiency induced immunogenic macrophage differentiation in the tumor microenvironment by upregulating gm-csf expression and poten-tiated t-cell activation in combination with anti–pd-1. our results provide a rationale for a novel combination therapy consisting of asf1a inhibition and anti–pd-1 immunotherapy. significance: using an in vivo epigenetic crispr screen, we identified asf1a as a critical regulator of luad sensitivity to anti–pd-1 therapy. asf1a deficiency synergized with anti–pd-1 immunotherapy by promoting m1-like macrophage polarization and t-cell activation. thus, we provide a new immunotherapeutic strategy for this subtype of patients with luad.”
Tomasetti, M., Gaetani, S., Monaco, F., Neuzil, J., & Santarelli, L.. (2019). Epigenetic Regulation of miRNA Expression in Malignant Mesothelioma: miRNAs as Biomarkers of Early Diagnosis and Therapy. Frontiers in Oncology
Plain numerical DOI: 10.3389/fonc.2019.01293
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“Asbestos exposure leads to epigenetic and epigenomic modifications that, in association with ros-induced dna damage, contribute to cancer onset. few mirnas epigenetically regulated in mm have been described in literature; mir-126, however, is one of them, and its expression is regulated by epigenetic mechanisms. asbestos exposure induces early changes in the mirnas, which are reversibly expressed as protective species, and their inability to reverse reflects the inability of the cells to restore the physiological mirna levels despite the cessation of carcinogen exposure. changes in mirna expression, which results from genetic/epigenetic changes during tumor formation and evolution, can be detected in fluids and used as cancer biomarkers. this article has reviewed the epigenetic mechanisms involved in mirna expression in mm, focusing on their role as biomarkers of early diagnosis and therapeutic effects.”
Gusyatiner, O., & Hegi, M. E.. (2018). Glioma epigenetics: From subclassification to novel treatment options. Seminars in Cancer Biology
Plain numerical DOI: 10.1016/j.semcancer.2017.11.010
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“Gliomas are the most common malignant primary brain tumors, of which glioblastoma is the most malignant form (who grade iv), and notorious for treatment resistance. over the last decade mutations in epigenetic regulator genes have been identified as key drivers of subtypes of gliomas with distinct clinical features. most characteristic are mutations in idh1 or idh2 in lower grade gliomas, and histone 3 mutations in pediatric high grade gliomas that are also associated with characteristic dna methylation patterns. furthermore, in adult glioblastoma patients epigenetic silencing of the dna repair gene mgmt by promoter methylation is predictive for benefit from alkylating agent therapy. these epigenetic alterations are used as biomarkers and play a central role for classification of gliomas (who 2016) and treatment decisions. here we review the pivotal role of epigenetic alterations in the etiology and biology of gliomas. we summarize the complex interactions between ‘driver’ mutations, dna methylation, histone post-translational modifications, and overall chromatin organization, and how they inform current efforts of testing epigenetic compounds and combinations in preclinical and clinical studies.”
Cossío, F. P., Esteller, M., & Berdasco, M.. (2020). Towards a more precise therapy in cancer: Exploring epigenetic complexity. Current Opinion in Chemical Biology
Plain numerical DOI: 10.1016/j.cbpa.2020.04.008
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“A plethora of preclinical evidences suggests that pharmacological targeting of epigenetic dysregulation is a potent strategy to combat human diseases. nevertheless, the implementation of epidrugs in clinical practice is very scarce and mainly limited to haematological malignancies. in this review, we discuss cutting-edge strategies to foster the chemical design, the biological rationale and the clinical trial development of epidrugs. specifically, we focus on the development of dual hybrids to exploit multitargeting of key epigenetic molecules deregulated in cancer; the study of epigenetic-synthetic lethality interactions as a mechanism to address loss-of-function mutations, and the combination of epidrugs with other therapies such as immunotherapy to avoid acquired chemoresistance and increase therapy sensitivity. by exploring these challenges, among others, the field of epigenetic chemical biology will increase its potential for clinical benefit, and more effective strategies targeting the aberrant epigenome in cancer are likely to be developed both in haematological and solid tumours.”
Bellanti, J. A.. (2020). Epigenetic studies and pediatric research. Pediatric Research
Plain numerical DOI: 10.1038/s41390-019-0644-9
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“The 2020 annual review issue, ‘preventing disease in the 21st century’ was selected by the editors-in-chief of pediatric research to include a variety of disease entities that confront health-care practitioners entrusted to the care of infants and children. in keeping with this mandate, this article reviews the subject of epigenetics, which impacts pediatric research from bench to bedside. epigenetic mechanisms exert their effects through the interaction of environment, various susceptibility genes, and immunologic development and include: (1) dna methylation; (2) posttranslational modifications of histone proteins through acetylation and methylation, and (3) rna-mediated gene silencing by microrna (mirna) regulation. the effects of epigenetics during fetal life and early periods of development are first reviewed together with clinical applications of cardiovascular and metabolic disorders in later life. the relationships of epigenetics to the allergic and autoimmune diseases and cancer are next reviewed. a specific focus of the article is directed to the recent recognition that many of these disorders are driven by aberrant immune responses in which immunoregulatory events are often poorly functioning and where through interventive epigenetic measures prevention may be possible by alterations in programming of dna during fetal and early periods as well as in later life.”
Nestler, E. J.. (2016). Transgenerational Epigenetic Contributions to Stress Responses: Fact or Fiction?. PLoS Biology
Plain numerical DOI: 10.1371/journal.pbio.1002426
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“There has been increasing interest in the possibility that behavioral experience—in particular, exposure to stress—can be passed on to subsequent generations through heritable epigenetic modifications. the possibility remains highly controversial, however, reflecting the lack of standardized definitions of epigenetics and the limited empirical support for potential mechanisms of transgenerational epigenetic inheritance. nonetheless, growing evidence supports a role for epigenetic regulation as a key mechanism underlying lifelong regulation of gene expression that mediates stress vulnerability. this perspective provides an overview of the multiple meanings of the term epigenetic, discusses the challenges of studying epigenetic contributions to stress susceptibility—and the experimental evidence for and against the existence of such mechanisms—and outlines steps required for future investigations.”
Huang, H., Ullah, F., Zhou, D. X., Yi, M., & Zhao, Y.. (2019). Mechanisms of ROS regulation of plant development and stress responses. Frontiers in Plant Science
Plain numerical DOI: 10.3389/fpls.2019.00800
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“Plants are subjected to various environmental stresses throughout their life cycle. reactive oxygen species (ros) play important roles in maintaining normal plant growth, and improving their tolerance to stress. this review describes the production and removal of ros in plants, summarizes recent progress in understanding the role of ros during plant vegetative apical meristem development, organogenesis, and abiotic stress responses, and some novel findings in recent years are discussed. more importantly, interplay between ros and epigenetic modifications in regulating gene expression is specifically discussed. to summarize, plants integrate ros with genetic, epigenetic, hormones and external signals to promote development and environmental adaptation.”
Wise, I. A., & Charchar, F. J.. (2016). Epigenetic modifications in essential hypertension. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms17040451
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“Essential hypertension (eh) is a complex, polygenic condition with no single causative agent. despite advances in our understanding of the pathophysiology of eh, hypertension remains one of the world’s leading public health problems. furthermore, there is increasing evidence that epigenetic modifications are as important as genetic predisposition in the development of eh. indeed, a complex and interactive genetic and environmental system exists to determine an individual’s risk of eh. epigenetics refers to all heritable changes to the regulation of gene expression as well as chromatin remodelling, without involvement of nucleotide sequence changes. epigenetic modification is recognized as an essential process in biology, but is now being investigated for its role in the development of specific pathologic conditions, including eh. epigenetic research will provide insights into the pathogenesis of blood pressure regulation that cannot be explained by classic mendelian inheritance. this review concentrates on epigenetic modifications to dna structure, including the influence of non-coding rnas on hypertension development.”
Saeed, S., Quintin, J., Kerstens, H. H. D., Rao, N. A., Aghajanirefah, A., Matarese, F., … Stunnenberg, H. G.. (2014). Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity. Science
Plain numerical DOI: 10.1126/science.1251086
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“Monocyte differentiation into macrophages represents a cornerstone process for host defense. concomitantly, immunological imprinting of either tolerance or trained immunity determines the functional fate of macrophages and susceptibility to secondary infections. we characterized the transcriptomes and epigenomes in four primary cell types: monocytes and in vitro-differentiated naïve, tolerized, and trained macrophages. inflammatory and metabolic pathways were modulated in macrophages, including decreased inflammasome activation, and we identified pathways functionally implicated in trained immunity, ß-glucan training elicits an exclusive epigenetic signature, revealing a complex network of enhancers and promoters. analysis of transcription factor motifs in deoxyribonuclease i hypersensitive sites at cell-type-specific epigenetic loci unveiled differentiation and treatment-specific repertoires. altogether, we provide a resource to understand the epigenetic changes that underlie innate immunity in humans.”
Fetahu, I. S., Ma, D., Rabidou, K., Argueta, C., Smith, M., Liu, H., … Shi, Y. G.. (2019). Epigenetic signatures of methylated DNA cytosine in Alzheimer’s disease. Science Advances
Plain numerical DOI: 10.1126/sciadv.aaw2880
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“Alzheimer’s disease (ad), a progressive neurodegenerative disorder, is the most common untreatable form of dementia. identifying molecular biomarkers that allow early detection remains a key challenge in the diagnosis, treatment, and prognostic evaluation of the disease. here, we report a novel experimental and analytical model characterizing epigenetic alterations during ad onset and progression. we generated the first integrated base-resolution genome-wide maps of the distribution of 5-methyl-cytosine (5mc), 5-hydroxymethyl-cytosine (5hmc), and 5-formyl/carboxy-cytosine (5fc/cac) in normal and ad neurons. we identified 27 ad region–specific and 39 cpg site–specific epigenetic signatures that were independently validated across our familial and sporadic ad models, and in an independent clinical cohort. thus, our work establishes a new model and strategy to study the epigenetic alterations underlying ad onset and progression and provides a set of highly reliable ad-specific epigenetic signatures that may have early diagnostic and prognostic implications.”
Hervouet, E., Cartron, P. F., Jouvenot, M., & Delage-Mourroux, R.. (2013). Epigenetic regulation of estrogen signaling in breast cancer. Epigenetics
Plain numerical DOI: 10.4161/epi.23790
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“Estrogen signaling is mediated by erα and erβ in hormone dependent breast cancer (bc). over the last decade the implication of epigenetic pathways in bc tumorigenesis has emerged: cancer-related epigenetic modifications are implicated in both gene expression regulation and chromosomal instability. in this review, the epigenetic-mediated estrogen signaling, controlling both er level and er-targeted gene expression in bc, are discussed: (1) er silencing is frequently observed in bc and is often associated with epigenetic regulations while chemical epigenetic modulators restore er expression and increase response to treatment; (2) er-targeted gene expression is tightly regulated by co-recruitment of er and both co-activators/co-repressors including hats, hdacs, hmts, dnmts and polycomb proteins. © 2013 landes bioscience.”
Reale, M.. (2021). Annual Report 2020. AIMS Allergy and Immunology
Plain numerical DOI: 10.3934/allergy.2021003
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“A growing body of evidence points towards epigenetic mechanisms being responsible for a wide range of biological phenomena, from the plasticity of plant growth and development to the nutritional control of caste determination in honeybees and the etiology of human disease (e.g., cancer). with the (partial) elucidation of the molecular basis of epigenetic variation and the heritability of certain of these changes, the field of evolutionary epigenetics is flourishing. despite this, the role of epigenetics in shaping host–pathogen interactions has received comparatively little attention. yet there is plenty of evidence supporting the implication of epigenetic mechanisms in the modulation of the biological interaction between hosts and pathogens. the phenotypic plasticity of many key parasite life-history traits appears to be under epigenetic control. moreover, pathogen-induced effects in host phenotype may have transgenerational consequences, and the bases of these changes and their heritability probably have an epigenetic component. the significance of epigenetic modifications may, however, go beyond providing a mechanistic basis for host and pathogen plasticity. epigenetic epidemiology has recently emerged as a promising area for future research on infectious diseases. in addition, the incorporation of epigenetic inheritance and epigenetic plasticity mechanisms to evolutionary models and empirical studies of host–pathogen interactions will provide new insights into the evolution and coevolution of these associations. here, we review the evidence available for the role epigenetics on host–pathogen interactions, and the utility and versatility of the epigenetic technologies available that can be cross-applied to host–pathogen studies. we conclude with recommendations and directions for future research on the burgeoning field of epigenetics as applied to host–pathogen interactions.”
Ilango, S., Paital, B., Jayachandran, P., Padma, P. R., & Nirmaladevi, R.. (2020). Epigenetic alterations in cancer. Frontiers in Bioscience – Landmark
Plain numerical DOI: 10.2741/4847
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“Genetic and epigenetic modifications in dna contribute to altered gene expression in aging and cancer. in human cancers, epigenetic changes such as dna methylation, histone modifications, micro rnas and nucleosome remodelling all control gene expression. the link between the genetics and epigenetics in cancer is further shown by existence of aberrant metabolism and biochemical pathways in cancer or mutation in genes that are epigenetic players. reversal of these epigenetic changes has been clearly shown to have therapeutic value in various forms of lymphoma and preleukemia and similar results are appearing for the treatment of solid tumors. in this review, we discuss the functional effects of epigenetic changes inducible by hypoxia, the epigenetic alterations in cancer and how they contribute to tumor progression and their relevance to epigenetic therapy.”
Ivanov, M., Barragan, I., & Ingelman-Sundberg, M.. (2014). Epigenetic mechanisms of importance for drug treatment. Trends in Pharmacological Sciences
Plain numerical DOI: 10.1016/j.tips.2014.05.004
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“There are pronounced interindividual variations in drug metabolism, drug responses, and the incidence of adverse drug reactions. to a certain extent such variability can be explained by genetic factors, but epigenetic modifications, which are relatively scarcely described so far, also contribute. it is known that a novel class of drugs termed epidrugs intervene in the epigenetic control of gene expression, and many of these are now in clinical trials for disease treatment. in addition, disease prognosis and drug treatment success can be monitored using epigenetic biomarkers. here we review these novel aspects in pharmacology and address intriguing future opportunities for gene-specific epigenetic editing. © 2014 elsevier ltd.”
Fang, H., Disteche, C. M., & Berletch, J. B.. (2019). X Inactivation and Escape: Epigenetic and Structural Features. Frontiers in Cell and Developmental Biology
Plain numerical DOI: 10.3389/fcell.2019.00219
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“X inactivation represents a complex multi-layer epigenetic mechanism that profoundly modifies chromatin composition and structure of one x chromosome in females. the heterochromatic inactive x chromosome adopts a unique 3d bipartite structure and a location close to the nuclear periphery or the nucleolus. x-linked lncrna loci and their transcripts play important roles in the recruitment of proteins that catalyze chromatin and dna modifications for silencing, as well as in the control of chromatin condensation and location of the inactive x chromosome. a subset of genes escapes x inactivation, raising questions about mechanisms that preserve their expression despite being embedded within heterochromatin. escape gene expression differs between males and females, which can lead to physiological sex differences. we review recent studies that emphasize challenges in understanding the role of lncrnas in the control of epigenetic modifications, structural features and nuclear positioning of the inactive x chromosome. second, we highlight new findings about the distribution of genes that escape x inactivation based on single cell studies, and discuss the roles of escape genes in eliciting sex differences in health and disease.”
Apprato, G., Fiz, C., Fusano, I., Bergandi, L., & Silvagno, F.. (2020). Natural epigenetic modulators of vitamin D receptor. Applied Sciences (Switzerland)
Plain numerical DOI: 10.3390/APP10124096
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“Vitamin d plays an important role in every tissue due to its differentiating properties and the control of calcium homeostasis. the reversion of the epigenetic repression of the vitamin d receptor (vdr) could lead to an increased sensitivity of the cells to the beneficial activity of the hormone and could be exploited in many vitamin d-resistant diseases. in this study we analyzed the effects of three natural epigenetic modulators: sulforaphane, curcumin, and the products of the fermentative activity of probiotics. sulforaphane and curcumin are inhibitors of the dna methyltransferases (dnmt) and of the histone deacetylases (hdac); it has been demonstrated that sulforaphane and curcumin increase vdr expression in intestinal epithelial cells and in a human liver cancer cell line, respectively. the anti-inflammatory properties associated with the probiotic administration in vivo can be linked to the increased activity of intestinal vdr. butyrate, an inhibitor of hdac and a known modulator of vdr expression, is the candidate byproduct of fermentation by gut microbiome that could mediate the enhanced expression of vdr triggered by probiotics in vivo. many other natural compounds wait to be investigated and recognized as epigenetic modulators of vdr, thus opening promising therapeutic avenues for many diseases by natural means.”
Horvath, S., Pirazzini, C., Bacalini, M. G., Gentilini, D., Di Blasio, A. M., Delledonne, M., … Franceschi, C.. (2015). Decreased epigenetic age of PBMCs from Italian semi-supercentenarians and their offspring. Aging
Plain numerical DOI: 10.18632/aging.100861
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“Given the dramatic increase in ageing populations, it is of great importance to understand the genetic and molecular determinants of healthy ageing and longevity. semi-supercentenarians (subjects who reached an age of 105-109 years) arguably represent the gold standard of successful human ageing because they managed to avoid or postpone the onset of major age-related diseases. relatively few studies have looked at epigenetic determinants of extreme longevity in humans. here we test whether families with extreme longevity are epigenetically distinct from controls according to an epigenetic biomarker of ageing which is known as ‘epigenetic clock’. we analyze the dna methylation levels of peripheral blood mononuclear cells (pbmcs) from italian families constituted of 82 semi-supercentenarians (mean age: 105.6 ± 1.6 years), 63 semi-supercentenarians’ offspring (mean age: 71.8 ± 7.8 years), and 47 age-matched controls (mean age: 69.8 ± 7.2 years). we demonstrate that the offspring of semi-supercentenarians have a lower epigenetic age than age-matched controls (age difference=5.1 years, p=0.00043) and that centenarians are younger (8.6 years) than expected based on their chronological age. by contrast, no significant difference could be observed for estimated blood cell counts (such as naïve or exhausted cytotoxic t cells or helper t cells). future studies will be needed to replicate these findings in different populations and to extend them to other tissues. overall, our results suggest that epigenetic processes might play a role in extreme longevity and healthy human ageing.”
Yu, C. C., Jiang, T., Yang, A. F., Du, Y. J., Wu, M., & Kong, L. H.. (2019). Epigenetic modulation on tau phosphorylation in Alzheimer’s disease. Neural Plasticity
Plain numerical DOI: 10.1155/2019/6856327
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“Tau hyperphosphorylation is a typical pathological change in alzheimer’s disease (ad) and is involved in the early onset and progression of ad. epigenetic modification refers to heritable alterations in gene expression that are not caused by direct changes in the dna sequence of the gene. epigenetic modifications, such as noncoding rna regulation, dna methylation, and histone modification, can directly or indirectly affect the regulation of tau phosphorylation, thereby participating in ad development and progression. this review summarizes the current research progress on the mechanisms of epigenetic modification associated with tau phosphorylation.”
Hervouet, E., Cartron, P. F., Jouvenot, M., & Delage-Mourroux, R.. (2013). Epigenetic regulation of estrogen signaling in breast cancer. Epigenetics
Plain numerical DOI: 10.4161/epi.23790
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“Estrogen signaling is mediated by erα and erβ in hormone dependent breast cancer (bc). over the last decade the implication of epigenetic pathways in bc tumorigenesis has emerged: cancer-related epigenetic modifications are implicated in both gene expression regulation and chromosomal instability. in this review, the epigenetic-mediated estrogen signaling, controlling both er level and er-targeted gene expression in bc, are discussed: (1) er silencing is frequently observed in bc and is often associated with epigenetic regulations while chemical epigenetic modulators restore er expression and increase response to treatment; (2) er-targeted gene expression is tightly regulated by co-recruitment of er and both co-activators/co-repressors including hats, hdacs, hmts, dnmts and polycomb proteins. © 2013 landes bioscience.”
Nestler, E. J.. (2016). Transgenerational Epigenetic Contributions to Stress Responses: Fact or Fiction?. PLoS Biology
Plain numerical DOI: 10.1371/journal.pbio.1002426
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“There has been increasing interest in the possibility that behavioral experience—in particular, exposure to stress—can be passed on to subsequent generations through heritable epigenetic modifications. the possibility remains highly controversial, however, reflecting the lack of standardized definitions of epigenetics and the limited empirical support for potential mechanisms of transgenerational epigenetic inheritance. nonetheless, growing evidence supports a role for epigenetic regulation as a key mechanism underlying lifelong regulation of gene expression that mediates stress vulnerability. this perspective provides an overview of the multiple meanings of the term epigenetic, discusses the challenges of studying epigenetic contributions to stress susceptibility—and the experimental evidence for and against the existence of such mechanisms—and outlines steps required for future investigations.”
Ilango, S., Paital, B., Jayachandran, P., Padma, P. R., & Nirmaladevi, R.. (2020). Epigenetic alterations in cancer. Frontiers in Bioscience – Landmark
Plain numerical DOI: 10.2741/4847
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“Genetic and epigenetic modifications in dna contribute to altered gene expression in aging and cancer. in human cancers, epigenetic changes such as dna methylation, histone modifications, micro rnas and nucleosome remodelling all control gene expression. the link between the genetics and epigenetics in cancer is further shown by existence of aberrant metabolism and biochemical pathways in cancer or mutation in genes that are epigenetic players. reversal of these epigenetic changes has been clearly shown to have therapeutic value in various forms of lymphoma and preleukemia and similar results are appearing for the treatment of solid tumors. in this review, we discuss the functional effects of epigenetic changes inducible by hypoxia, the epigenetic alterations in cancer and how they contribute to tumor progression and their relevance to epigenetic therapy.”
Banik, A., Kandilya, D., Ramya, S., Stünkel, W., Chong, Y. S., & Thameem Dheen, S.. (2017). Maternal factors that induce epigenetic changes contribute to neurological disorders in offspring. Genes
Plain numerical DOI: 10.3390/genes8060150
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“It is well established that the regulation of epigenetic factors, including chromatic reorganization, histone modifications, dna methylation, and mirna regulation, is critical for the normal development and functioning of the human brain. there are a number of maternal factors influencing epigenetic pathways such as lifestyle, including diet, alcohol consumption, and smoking, as well as age and infections (viral or bacterial). genetic and metabolic alterations such as obesity, gestational diabetes mellitus (gdm), and thyroidism alter epigenetic mechanisms, thereby contributing to neurodevelopmental disorders (nds) such as embryonic neural tube defects (ntds), autism, down’s syndrome, rett syndrome, and later onset of neuropsychological deficits. this review comprehensively describes the recent findings in the epigenetic landscape contributing to altered molecular profiles resulting in nds. furthermore, we will discuss potential avenues for future research to identify diagnostic markers and therapeutic epi-drugs to reverse these abnormalities in the brain as epigenetic marks are plastic and reversible in nature.”
Landgrave-Gómez, J., Mercado-Gómez, O., & Guevara-Guzmán, R.. (2015). Epigenetic mechanisms in neurological and neurodegenerative diseases. Frontiers in Cellular Neuroscience
Plain numerical DOI: 10.3389/fncel.2015.00058
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“The role of epigenetic mechanisms in the function and homeostasis of the central nervous system (cns) and its regulation in diseases is one of the most interesting processes of contemporary neuroscience. in the last decade, a growing body of literature suggests that long-term changes in gene transcription associated with cns’s regulation and neurological disorders are mediated via modulation of chromatin structure. ‘epigenetics’, introduced for the first time by waddington in the early 1940s, has been traditionally referred to a variety of mechanisms that allow heritable changes in gene expression even in the absence of dna mutation. however, new definitions acknowledge that many of these mechanisms used to perpetuate epigenetic traits in dividing cells are used by neurons to control a variety of functions dependent on gene expression. indeed, in the recent years these mechanisms have shown their importance in the maintenance of a healthy cns. moreover, environmental inputs that have shown effects in cns diseases, such as nutrition, that can modulate the concentration of a variety of metabolites such as acetyl-coenzyme a (acetyl-coa), nicotinamide adenine dinucleotide (nad+) and beta hydroxybutyrate (β-hb), regulates some of these epigenetic modifications, linking in a precise way environment with gene expression. this manuscript will portray what is currently understood about the role of epigenetic mechanisms in the function and homeostasis of the cns and their participation in a variety of neurological disorders. we will discuss how the machinery that controls these modifications plays an important role in processes involved in neurological disorders such as neurogenesis and cell growth. moreover, we will discuss how environmental inputs modulate these modifications producing metabolic and physiological alterations that could exert beneficial effects on neurological diseases. finally, we will highlight possible future directions in the field of epigenetics and neurological disorders.”
Wise, I. A., & Charchar, F. J.. (2016). Epigenetic modifications in essential hypertension. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms17040451
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“Essential hypertension (eh) is a complex, polygenic condition with no single causative agent. despite advances in our understanding of the pathophysiology of eh, hypertension remains one of the world’s leading public health problems. furthermore, there is increasing evidence that epigenetic modifications are as important as genetic predisposition in the development of eh. indeed, a complex and interactive genetic and environmental system exists to determine an individual’s risk of eh. epigenetics refers to all heritable changes to the regulation of gene expression as well as chromatin remodelling, without involvement of nucleotide sequence changes. epigenetic modification is recognized as an essential process in biology, but is now being investigated for its role in the development of specific pathologic conditions, including eh. epigenetic research will provide insights into the pathogenesis of blood pressure regulation that cannot be explained by classic mendelian inheritance. this review concentrates on epigenetic modifications to dna structure, including the influence of non-coding rnas on hypertension development.”
Lehmann, M., Canatelli-Mallat, M., Chiavellini, P., & Goya, R. G.. (2020). A HIERARCHICAL MODEL FOR THE CONTROL OF EPIGENETIC AGING IN MAMMALS. Ageing Research Reviews
Plain numerical DOI: 10.1016/j.arr.2020.101134
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“Regulatory mechanisms range from a single level of control in simple metazoans to multi-level hierarchical control networks in higher animals. organismal regulation encompasses homeostatic and circadian networks that are interconnected, with no documented exceptions. the epigenetic clock is a highly accurate biomarker of age in humans, defined by a mathematical algorithm based on the methylation of a subset of age-related cpg sites on dna. experimental evidence suggests the existence of an underlying regulatory mechanism. by analogy with other integrative systems as the neuroendocrine-immune network and the circadian clocks, a hierarchical organization in the control of the ticking rate of the epigenetic clock is hypothesized here. the hierarchical organization of the neuroendocrine, immune and circadian systems is briefly reviewed. this is followed by a brief review of the epigenetic clock at cell level. finally, different lines of indirect evidence, consistent with the existence of a central pacemaker controlling the ticking rate of the epigenetic clock at organismal level are discussed. the concluding remarks put the hierarchical model proposed for the control of the clock into an evolutionary perspective. within this perspective, the present hypothesis is intended as a conceptual outline based on designs consistently favored by evolution in higher animals.”
Reale, M.. (2021). Annual Report 2020. AIMS Allergy and Immunology
Plain numerical DOI: 10.3934/allergy.2021003
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“A growing body of evidence points towards epigenetic mechanisms being responsible for a wide range of biological phenomena, from the plasticity of plant growth and development to the nutritional control of caste determination in honeybees and the etiology of human disease (e.g., cancer). with the (partial) elucidation of the molecular basis of epigenetic variation and the heritability of certain of these changes, the field of evolutionary epigenetics is flourishing. despite this, the role of epigenetics in shaping host–pathogen interactions has received comparatively little attention. yet there is plenty of evidence supporting the implication of epigenetic mechanisms in the modulation of the biological interaction between hosts and pathogens. the phenotypic plasticity of many key parasite life-history traits appears to be under epigenetic control. moreover, pathogen-induced effects in host phenotype may have transgenerational consequences, and the bases of these changes and their heritability probably have an epigenetic component. the significance of epigenetic modifications may, however, go beyond providing a mechanistic basis for host and pathogen plasticity. epigenetic epidemiology has recently emerged as a promising area for future research on infectious diseases. in addition, the incorporation of epigenetic inheritance and epigenetic plasticity mechanisms to evolutionary models and empirical studies of host–pathogen interactions will provide new insights into the evolution and coevolution of these associations. here, we review the evidence available for the role epigenetics on host–pathogen interactions, and the utility and versatility of the epigenetic technologies available that can be cross-applied to host–pathogen studies. we conclude with recommendations and directions for future research on the burgeoning field of epigenetics as applied to host–pathogen interactions.”
Verma, A., Maini, J., Jain, S., Ghasemi, M., Kohli, S., & Brahmachari, V.. (2020). Epigenetic regulation and transcriptional memory in development; selection facilitating prudence. International Journal of Developmental Biology
Plain numerical DOI: 10.1387/ijdb.190285vb
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“The epigenetic mechanisms regulating developmental gene expression are examples of a strategy to generate unique expression profiles with global regulators controlling several genes. in a simplified view, a common set of tools, that include dna motif recognizing proteins (recruiters), binding/interacting surfaces (arps-actin related proteins), epigenetic writers (histone methyltransferases, acetylases), readers (chromatin remodeling proteins, prc1 members) and erasers (demethylases, deacetylases) form complexes which not only regulate transcription, but also retain the transcriptional memory through mitosis. there are two arms of epigenetic regulation: covalent modification of dna and the post-translational modification of histones. in this review, we discuss both of these aspects briefly to illustrate functional diversity. we discuss our efforts at utilization of the genome sequence data for de novo identification of new players and their functional validation in this remarkable process.”
Amabile, A., Migliara, A., Capasso, P., Biffi, M., Cittaro, D., Naldini, L., & Lombardo, A.. (2016). Inheritable Silencing of Endogenous Genes by Hit-and-Run Targeted Epigenetic Editing. Cell
Plain numerical DOI: 10.1016/j.cell.2016.09.006
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“Gene silencing is instrumental to interrogate gene function and holds promise for therapeutic applications. here, we repurpose the endogenous retroviruses’ silencing machinery of embryonic stem cells to stably silence three highly expressed genes in somatic cells by epigenetics. this was achieved by transiently expressing combinations of engineered transcriptional repressors that bind to and synergize at the target locus to instruct repressive histone marks and de novo dna methylation, thus ensuring long-term memory of the repressive epigenetic state. silencing was highly specific, as shown by genome-wide analyses, sharply confined to the targeted locus without spreading to nearby genes, resistant to activation induced by cytokine stimulation, and relieved only by targeted dna demethylation. we demonstrate the portability of this technology by multiplex gene silencing, adopting different dna binding platforms and interrogating thousands of genomic loci in different cell types, including primary t lymphocytes. targeted epigenome editing might have broad application in research and medicine.”
Cossío, F. P., Esteller, M., & Berdasco, M.. (2020). Towards a more precise therapy in cancer: Exploring epigenetic complexity. Current Opinion in Chemical Biology
Plain numerical DOI: 10.1016/j.cbpa.2020.04.008
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“A plethora of preclinical evidences suggests that pharmacological targeting of epigenetic dysregulation is a potent strategy to combat human diseases. nevertheless, the implementation of epidrugs in clinical practice is very scarce and mainly limited to haematological malignancies. in this review, we discuss cutting-edge strategies to foster the chemical design, the biological rationale and the clinical trial development of epidrugs. specifically, we focus on the development of dual hybrids to exploit multitargeting of key epigenetic molecules deregulated in cancer; the study of epigenetic-synthetic lethality interactions as a mechanism to address loss-of-function mutations, and the combination of epidrugs with other therapies such as immunotherapy to avoid acquired chemoresistance and increase therapy sensitivity. by exploring these challenges, among others, the field of epigenetic chemical biology will increase its potential for clinical benefit, and more effective strategies targeting the aberrant epigenome in cancer are likely to be developed both in haematological and solid tumours.”
Cheedipudi, S., Genolet, O., & Dobreva, G.. (2014). Epigenetic inheritance of cell fates during embryonic development. Frontiers in Genetics
Plain numerical DOI: 10.3389/fgene.2014.00019
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“During embryonic development a large number of widely differing and specialized cell types with identical genomes are generated from a single totipotent zygote. tissue specific transcription factors cooperate with epigenetic modifiers to establish cellular identity in differentiated cells and epigenetic regulatory mechanisms contribute to the maintenance of distinct chromatin states and cell-type specific gene expression patterns, a phenomenon referred to as epigenetic memory. this is accomplished via the stable maintenance of various epigenetic marks through successive rounds of cell division. preservation of dna methylation patterns is a well-established mechanism of epigenetic memory, but more recently it has become clear that many other epigenetic modifications can also be maintained following dna replication and cell division. in this review, we present an overview of the current knowledge regarding the role of histone lysine methylation in the establishment and maintenance of stable epigenetic states. © 2014 cheedipudi, genolet and dobreva.”
Hanieh, H., Ahmed, E. A., Vishnubalaji, R., & Alajez, N. M.. (2020). SOX4: Epigenetic regulation and role in tumorigenesis. Seminars in Cancer Biology
Plain numerical DOI: 10.1016/j.semcancer.2019.06.022
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“Sex-determining region y-related (sry) high-mobility group box 4 (sox4) is a member of the group c subfamily of sox transcription factors and promotes tumorigenesis by endowing cancer cells with survival, migratory, and invasive capacities. emerging evidence has highlighted an unequivocal role for this transcription factor in mediating various signaling pathways involved in tumorigenesis, epithelial-to-mesenchymal transition (emt), and tumor progression. during the last decade, numerous studies have highlighted the epigenetic interplay between sox4-targeting micrornas (mirnas), long noncoding rnas (lncrnas) and sox4 and the subsequent modulation of tumorigenesis, invasion and metastasis. in this review, we summarize the current state of knowledge about the role of sox4 in cancer development and progression, the epigenetic regulation of sox4, and the potential utilization of sox4 as a diagnostic and prognostic biomarker and its depletion as a therapeutic target.”
Fetahu, I. S., Ma, D., Rabidou, K., Argueta, C., Smith, M., Liu, H., … Shi, Y. G.. (2019). Epigenetic signatures of methylated DNA cytosine in Alzheimer’s disease. Science Advances
Plain numerical DOI: 10.1126/sciadv.aaw2880
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“Alzheimer’s disease (ad), a progressive neurodegenerative disorder, is the most common untreatable form of dementia. identifying molecular biomarkers that allow early detection remains a key challenge in the diagnosis, treatment, and prognostic evaluation of the disease. here, we report a novel experimental and analytical model characterizing epigenetic alterations during ad onset and progression. we generated the first integrated base-resolution genome-wide maps of the distribution of 5-methyl-cytosine (5mc), 5-hydroxymethyl-cytosine (5hmc), and 5-formyl/carboxy-cytosine (5fc/cac) in normal and ad neurons. we identified 27 ad region–specific and 39 cpg site–specific epigenetic signatures that were independently validated across our familial and sporadic ad models, and in an independent clinical cohort. thus, our work establishes a new model and strategy to study the epigenetic alterations underlying ad onset and progression and provides a set of highly reliable ad-specific epigenetic signatures that may have early diagnostic and prognostic implications.”
Bale, T. L.. (2015). Epigenetic and transgenerational reprogramming of brain development. Nature Reviews Neuroscience
Plain numerical DOI: 10.1038/nrn3818
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“Neurodevelopmental programming-the implementation of the genetic and epigenetic blueprints that guide and coordinate normal brain development-requires tight regulation of transcriptional processes. during prenatal and postnatal time periods, epigenetic processes fine-tune neurodevelopment towards an end product that determines how an organism interacts with and responds to exposures and experiences throughout life. epigenetic processes also have the ability to reprogramme the epigenome in response to environmental challenges, such as maternal stress, making the organism more or less adaptive depending on the future challenges presented. epigenetic marks generated within germ cells as a result of environmental influences throughout life can also shape future generations long before conception occurs.”
Kulikova, T., Surkova, A., Zlotina, A., & Krasikova, A.. (2020). Mapping epigenetic modifications on chicken lampbrush chromosomes. Molecular Cytogenetics
Plain numerical DOI: 10.1186/s13039-020-00496-0
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“Background: the epigenetic regulation of genome is crucial for implementation of the genetic program of ontogenesis through establishing and maintaining differential gene expression. thus mapping of various epigenetic modifications to the genome is relevant for studying the regulation of gene expression. giant transcriptionally active lampbrush chromosomes are an established tool for high resolution physical mapping of the genome and its epigenetic modifications. this study is aimed at characterizing the epigenetic status of compact chromatin domains (chromomeres) of chicken lampbrush macrochromosomes. results: distribution of three epigenetic modifications – 5-methylcytosine, histone h3 trimethylated at lysine 9 and hyperacetylated histone h4 – along the axes of chicken lampbrush chromosomes 1-4, z and w was analyzed in details. enrichment of chromatin domains with the investigated epigenetic modifications was indicated on the cytological chromomere-loop maps for corresponding chicken lampbrush chromosomes. heterogeneity in the distribution of 5-methylcytosine and histone h3 trimethylated at lysine 9 along the chromosome axes was revealed. conclusions: on examples of certain chromomeres of chicken lampbrush chromosomes 1, 3, 4 and w we demonstrated that a combination of immunofluorescent staining and fluorescence in situ hybridization allows to relate the epigenetic status and a dna sequence context of individual chromomeres.”
Goyal, D., Limesand, S. W., & Goyal, R.. (2019). Epigenetic responses and the developmental origins of health and disease. Journal of Endocrinology
Plain numerical DOI: 10.1530/JOE-19-0009
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“Maternal and paternal factors influence offspring development and program its genome for successful postnatal life. based on the stressors during gestation, the pregnant female prepares the fetus for the outside environment. this preparation is achieved by changing the epigenome of the fetus and is referred to as ‘developmental programming’. for instance, nutritional insufficiency in utero will lead to programming events that prepare the fetus to cope up with nutrient scarcity following birth; however, offspring may not face nutrient scarcity following birth. this d iscrepancy between predicted and exposed postnatal environments are perceived as ’ stress’ by the offspring and may result in cardiovascular and metabolic disorders. thus, this developmental programming may be both beneficial as well as harmful depending on the prenatal vs postnatal environment. over the past three decades, accumulating evidence supports the hypothesis of developmental origin of health and disease (dohad) by the programming of the fetal phenotype without altering the genotype per se. these heritable modifications in gene expression occur through dna met hylation, histone modification and noncoding rna-associated gene activation or sil encing, and all are defined as epigenetic modifications. in the present review, we wi ll summarize the evidence supporting epigenetic regulation as a significant compo nent in dohad.”
Feng, Y., Jankovic, J., & Wu, Y. C.. (2015). Epigenetic mechanisms in Parkinson’s disease. Journal of the Neurological Sciences
Plain numerical DOI: 10.1016/j.jns.2014.12.017
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“Parkinson’s disease (pd) is the second most common age-related neurodegenerative disease, but its pathogenesis is not fully understood. the selective neuronal cell death in pd has been considered to result from a complex interaction between genetic and environmental factors, but the nature of the relationship between the two chief modifiers remains to be elucidated. there is a growing body of evidence supporting the role of epigenetics in the development and progression of many neurodegenerative diseases including pd. epigenetic modification refers to changes in gene expression or function without changes in dna sequence, which mainly includes dna methylation, post-modifications of histone, and non-coding rnas. in this review, we will focus on the abnormal epigenetic modifications involved in the pathogenesis of pd and their implications for the development of future diagnostic and therapeutic strategies.”
Perła-Kaján, J., & Jakubowski, H.. (2019). Dysregulation of epigenetic mechanisms of gene expression in the pathologies of hyperhomocysteinemia. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms20133140
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“Hyperhomocysteinemia (hhcy) exerts a wide range of biological effects and is associated with a number of diseases, including cardiovascular disease, dementia, neural tube defects, and cancer. although mechanisms of hhcy toxicity are not fully uncovered, there has been a significant progress in their understanding. the picture emerging from the studies of homocysteine (hcy) metabolism and pathophysiology is a complex one, as hcy and its metabolites affect biomolecules and processes in a tissue-and sex-specific manner. because of their connection to one carbon metabolism and editing mechanisms in protein biosynthesis, hcy and its metabolites impair epigenetic control of gene expression mediated by dna methylation, histone modifications, and non-coding rna, which underlies the pathology of human disease. in this review we summarize the recent evidence showing that epigenetic dysregulation of gene expression, mediated by changes in dna methylation and histone n-homocysteinylation, is a pathogenic consequence of hhcy in many human diseases. these findings provide new insights into the mechanisms of human disease induced by hcy and its metabolites, and suggest therapeutic targets for the prevention and/or treatment.”
Martín-Del-Campo, R., Sifuentes-Romero, I., & García-Gasca, A.. (2019). Hox genes in reptile development, epigenetic regulation, and teratogenesis. Cytogenetic and Genome Research
Plain numerical DOI: 10.1159/000495712
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“Reptiles are ancestral organisms presenting a variety of shapes, from the elongated vertebral column of the snake to the turtle dorsalized ribs or retractile neck. body plans are specified by a conserved group of homeobox-containing genes (hox genes), which encode transcription factors important in cell fate and vertebral architecture along the anteroposterior axis during embryonic development; thus, dysregulation of these genes may cause congenital malformations, from mild-sublethal to embryonic-lethal. the genetic pool, maternal transfer, and environmental conditions during egg incubation affect development; environmental factors such as temperature, moisture, oxygen, and pollution may alter gene expression by epigenetic mechanisms. thus, in this review, we present information regarding hox genes and development in reptiles, including sex determination and teratogenesis. we also present some evidence of epigenetic regulation of hox genes and the role of the environment in epigenetic modulation of gene expression. so far, the evidence suggests that the molecular instructions encoded by hox genes to build a snake, a lizard, or a turtle represent the interplay between genome and epigenome after years of evolution, with occasional environmentally induced molecular mistakes leading to abnormal body shapes.”
Kasinska, M. A., Drzewoski, J., & Sliwinska, A.. (2016). Epigenetic modifications in adipose tissue – Relation to obesity and diabetes. Archives of Medical Science
Plain numerical DOI: 10.5114/aoms.2015.53616
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“The growing number of people suffering from obesity and type 2 diabetes mellitus (t2dm) is a global health problem that results in increased mortality from their complications, mainly cardiovascular diseases. although the relationship between obesity and t2dm is well established, the common molecular pathomechanisms are still under investigation. recently, it has been suggested that epigenetic modifications may be involved in both obesity and t2dm development. epigenetics plays a pivotal role in the regulation of gene expression by the reversible modifications of chromatin structure without any changes in dna sequence. epigenetic modifications include dna methylation, posttranslational histone modifications and mirna interference. therefore, the aim of this article is to discuss the current knowledge on epigenetic modifications in adipose tissue and their association with obesity and t2dm.”
Harvey, Z. H., Chakravarty, A. K., Futia, R. A., & Jarosz, D. F.. (2020). A Prion Epigenetic Switch Establishes an Active Chromatin State. Cell
Plain numerical DOI: 10.1016/j.cell.2020.02.014
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“Covalent modifications to histones are essential for development, establishing distinct and functional chromatin domains from a common genetic sequence. whereas repressed chromatin is robustly inherited, no mechanism that facilitates inheritance of an activated domain has been described. here, we report that the set3c histone deacetylase scaffold snt1 can act as a prion that drives the emergence and transgenerational inheritance of an activated chromatin state. this prion, which we term [esi+] for expressed sub-telomeric information, is triggered by transient snt1 phosphorylation upon cell cycle arrest. once engaged, the prion reshapes the activity of snt1 and the set3c complex, recruiting rna pol ii and interfering with rap1 binding to activate genes in otherwise repressed sub-telomeric domains. this transcriptional state confers broad resistance to environmental stress, including antifungal drugs. altogether, our results establish a robust means by which a prion can facilitate inheritance of an activated chromatin state to provide adaptive benefit.”
Jubierre, L., Jiménez, C., Rovira, E., Soriano, A., Sábado, C., Gros, L., … Segura, M. F.. (2018). Targeting of epigenetic regulators in neuroblastoma. Experimental and Molecular Medicine
Plain numerical DOI: 10.1038/s12276-018-0077-2
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“Approximately 15,000 new cases of pediatric cancer are diagnosed yearly in europe, with 8–10% corresponding to neuroblastoma, a rare disease with an incidence of 8–9 cases per million children <15 years of age. although the survival rate for low-risk and intermediate-risk patients is excellent, half of children with high-risk, refractory, or relapsed tumors will be cured, and two-thirds of the other half will suffer major side effects and life-long disabilities. epigenetic therapies aimed at reversing the oncogenic alterations in chromatin structure and function are an emerging alternative against aggressive tumors that are or will become resistant to conventional treatments. this approach proposes targeting epigenetic regulators, which are proteins that are involved in the creation, detection, and interpretation of epigenetic signals, such as methylation or histone post-translational modifications. in this review, we focused on the most promising epigenetic regulators for targeting and current drugs that have already reached clinical trials.”
Shin, H. J. R., Kim, H., Kim, K. Il, & Baek, S. H.. (2016). Epigenetic and transcriptional regulation of autophagy. Autophagy
Plain numerical DOI: 10.1080/15548627.2016.1214780
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“Macroautophagy (hereafter referred to as autophagy) is an essential self-digestion process to maintain homeostasis and promote survival in response to starvation. although the components of autophagy in the cytoplasm have been well studied, little has been known about the fine-tuning mechanism of autophagy through epigenetic regulations. recently, we identified the histone arginine methyltransferase carm1 as a new component and followed histone h3r17 dimethylation as a critical epigenetic mark in starvation-induced autophagy. upon nutrient starvation, carm1 is stabilized in the nucleus, but not in the cytoplasm, whereas it is constantly degraded under nutrient-rich conditions by the skp2-containing scf (skp1-cul1-f-box protein) e3 ubiquitin ligase. we further showed that nutrient starvation induces the protein levels and activity of ampk in the nucleus. activated ampk then phosphorylates foxo3, leading to skp2 downregulation and increased carm1 protein levels in the nucleus. stabilized carm1 in turn functions as an essential co-activator of tfeb and regulates the expression of autophagy and lysosomal genes. our findings provide a conceptual advance that activation of specific epigenetic programs is indispensable for a sustained autophagic response, and shed light on a potential therapeutic targeting of the newly identified ampk-skp2-carm1 signaling axis in autophagy-related diseases.”
Hernández-Saavedra, D., Moody, L., Xu, G. B., Chen, H., & Pan, Y. X.. (2019). Epigenetic Regulation of Metabolism and Inflammation by Calorie Restriction. Advances in Nutrition
Plain numerical DOI: 10.1093/advances/nmy129
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“Chronic caloric restriction (cr) without malnutrition is known to affect different cellular processes such as stem cell function, cell senescence, inflammation, and metabolism. despite the differences in the implementation of cr, the reduction of calories produces a widespread beneficial effect in noncommunicable chronic diseases, which can be explained by improvements in immuno-metabolic adaptation. cellular adaptation that occurs in response to dietary patterns can be explained by alterations in epigenetic mechanisms such as dna methylation, histone modifications, and microrna. in this review, we define these modifications and systematically summarize the current evidence related to cr and the epigenome. we then explain the significance of genome-wide epigenetic modifications in the context of disease development. although substantial evidence exists for the widespread effect of cr on longevity, there is no consensus regarding the epigenetic regulations of the underlying cellularmechanisms that lead to improved health. we provide compelling evidence that cr produces long-lasting epigenetic effects that mediate expression of genes related to immuno-metabolic processes. epigenetic reprogramming of the underlying chronic low-grade inflammation by cr can lead to immunometabolic adaptations that enhance quality of life, extend lifespan, and delay chronic disease onset.”
Guzman, F., Fazeli, Y., Khuu, M., Salcido, K., Singh, S., & Benavente, C. A.. (2020). Retinoblastoma tumor suppressor protein roles in epigenetic regulation. Cancers
Plain numerical DOI: 10.3390/cancers12102807
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“Mutations that result in the loss of function of prb were first identified in retinoblastoma and since then have been associated with the propagation of various forms of cancer. prb is best known for its key role as a transcriptional regulator during cell cycle exit. beyond the ability of prb to regulate transcription of cell cycle progression genes, prb can remodel chromatin to exert several of its other biological roles. in this review, we discuss the diverse functions of prb in epigenetic regulation including nucleosome mobilization, histone modifications, dna methylation and non-coding rnas.”
Nam, H. J., & Baek, S. H.. (2019). Epigenetic regulation of the hypoxic response. Current Opinion in Physiology
Plain numerical DOI: 10.1016/j.cophys.2018.11.007
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“Hypoxic signaling occurs under several physiological and pathological conditions, such as in solid tumors. hypoxia inducible factor 1 (hif-1) mediates many hypoxic responses, and regulates hundreds of genes involved in many biological processes including tumor angiogenesis, invasion, and metabolism. although the components of hypoxia that initiate and maintain the hypoxic responses have been well-studied, epigenetic regulation of the hypoxic responses is poorly understood. thus, it would be useful to summarize current status of the field and discuss future directions. in this review, we will focus on the current understandings of epigenetic regulation in hypoxic response and discuss currently available epigenetic drugs to treat hypoxia-driven or related diseases.”
Tekola-Ayele, F., Workalemahu, T., Gorfu, G., Shrestha, D., Tycko, B., Wapner, R., … Louis, G. M. B.. (2019). Sex differences in the associations of placental epigenetic aging with fetal growth. Aging
Plain numerical DOI: 10.18632/aging.102124
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“Identifying factors that influence fetal growth in a sex-specific manner can help unravel mechanisms that explain sex differences in adverse neonatal outcomes and in-utero origins of cardiovascular disease disparities. premature aging of the placenta, a tissue that supports fetal growth and exhibits sex-specific epigenetic changes, is associated with pregnancy complications. using dna methylation-based age estimator, we investigated the sex-specific relationship of placental epigenetic aging with fetal growth across 13-40 weeks gestation, neonatal size, and risk of low birth weight. placental epigenetic age acceleration (paa), the difference between dna methylation age and gestational age, was associated with reduced fetal weight among males but with increased fetal weight among females. paa was inversely associated with fetal weight, abdominal circumference, and biparietal diameter at 32-40 weeks among males but was positively associated with all growth measures among females across 13-40 weeks. a 1-week increase in paa was associated with 2- fold (95% ci 1.2, 3.2) increased odds for low birth weight and 1.5-fold (95% ci 1.1, 2.0) increased odds for smallfor- gestational age among males. in all, fetal growth was significantly reduced in males but not females exposed to a rapidly aging placenta. epigenetic aging of the placenta may underlie sex differences in neonatal outcomes.”
Selma, S., & Orzáez, D.. (2021). Perspectives for epigenetic editing in crops. Transgenic Research
Plain numerical DOI: 10.1007/s11248-021-00252-z
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“Site-specific nucleases (ssns) have drawn much attention in plant biotechnology due to their ability to drive precision mutagenesis, gene targeting or allele replacement. however, when devoid of its nuclease activity, the underlying dna-binding activity of ssns can be used to bring other protein functional domains close to specific genomic sites, thus expanding further the range of applications of the technology. in particular, the addition of functional domains encoding epigenetic effectors and chromatin modifiers to the crispr/cas ribonucleoprotein complex opens the possibility to introduce targeted epigenomic modifications in plants in an easily programmable manner. here we examine some of the most important agronomic traits known to be controlled epigenetically and review the best studied epigenetic catalytic effectors in plants, such as dna methylases/demethylases or histone acetylases/deacetylases and their associated marks. we also review the most efficient strategies developed to date to functionalize cas proteins with both catalytic and non-catalytic epigenetic effectors, and the ability of these domains to influence the expression of endogenous genes in a regulatable manner. based on these new technical developments, we discuss the possibilities offered by epigenetic editing tools in plant biotechnology and their implications in crop breeding.”
Sang, E. R., Tian, Y., Miller, L. C., & Sang, Y.. (2021). Epigenetic evolution of ACE2 and IL-6 genes: Non-canonical interferon-stimulated genes correlate to COVID-19 susceptibility in vertebrates. Genes
Plain numerical DOI: 10.3390/genes12020154
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“The current novel coronavirus disease (covid-19) has spread globally within a matter of months. the virus establishes a success in balancing its deadliness and contagiousness, and causes substantial differences in susceptibility and disease progression in people of different ages, genders and pre-existing comorbidities. these host factors are subjected to epigenetic regulation; therefore, relevant analyses on some key genes underlying covid-19 pathogenesis were performed to longitudinally decipher their epigenetic correlation to covid-19 susceptibility. the genes of host angiotensin-converting enzyme 2 (ace2, as the major virus receptor) and interleukin (il)-6 (a key immuno-pathological factor triggering cytokine storm) were shown to evince active epigenetic evolution via histone modification and cis/trans-factors interaction across different vertebrate species. extensive analyses revealed that ace2 ad il-6 genes are among a subset of non-canonical interferon-stimulated genes (non-isgs), which have been designated for their unconventional responses to interferons (ifns) and inflammatory stimuli through an epigenetic cascade. furthermore, significantly higher positive histone modification markers and position weight matrix (pwm) scores of key cis-elements corresponding to inflammatory and ifn signaling, were discovered in both ace2 and il6 gene promoters across representative covid-19-susceptible species compared to unsuscep-tible ones. the findings characterize ace2 and il-6 genes as non-isgs that respond differently to inflammatory and ifn signaling from the canonical isgs. the epigenetic properties ace2 and il-6 genes may serve as biomarkers to longitudinally predict covid-19 susceptibility in vertebrates and partially explain covid-19 inequality in people of different subgroups.”
Angermueller, C., Clark, S. J., Lee, H. J., Macaulay, I. C., Teng, M. J., Hu, T. X., … Reik, W.. (2016). Parallel single-cell sequencing links transcriptional and epigenetic heterogeneity. Nature Methods
Plain numerical DOI: 10.1038/nmeth.3728
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“We report scm&t-seq, a method for parallel single-cell genome-wide methylome and transcriptome sequencing that allows for the discovery of associations between transcriptional and epigenetic variation. profiling of 61 mouse embryonic stem cells confirmed known links between dna methylation and transcription. notably, the method revealed previously unrecognized associations between heterogeneously methylated distal regulatory elements and transcription of key pluripotency genes.”
Snir, S., Farrell, C., & Pellegrini, M.. (2019). Human epigenetic ageing is logarithmic with time across the entire lifespan. Epigenetics
Plain numerical DOI: 10.1080/15592294.2019.1623634
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“Epigenetic changes during ageing have been characterized by multiple epigenetic clocks that allow the prediction of chronological age based on methylation status. despite their accuracy and utility, epigenetic age biomarkers leave many questions about epigenetic ageing unanswered. specifically, they do not permit the unbiased characterization of non-linear epigenetic ageing trends across entire life spans, a critical question underlying this field of research. here we provide an integrated framework to address this question. our model, inspired from evolutionary models, is able to account for acceleration/deceleration in epigenetic changes by fitting an individual’s model age, the epigenetic age, which is related to chronological age in a non-linear fashion. application of this model to dna methylation data measured across broad age ranges, from before birth to old age, and from two tissue types, suggests a universal logarithmic trend characterizes epigenetic ageing across entire lifespans.”
Cherneva, R. V., & Kostadinov, D.. (2019). Epigenetic Targets for Therapeutic Approaches in COPD and Asthma. Nutrigenomics – Possible or Illusive. Folia Medica
Plain numerical DOI: 10.3897/folmed.61.e39160
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“Oxidative stress generated by cigarette smoking, environmental pollution, or other noxious particles leads to epigenetic changes in the cells of the respiratory tract. they reflect cell adaptation in response to chronic exposure to external factors. although there is no change in the genetic code, epigenetic changes may be heritable and translated from one generation to another, accumulating abnormalities and rendering cells into entirely different phenotype, causing disease. dna methylation, post-translation histone modification, ubiquitination, sumoylation and mirna transcriptional regulation are the major processes that are responsible for the epigenetic control of gene expression. all of them are reversible. they can be regulated by targeting specific enzymes/proteins involved in the process in order to mitigate inflammation. chronic respiratory diseases have epigenetic signatures that affect gene expression in the lung. targeting them provides the development of novel diagnostic and therapeutic approaches in respiratory medicine. nutrigenomics reveals the beneficial effect of natural phytochemicals, affecting key steps in the signaling pathways of chronic respiratory diseases.”
Jin, Z., & Liu, Y.. (2018). DNA methylation in human diseases. Genes and Diseases
Plain numerical DOI: 10.1016/j.gendis.2018.01.002
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“Even though the importance of epigenetics was first recognized in light of its role in tissue development, an increasing amount of evidence has shown that it also plays an important role in the development and progression of many common diseases. we discuss some recent findings on one representative epigenetic modification, dna methylation, in some common diseases. while many new risk factors have been identified through the population-based epigenetic epidemiologic studies on the role of epigenetics in common diseases, this relatively new field still faces many unique challenges. here, we describe those promises and unique challenges of epigenetic epidemiological studies and propose some potential solutions.”
da Cruz, R. S., Chen, E., Smith, M., Bates, J., & de Assis, S.. (2020). Diet and Transgenerational Epigenetic Inheritance of Breast Cancer: The Role of the Paternal Germline. Frontiers in Nutrition
Plain numerical DOI: 10.3389/fnut.2020.00093
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“The past decade has made evident that in addition to passing their genetic material at conception, parents also transmit a molecular memory of past environmental experiences, including nutritional status, to their progeny through epigenetic mechanisms. in the 1990s, it was proposed that breast cancer originates in utero. since then, an overwhelming number of studies in human cohorts and animal models have provided support for that hypothesis. it is becoming clear, however, that exposure in the parent generation can lead to multigenerational and transgenerational inheritance of breast cancer. importantly, recent data from our lab and others show that pre-conception paternal diets reprogram the male germline and modulate breast cancer development in offspring. this review explores the emerging evidence for transgenerational epigenetic inheritance of breast cancer focusing on studies associated with ancestral nutritional factors or related markers such as birth weight. we also explore paternal factors and the epigenetic mechanisms of inheritance through the male germline while also reviewing the existing literature on maternal exposures in pregnancy and its effects on subsequent generations. finally, we discuss the importance of this mode of inheritance in the context of breast cancer prevention, the challenges, and outstanding research questions in the field.”
Carskadon, M. A., Chappell, K. R., Barker, D. H., Hart, A. C., Dwyer, K., Gredvig-Ardito, C., … McGeary, J. E.. (2019). A pilot prospective study of sleep patterns and DNA methylation-characterized epigenetic aging in young adults. BMC Research Notes
Plain numerical DOI: 10.1186/s13104-019-4633-1
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“OBJECTIVE: molecular markers in dna methylation at a subset of cpg sites are affected by the environment and contribute to biological (epigenetic) age. we hypothesized that shorter sleep duration and possibly irregular sleep would be associated with accelerated epigenetic aging. we examined epigenetic vs. chronological age in 12 young women selected as shorter or longer sleepers studied prospectively across the first 9 weeks of college using a daily online sleep log. genomic dna was isolated from two blood samples spanning the interval, and dna methylation levels were determined and used to measure epigenetic age. results: epigenetic vs. chronological age differences averaged 2.07 at time 1 and 1.21 at time 2. sleep duration was computed as average daily total sleep time and sleep regularity was indexed using the sleep regularity index. participants with longer and more regular sleep showed reduced age difference: mean = – 2.48 [95% ci – 6.11; 1.15]; those with shorter and more irregular sleep showed an increased age difference: 3.03 [0.02; 6.03]; and those with either shorter or more irregular sleep averaged no significant change: – 0.49 [- 3.55; 2.56]. these pilot data suggest that short and irregular sleep, even in a young healthy sample, may be associated with accelerated epigenetic aging.”
Rodgers, A. B., Morgan, C. P., Leu, N. A., & Bale, T. L.. (2015). Transgenerational epigenetic programming via sperm microRNA recapitulates effects of paternal stress. Proceedings of the National Academy of Sciences of the United States of America
Plain numerical DOI: 10.1073/pnas.1508347112
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“Epigenetic signatures in germ cells, capable of both responding to the parental environment and shaping offspring neurodevelopment, are uniquely positioned to mediate transgenerational outcomes. however, molecular mechanisms by which these marks may communicate experience-dependent information across generations are currently unknown. in our model of chronic paternal stress, we previously identified nine micrornas (mirs) that were increased in the sperm of stressed sires and associated with reduced hypothalamic-pituitary- adrenal (hpa) stress axis reactivity in offspring. in the current study, we rigorously examine the hypothesis that these sperm mirs function postfertilization to alter offspring stress responsivity and, using zygote microinjection of the nine specific mirs, demonstrated a remarkable recapitulation of the offspring stress dysregulation phenotype. further,we associated long-term reprogramming of the hypothalamic transcriptome with hpa axis dysfunction, noting a marked decreased in the expression of extracellular matrix and collagen gene sets that may reflect an underlying change in blood-brain barrier permeability. we conclude by investigating the developmental impact of sperm mirs in early zygotes with single-cell amplification technology, identifying the targeted degradation of stored maternal mrna transcripts including sirtuin 1 and ubiquitin protein ligase e3a, two genes with established function in chromatin remodeling, and this potent regulatory function of mirs postfertilization likely initiates a cascade of molecular events that eventually alters stress reactivity. overall, these findings demonstrate a clear mechanistic role for sperm mirs in the transgenerational transmission of paternal lifetime experiences.”
Riasat, K., Bardell, D., Goljanek-Whysall, K., Clegg, P. D., & Peffers, M. J.. (2020). Epigenetic mechanisms in Tendon Ageing. British Medical Bulletin
Plain numerical DOI: 10.1093/bmb/ldaa023
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“Introduction: tendon is a composite material with a well-ordered hierarchical structure exhibiting viscoelastic properties designed to transfer force. it is recognized that the incidence of tendon injury increases with age, suggesting a deterioration in homeostaticmechanisms or reparative processes. this review summarizes epigeneticmechanisms identified in ageing healthy tendon. sources of data: we searched multiple databases to produce a systematic review on the role of epigenetic mechanisms in tendon ageing. areas of agreement: epigenetic mechanisms are important in predisposing ageing tendon to injury. areas of controversy: the relative importance of epigeneticmechanisms are unknown in terms of promoting healthy ageing. it is also unknown whether these changes represent protective mechanisms to function or predispose to pathology. growing point: epigenetic markers in ageing tendon, which are underresearched including genome-wide chromatin accessibility, should be investigated. areas timely for developing research: metanalysis through integration of multiple datasets and platforms will enable a holistic understanding of the epigenome in ageing and its relevance to disease.”
Nervi, C., De Marinis, E., & Codacci-Pisanelli, G.. (2015). Epigenetic treatment of solid tumours: A review of clinical trials. Clinical Epigenetics
Plain numerical DOI: 10.1186/s13148-015-0157-2
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“Epigenetic treatment has been approved by regulatory agencies for haematological malignancies. the success observed in cutaneous lymphomas represents a proof of principle that similar results may be obtained in solid tumours. several agents that interfere with dna methylation-demethylation and histones acetylation/deacetylation have been studied, and some (such as azacytidine, decitabine, valproic acid and vorinostat) are already in clinical use. the aim of this review is to provide a brief overview of the molecular events underlying the antitumour effects of epigenetic treatments and to summarise data available on clinical trials that tested the use of epigenetic agents against solid tumours. we not only list results but also try to indicate how the proper evaluation of this treatment might result in a better selection of effective agents and in a more rapid development. we divided compounds in demethylating agents and hdac inhibitors. for each class, we report the antitumour activity and the toxic side effects. when available, we describe plasma pharmacokinetics and pharmacodynamic evaluation in tumours and in surrogate tissues (generally white blood cells). epigenetic treatment is a reality in haematological malignancies and deserves adequate attention in solid tumours. a careful consideration of available clinical data however is required for faster drug development and possibly to re-evaluate some molecules that were perhaps discarded too early.”
Mahurkar-Joshi, S., & Chang, L.. (2020). Epigenetic Mechanisms in Irritable Bowel Syndrome. Frontiers in Psychiatry
Plain numerical DOI: 10.3389/fpsyt.2020.00805
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“Irritable bowel syndrome (ibs) is a brain-gut axis disorder characterized by abdominal pain and altered bowel habits. ibs is a multifactorial, stress-sensitive disorder with evidence for familial clustering attributed to genetic or shared environmental factors. however, there are weak genetic associations reported with ibs and a lack of evidence to suggest that major genetic factor(s) contribute to ibs pathophysiology. studies on animal models of stress, including early life stress, suggest a role for environmental factors, specifically, stress associated with dysregulation of corticotropin releasing factor and hypothalamus-pituitary-adrenal (hpa) axis pathways in the pathophysiology of ibs. recent evidence suggests that epigenetic mechanisms, which constitute molecular changes not driven by a change in gene sequence, can mediate environmental effects on central and peripheral function. epigenetic alterations including dna methylation changes, histone modifications, and differential expression of non-coding rnas (microrna [mirna] and long non-coding rna) have been associated with several diseases. the objective of this review is to elucidate the molecular factors in the pathophysiology of ibs with an emphasis on epigenetic mechanisms. emerging evidence for epigenetic changes in ibs includes changes in dna methylation in animal models of ibs and patients with ibs, and various mirnas that have been associated with ibs and endophenotypes, such as increased visceral sensitivity and intestinal permeability. dna methylation, in particular, is an emerging field in the realm of complex diseases and a promising mechanism which can provide important insights into ibs pathogenesis and identify potential targets for treatment.”
Özyalçin, B., & Sanlier, N.. (2020). The effect of diet components on cancer with epigenetic mechanisms. Trends in Food Science and Technology
Plain numerical DOI: 10.1016/j.tifs.2020.06.004
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“Cancer is the most important cause of mortality worldwide. nutritional style, smoking habgsits, body weight and some lifestyle factors such as modifiable risk factors are also effective in increasing of disease. it is known that dietary components that have an effect on cancer may affect the carcinogenesis process. it is believed that resveratrol, selenium, isothiocyanates such as sulforafan, curcumin, tea polyphenols, genistein, quercetin, anthocyanins, withaferin a and indole-3-carbinol may prevent and/or be effective in the treatment of various types of cancer by epigenetic mechanisms. these epigenetic mechanisms include dna methylation, histone modification, and non-coding rnas. it is hopeful that bioactive dietary components may prevent and/or treat cancer by epigenetic mechanisms, either alone or often in combination with several dietary components. in general, studies supporting the health benefits of epigenetics are increasing and it is thought that nutrients and food components may have an epigenetic effect on cancer with the available information. at the same time, nutrients and bioactive nutrients can slow the progression of cancer. this study was planned and conducted to investigate the effect of cancer on the epigenetic mechanisms of nutrients and their components.”
Benoit, M., Drost, H. G., Catoni, M., Gouil, Q., Lopez-Gomollon, S., Baulcombe, D., & Paszkowski, J.. (2019). Environmental and epigenetic regulation of Rider retrotransposons in tomato. PLoS Genetics
Plain numerical DOI: 10.1371/journal.pgen.1008370
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“Transposable elements in crop plants are the powerful drivers of phenotypic variation that has been selected during domestication and breeding programs. in tomato, transpositions of the ltr (long terminal repeat) retrotransposon family rider have contributed to various phenotypes of agronomical interest, such as fruit shape and colour. however, the mechanisms regulating rider activity are largely unknown. we have developed a bioinformatics pipeline for the functional annotation of retrotransposons containing ltrs and defined all full-length rider elements in the tomato genome. subsequently, we showed that accumulation of rider transcripts and transposition intermediates in the form of extrachromosomal dna is triggered by drought stress and relies on abscisic acid signalling. we provide evidence that residual activity of rider is controlled by epigenetic mechanisms involving sirnas and the rna-dependent dna methylation pathway. finally, we demonstrate the broad distribution of rider-like elements in other plant species, including crops. our work identifies rider as an environment-responsive element and a potential source of genetic and epigenetic variation in plants.”
Hardy, T. M., & Tollefsbol, T. O.. (2011). Epigenetic diet: Impact on the epigenome and cancer. Epigenomics
Plain numerical DOI: 10.2217/epi.11.71
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“A number of bioactive dietary components are of particular interest in the field of epigenetics. many of these compounds display anticancer properties and may play a role in cancer prevention. numerous studies suggest that a number of nutritional compounds have epigenetic targets in cancer cells. importantly, emerging evidence strongly suggests that consumption of dietary agents can alter normal epigenetic states as well as reverse abnormal gene activation or silencing. epigenetic modifications induced by bioactive dietary compounds are thought to be beneficial. substantial evidence is mounting proclaiming that commonly consumed bioactive dietary factors act to modify the epigenome and may be incorporated into an ’epigenetic diet. bioactive nutritional components of an epigenetic diet may be incorporated into ones regular dietary regimen and used therapeutically for medicinal or chemopreventive purposes. this article will primarily focus on dietary factors that have been demonstrated to influence the epigenome and that may be used in conjunction with other cancer prevention and chemotherapeutic therapies. © 2011 future medicine ltd.”
Fu, S., & Kurzrock, R.. (2010). Development of curcumin as an epigenetic agent. Cancer
Plain numerical DOI: 10.1002/cncr.25414
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“The clinical benefits of curcumin as a single agent were demonstrated in patients with advanced pancreatic cancer in a phase 2 study despite pharmacokinetic analysis showing a much lower plasma concentration of curcumin in humans than in vitro. the diverse and broad biological activities of curcumin are mediated through direct interaction of curcumin with target proteins as well as epigenetic modulation of target genes, supported by evidence that curcumin modulates gene expression in a time- and concentration-dependent manner in human cancer cells. this review delineates the novel mechanisms of curcumin as an epigenetic agent through its interaction with histone deacetylases, histone acetyltransferases, dna methyltransferase i, and micrornas. accumulating data support curcumin’s functionality in modulating multiple biological processes at low concentrations through its activity as an epigenetic agent. the development of curcumin as an epigenetic agent warrants further preclinical and clinical studies to explore its diversity and efficacy in cancer treatment and in combination with other anticancer agents. © 2010 american cancer society.”
Marioni, R. E., Belsky, D. W., Deary, I. J., & Wagner, W.. (2018). Association of facial ageing with DNA methylation and epigenetic age predictions. Clinical Epigenetics
Plain numerical DOI: 10.1186/s13148-018-0572-2
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“Evaluation of biological age, as opposed to chronological age, is of high relevance for interventions to increase healthy ageing. highly reproducible age-associated dna methylation (dnam) changes can be integrated into algorithms for epigenetic age predictions. these predictors have mostly been trained to correlate with chronological age, but they are also indicative for biological ageing. for example, accelerated epigenetic age of blood is associated with higher risk of all-cause mortality in later life. the perceived age of facial images (face-age) is also associated with all-cause mortality and other ageing-associated traits. in this study, we therefore tested the hypothesis that an epigenetic predictor for biological age might be trained on face-age as a surrogate for biological age rather than on chronological age. our data demonstrate that facial ageing does not correlate with either the epigenetic clock or blood-based dnam measures.”
Stols-Gonçalves, D., Tristão, L. S., Henneman, P., & Nieuwdorp, M.. (2019). Epigenetic Markers and Microbiota/Metabolite-Induced Epigenetic Modifications in the Pathogenesis of Obesity, Metabolic Syndrome, Type 2 Diabetes, and Non-alcoholic Fatty Liver Disease. Current Diabetes Reports
Plain numerical DOI: 10.1007/s11892-019-1151-4
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“Purpose of review: the metabolic syndrome is a pathological state in which one of the key components is insulin resistance. a wide spectrum of body compartments is involved in its pathophysiology. genetic and environmental factors such as diet and physical activity are both related to its etiology. reversible modulation of gene expression without altering the dna sequence, known as epigenetic modifications, has been shown to drive this complex metabolic cluster of conditions. here, we aim to examine some of the recent research of specific epigenetically mediated mechanisms and microbiota-induced epigenetic modifications on the development of adipose tissue and obesity, β-cell dysfunction and diabetes, and hepatocytes and non-alcoholic fatty disease. recent findings: dna methylation patterns and histone modifications have been identified in this context; the integrated analysis of genome, epigenome, and transcriptome is likely to expand our knowledge of epigenetics in health and disease. epigenetic modifications induced by diet-related microbiota or metabolites possibly contribute to the insulin-resistant state. summary: the identification of epigenetic signatures on diabetes and obesity may give us the possibility of developing new interventions, prevention measures, and follow-up strategies.”
Marioni, R. E., Belsky, D. W., Deary, I. J., & Wagner, W.. (2018). Association of facial ageing with DNA methylation and epigenetic age predictions. Clinical Epigenetics
Plain numerical DOI: 10.1186/s13148-018-0572-2
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“Evaluation of biological age, as opposed to chronological age, is of high relevance for interventions to increase healthy ageing. highly reproducible age-associated dna methylation (dnam) changes can be integrated into algorithms for epigenetic age predictions. these predictors have mostly been trained to correlate with chronological age, but they are also indicative for biological ageing. for example, accelerated epigenetic age of blood is associated with higher risk of all-cause mortality in later life. the perceived age of facial images (face-age) is also associated with all-cause mortality and other ageing-associated traits. in this study, we therefore tested the hypothesis that an epigenetic predictor for biological age might be trained on face-age as a surrogate for biological age rather than on chronological age. our data demonstrate that facial ageing does not correlate with either the epigenetic clock or blood-based dnam measures.”
Ruoß, M., Damm, G., Vosough, M., Ehret, L., Grom-Baumgarten, C., Petkov, M., … Sajadian, S.. (2019). Epigenetic modifications of the liver tumor cell line HepG2 increase their drug metabolic capacity. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms20020347
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“Although human liver tumor cells have reduced metabolic functions as compared to primary human hepatocytes (phh) they are widely used for pre-screening tests of drug metabolism and toxicity. the aim of the present study was to modify liver cancer cell lines in order to improve their drug-metabolizing activities towards phh. it is well-known that epigenetics is strongly modified in tumor cells and that epigenetic regulators influence the expression and function of cytochrome p450 (cyp) enzymes through altering crucial transcription factors responsible for drug-metabolizing enzymes. therefore, we screened the epigenetic status of four different liver cancer cell lines (huh7, hle, hepg2 and akn-1) which were reported to have metabolizing drug activities. our results showed that hepg2 cells demonstrated the highest similarity compared to phh. thus, we modified the epigenetic status of hepg2 cells towards ‘normal’ liver cells by 5-azacytidine (5-aza) and vitamin c exposure. then, mrna expression of epithelial-mesenchymal transition (emt) marker snail and cyp enzymes were measured by pcr and determinate specific drug metabolites, associated with cyp enzymes by lc/ms. our results demonstrated an epigenetic shift in hepg2 cells towards phh after exposure to 5-aza and vitamin c which resulted in a higher expression and activity of specific drug metabolizing cyp enzymes. finally, we observed that 5-aza and vitamin c led to an increased expression of hepatocyte nuclear factor 4α (hnf4α) and e-cadherin and a significant down regulation of snail1 (snail), the key transcriptional repressor of e-cadherin. our study shows, that certain phase i genes and their enzyme activities are increased by epigenetic modification in hepg2 cells with a concomitant reduction of emt marker gene snail. the enhancing of liver specific functions in hepatoma cells using epigenetic modifiers opens new opportunities for the usage of cell lines as a potential liver in vitro model for drug testing and development.”
Youngson, N. A., & Whitelaw, E.. (2008). Transgenerational epigenetic effects. Annual Review of Genomics and Human Genetics
Plain numerical DOI: 10.1146/annurev.genom.9.081307.164445
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“Transgenerational epigenetic effects include all processes that have evolved to achieve the nongenetic determination of phenotype. there has been a long-standing interest in this area from evolutionary biologists, who refer to it as non-mendelian inheritance. transgenerational epigenetic effects include both the physiological and behavioral (intellectual) transfer of information across generations. although in most cases the underlying molecular mechanisms are not understood, modifications of the chromosomes that pass to the next generation through gametes are sometimes involved, which is called transgenerational epigenetic inheritance. there is a trend for those outside the field of molecular biology to assume that most cases of transgenerational epigenetic effects are the result of transgenerational epigenetic inheritance, in part because of a misunderstanding of the terms. unfortunately, this is likely to be far from the truth. copyright © 2008 by annual reviews. all rights reserved.”
Horvath, S., & Ritz, B. R.. (2015). Increased epigenetic age and granulocyte counts in the blood of Parkinson’s disease patients. Aging
Plain numerical DOI: 10.18632/aging.100859
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“It has been a long standing hypothesis that blood tissue of pd parkinson’s disease (pd) patients may exhibit signs of accelerated aging. here we use dna methylation based biomarkers of aging (‘epigenetic clock’) to assess the aging rate of blood in two ethnically distinct case-control data sets. using n=508 caucasian and n=84 hispanic blood samples, we assess a) the intrinsic epigenetic age acceleration of blood (ieaa), which is independent of blood cell counts, and b) the extrinsic epigenetic age acceleration rate of blood (eeaa) which is associated with age dependent changes in blood cell counts. blood of pd subjects exhibits increased age acceleration according to both ieaa (p=0.019) and eeaa (p=6.1×10-3). we find striking differences in imputed blood cell counts between pd cases and controls. compared to control subjects, pd subjects contains more granulocytes (p=1.0×10-9 in caucasians, p=0.00066 in hispanics) but fewer t helper cells (p=1.4×10-6 in caucasians, p=0.0024 in hispanics) and fewer b cells (p=1.6×10-5 in caucasians, p=4.5×10-5 in hispanics). overall, this study shows that the epigenetic age of the immune system is significantly increased in pd patients and that granulocytes play a significant role.”
Xiong, X. R., Lan, D. L., Li, J., Yin, S., Xiong, Y., & Zi, X. D.. (2019). Effects of Cellular Extract on Epigenetic Reprogramming. Cellular Reprogramming
Plain numerical DOI: 10.1089/cell.2018.0074
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“Functional reprogramming of a differentiated cell toward pluripotent cell may have long-term applications in numerous aspects, especially in regenerative medicine. evidences accumulating from recent studies suggest that cellular extracts from stem cells or pluripotent cells can induce epigenetic reprogramming and facilitate pluripotency in otherwise highly differentiated cell types. epigenetic reprogramming using cellular extracts has gained increasing attention and applied to recognize the functional factors, acquire the target cell types, and explain the mechanism of reprogramming. now, more and more researches have proved that cellular extract treatment is an important strategy of cellular reprogramming. thus, this review mainly focused on the progresses and potential mechanisms in epigenetic reprogramming using cellular extracts.”
Minow, M. A. A., & Colasanti, J.. (2020). Does variable epigenetic inheritance fuel plant evolution?. Genome
Plain numerical DOI: 10.1139/gen-2019-0190
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“Epigenetic changes influence gene expression and contribute to the modulation of biological processes in response to the environment. transgenerational epigenetic changes in gene expression have been described in many eukaryotes. however, plants appear to have a stronger propensity for inheriting novel epialleles. this mini-review discusses how plant traits, such as meristematic growth, totipotency, and incomplete epigenetic erasure in gametes promote epiallele inheritance. additionally, we highlight how plant biology may be inherently tailored to reap the benefits of epigenetic metastability. importantly, environmentally triggered small rna expression and subsequent epigenetic changes may allow immobile plants to adapt themselves, and possibly their progeny, to thrive in local environments. the change of epigenetic states through the passage of generations has ramifications for evolution in the natural and agricultural world. in populations containing little genetic diversity, such as elite crop germplasm or habitually self-reproducing species, epigenetics may provide an important source of heritable phenotypic variation. basic understanding of the processes that direct epigenetic shifts in the genome may allow for breeding or bioengineering for improved plant traits that do not require changes to dna sequence.”
Khaled, N., & Bidet, Y.. (2019). New insights into the implication of epigenetic alterations in the EMT of triple negative breast cancer. Cancers
Plain numerical DOI: 10.3390/cancers11040559
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“Breast cancer is the most common cancer and leading cause of cancer death among women worldwide, encompassing a wide heterogeneity of subtypes with different clinical features. during the last two decades, the use of targeted therapies has emerged in clinical research in order to increase treatment efficiency, improve prognosis and reduce recurrence. however, the triple negative breast cancer (tnbc) subtype remains a clinical challenge, with poor prognosis since no therapeutic targets have been identified. this aggressive breast cancer entity lacks expression of oestrogen receptor (er) and progesterone receptor (pr), and it does not overexpress human epidermal growth factor receptor 2 (her2). the major reason for tnbc poor prognosis is early therapeutic escape from conventional treatments, leading to aggressive metastatic relapse. metastases occur after an epithelial-mesenchymal transition emt of epithelial cells, allowing them to break free from the primary tumour site and to colonize distant organs. cancer-associated emt consists not only of acquired migration and invasion ability, but involves complex and comprehensive reprogramming, including changes in metabolism, expression levels and epigenetic. recently, many studies have considered epigenetic alterations as the primary initiator of cancer development and metastasis. this review builds a picture of the epigenetic modifications implicated in the emt of breast cancer. it focuses on tnbc and allows comparisons with other subtypes. it emphasizes the role of the main epigenetic modifications lncrnas, mirnas, histone and dna- modifications in tumour invasion and appearance of metastases. these epigenetic alterations can be considered biomarkers representing potential diagnostic and prognostic factors in order to define a global metastatic signature for tnbc.”
Amabile, A., Migliara, A., Capasso, P., Biffi, M., Cittaro, D., Naldini, L., & Lombardo, A.. (2016). Inheritable Silencing of Endogenous Genes by Hit-and-Run Targeted Epigenetic Editing. Cell
Plain numerical DOI: 10.1016/j.cell.2016.09.006
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“Gene silencing is instrumental to interrogate gene function and holds promise for therapeutic applications. here, we repurpose the endogenous retroviruses’ silencing machinery of embryonic stem cells to stably silence three highly expressed genes in somatic cells by epigenetics. this was achieved by transiently expressing combinations of engineered transcriptional repressors that bind to and synergize at the target locus to instruct repressive histone marks and de novo dna methylation, thus ensuring long-term memory of the repressive epigenetic state. silencing was highly specific, as shown by genome-wide analyses, sharply confined to the targeted locus without spreading to nearby genes, resistant to activation induced by cytokine stimulation, and relieved only by targeted dna demethylation. we demonstrate the portability of this technology by multiplex gene silencing, adopting different dna binding platforms and interrogating thousands of genomic loci in different cell types, including primary t lymphocytes. targeted epigenome editing might have broad application in research and medicine.”
Özyalçin, B., & Sanlier, N.. (2020). The effect of diet components on cancer with epigenetic mechanisms. Trends in Food Science and Technology
Plain numerical DOI: 10.1016/j.tifs.2020.06.004
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“Cancer is the most important cause of mortality worldwide. nutritional style, smoking habgsits, body weight and some lifestyle factors such as modifiable risk factors are also effective in increasing of disease. it is known that dietary components that have an effect on cancer may affect the carcinogenesis process. it is believed that resveratrol, selenium, isothiocyanates such as sulforafan, curcumin, tea polyphenols, genistein, quercetin, anthocyanins, withaferin a and indole-3-carbinol may prevent and/or be effective in the treatment of various types of cancer by epigenetic mechanisms. these epigenetic mechanisms include dna methylation, histone modification, and non-coding rnas. it is hopeful that bioactive dietary components may prevent and/or treat cancer by epigenetic mechanisms, either alone or often in combination with several dietary components. in general, studies supporting the health benefits of epigenetics are increasing and it is thought that nutrients and food components may have an epigenetic effect on cancer with the available information. at the same time, nutrients and bioactive nutrients can slow the progression of cancer. this study was planned and conducted to investigate the effect of cancer on the epigenetic mechanisms of nutrients and their components.”
Zheng, Z., Huang, G., Gao, T., Huang, T., Zou, M., Zou, Y., & Duan, S.. (2020). Epigenetic Changes Associated With Interleukin-10. Frontiers in Immunology
Plain numerical DOI: 10.3389/fimmu.2020.01105
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“IL-10 is a regulator of inflammation and immunosuppression. il-10 regulates a variety of immune cells to limit and stop the inflammatory response, and thus plays an important role in autoimmune diseases, inflammatory diseases and cancer. il-10 is closely related to epigenetic modification, in which changes in dna methylation of il-10 gene can affect mrna and protein levels of il-10. in addition, changes in histone modifications, especially histone acetylation, can also lead to abnormal expression of il-10 mrna. at the same time, a handful of il-10 related micrornas (mirnas) are found to be aberrantly expressed in multiple diseases. besides, long non-coding rna (lncrna) growth arrest specific transcript 5 (gas5) also inhibits il-10 expression. here, we reviewed the epigenetic changes related to il-10 in various diseases, as well as the regulation of il-10 gene expression in various diseases by epigenetic modifications such as dna methylation, histone modification, mirna, and lncrna.”
da Cruz, R. S., Chen, E., Smith, M., Bates, J., & de Assis, S.. (2020). Diet and Transgenerational Epigenetic Inheritance of Breast Cancer: The Role of the Paternal Germline. Frontiers in Nutrition
Plain numerical DOI: 10.3389/fnut.2020.00093
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“The past decade has made evident that in addition to passing their genetic material at conception, parents also transmit a molecular memory of past environmental experiences, including nutritional status, to their progeny through epigenetic mechanisms. in the 1990s, it was proposed that breast cancer originates in utero. since then, an overwhelming number of studies in human cohorts and animal models have provided support for that hypothesis. it is becoming clear, however, that exposure in the parent generation can lead to multigenerational and transgenerational inheritance of breast cancer. importantly, recent data from our lab and others show that pre-conception paternal diets reprogram the male germline and modulate breast cancer development in offspring. this review explores the emerging evidence for transgenerational epigenetic inheritance of breast cancer focusing on studies associated with ancestral nutritional factors or related markers such as birth weight. we also explore paternal factors and the epigenetic mechanisms of inheritance through the male germline while also reviewing the existing literature on maternal exposures in pregnancy and its effects on subsequent generations. finally, we discuss the importance of this mode of inheritance in the context of breast cancer prevention, the challenges, and outstanding research questions in the field.”
Stols-Gonçalves, D., Tristão, L. S., Henneman, P., & Nieuwdorp, M.. (2019). Epigenetic Markers and Microbiota/Metabolite-Induced Epigenetic Modifications in the Pathogenesis of Obesity, Metabolic Syndrome, Type 2 Diabetes, and Non-alcoholic Fatty Liver Disease. Current Diabetes Reports
Plain numerical DOI: 10.1007/s11892-019-1151-4
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“Purpose of review: the metabolic syndrome is a pathological state in which one of the key components is insulin resistance. a wide spectrum of body compartments is involved in its pathophysiology. genetic and environmental factors such as diet and physical activity are both related to its etiology. reversible modulation of gene expression without altering the dna sequence, known as epigenetic modifications, has been shown to drive this complex metabolic cluster of conditions. here, we aim to examine some of the recent research of specific epigenetically mediated mechanisms and microbiota-induced epigenetic modifications on the development of adipose tissue and obesity, β-cell dysfunction and diabetes, and hepatocytes and non-alcoholic fatty disease. recent findings: dna methylation patterns and histone modifications have been identified in this context; the integrated analysis of genome, epigenome, and transcriptome is likely to expand our knowledge of epigenetics in health and disease. epigenetic modifications induced by diet-related microbiota or metabolites possibly contribute to the insulin-resistant state. summary: the identification of epigenetic signatures on diabetes and obesity may give us the possibility of developing new interventions, prevention measures, and follow-up strategies.”
Lange, U. C., Verdikt, R., Ait-Ammar, A., & Van Lint, C.. (2020). Epigenetic crosstalk in chronic infection with HIV-1. Seminars in Immunopathology
Plain numerical DOI: 10.1007/s00281-020-00783-3
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“Human immunodeficiency virus 1 (hiv-1) replicates through the integration of its viral dna into the genome of human immune target cells. chronically infected individuals thus carry a genomic burden of virus-derived sequences that persists through antiretroviral therapy. this burden consists of a small fraction of intact, but transcriptionally silenced, i.e. latent, viral genomes and a dominant fraction of defective sequences. remarkably, all viral-derived sequences are subject to interaction with host cellular physiology at various levels. in this review, we focus on epigenetic aspects of this interaction. we provide a comprehensive overview of how epigenetic mechanisms contribute to establishment and maintenance of hiv-1 gene repression during latency. we furthermore summarize findings indicating that hiv-1 infection leads to changes in the epigenome of target and bystander immune cells. finally, we discuss how an improved understanding of epigenetic features and mechanisms involved in hiv-1 infection could be exploited for clinical use.”
Liu, W., Cui, Y., Ren, W., & Irudayaraj, J.. (2019). Epigenetic biomarker screening by FLIM-FRET for combination therapy in ER+ breast cancer. Clinical Epigenetics
Plain numerical DOI: 10.1186/s13148-019-0620-6
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“Hormone-dependent gene expression involves dynamic and orchestrated regulation of epigenome leading to a cancerous state. estrogen receptor (er)-positive breast cancer rely on chromatin remodeling and association with epigenetic factors in inducing er-dependent oncogenesis and thus cell over-proliferation. the mechanistic differences between epigenetic regulation and hormone signaling provide an avenue for combination therapy of er-positive breast cancer. we hypothesized that epigenetic biomarkers within single nucleosome proximity of er-dependent genes could serve as potential therapeutic targets. we described here a fluorescence lifetime imaging-based förster resonance energy transfer (flim-fret) methodology for biomarker screening that could facilitate combination therapy based on our study. we screened 11 epigenetic-related markers which include oxidative forms of dna methylation, histone modifications, and methyl-binding domain proteins. among them, we identified h4k12acetylation (h4k12ac) and h3k27 acetylation (h3k27ac) as potential epigenetic therapeutic targets. when histone acetyltransferase inhibitor targeting h4k12ac and h3k27ac was combined with tamoxifen, an enhanced therapeutic outcome was observed against er-positive breast cancer both in vitro and in vivo. together, we demonstrate a single molecule approach as an effective screening tool for devising targeted epigenetic therapy.”
Landgrave-Gómez, J., Mercado-Gómez, O., & Guevara-Guzmán, R.. (2015). Epigenetic mechanisms in neurological and neurodegenerative diseases. Frontiers in Cellular Neuroscience
Plain numerical DOI: 10.3389/fncel.2015.00058
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“The role of epigenetic mechanisms in the function and homeostasis of the central nervous system (cns) and its regulation in diseases is one of the most interesting processes of contemporary neuroscience. in the last decade, a growing body of literature suggests that long-term changes in gene transcription associated with cns’s regulation and neurological disorders are mediated via modulation of chromatin structure. ‘epigenetics’, introduced for the first time by waddington in the early 1940s, has been traditionally referred to a variety of mechanisms that allow heritable changes in gene expression even in the absence of dna mutation. however, new definitions acknowledge that many of these mechanisms used to perpetuate epigenetic traits in dividing cells are used by neurons to control a variety of functions dependent on gene expression. indeed, in the recent years these mechanisms have shown their importance in the maintenance of a healthy cns. moreover, environmental inputs that have shown effects in cns diseases, such as nutrition, that can modulate the concentration of a variety of metabolites such as acetyl-coenzyme a (acetyl-coa), nicotinamide adenine dinucleotide (nad+) and beta hydroxybutyrate (β-hb), regulates some of these epigenetic modifications, linking in a precise way environment with gene expression. this manuscript will portray what is currently understood about the role of epigenetic mechanisms in the function and homeostasis of the cns and their participation in a variety of neurological disorders. we will discuss how the machinery that controls these modifications plays an important role in processes involved in neurological disorders such as neurogenesis and cell growth. moreover, we will discuss how environmental inputs modulate these modifications producing metabolic and physiological alterations that could exert beneficial effects on neurological diseases. finally, we will highlight possible future directions in the field of epigenetics and neurological disorders.”
Mahurkar-Joshi, S., & Chang, L.. (2020). Epigenetic Mechanisms in Irritable Bowel Syndrome. Frontiers in Psychiatry
Plain numerical DOI: 10.3389/fpsyt.2020.00805
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“Irritable bowel syndrome (ibs) is a brain-gut axis disorder characterized by abdominal pain and altered bowel habits. ibs is a multifactorial, stress-sensitive disorder with evidence for familial clustering attributed to genetic or shared environmental factors. however, there are weak genetic associations reported with ibs and a lack of evidence to suggest that major genetic factor(s) contribute to ibs pathophysiology. studies on animal models of stress, including early life stress, suggest a role for environmental factors, specifically, stress associated with dysregulation of corticotropin releasing factor and hypothalamus-pituitary-adrenal (hpa) axis pathways in the pathophysiology of ibs. recent evidence suggests that epigenetic mechanisms, which constitute molecular changes not driven by a change in gene sequence, can mediate environmental effects on central and peripheral function. epigenetic alterations including dna methylation changes, histone modifications, and differential expression of non-coding rnas (microrna [mirna] and long non-coding rna) have been associated with several diseases. the objective of this review is to elucidate the molecular factors in the pathophysiology of ibs with an emphasis on epigenetic mechanisms. emerging evidence for epigenetic changes in ibs includes changes in dna methylation in animal models of ibs and patients with ibs, and various mirnas that have been associated with ibs and endophenotypes, such as increased visceral sensitivity and intestinal permeability. dna methylation, in particular, is an emerging field in the realm of complex diseases and a promising mechanism which can provide important insights into ibs pathogenesis and identify potential targets for treatment.”
Rando, T. A., & Chang, H. Y.. (2012). Aging, rejuvenation, and epigenetic reprogramming: Resetting the aging clock. Cell
Plain numerical DOI: 10.1016/j.cell.2012.01.003
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“The underlying cause of aging remains one of the central mysteries of biology. recent studies in several different systems suggest that not only may the rate of aging be modified by environmental and genetic factors, but also that the aging clock can be reversed, restoring characteristics of youthfulness to aged cells and tissues. this review focuses on the emerging biology of rejuvenation through the lens of epigenetic reprogramming. by defining youthfulness and senescence as epigenetic states, a framework for asking new questions about the aging process emerges. © 2012 elsevier inc.”
Nam, H. J., & Baek, S. H.. (2019). Epigenetic regulation of the hypoxic response. Current Opinion in Physiology
Plain numerical DOI: 10.1016/j.cophys.2018.11.007
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“Hypoxic signaling occurs under several physiological and pathological conditions, such as in solid tumors. hypoxia inducible factor 1 (hif-1) mediates many hypoxic responses, and regulates hundreds of genes involved in many biological processes including tumor angiogenesis, invasion, and metabolism. although the components of hypoxia that initiate and maintain the hypoxic responses have been well-studied, epigenetic regulation of the hypoxic responses is poorly understood. thus, it would be useful to summarize current status of the field and discuss future directions. in this review, we will focus on the current understandings of epigenetic regulation in hypoxic response and discuss currently available epigenetic drugs to treat hypoxia-driven or related diseases.”
Kulikova, T., Surkova, A., Zlotina, A., & Krasikova, A.. (2020). Mapping epigenetic modifications on chicken lampbrush chromosomes. Molecular Cytogenetics
Plain numerical DOI: 10.1186/s13039-020-00496-0
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“Background: the epigenetic regulation of genome is crucial for implementation of the genetic program of ontogenesis through establishing and maintaining differential gene expression. thus mapping of various epigenetic modifications to the genome is relevant for studying the regulation of gene expression. giant transcriptionally active lampbrush chromosomes are an established tool for high resolution physical mapping of the genome and its epigenetic modifications. this study is aimed at characterizing the epigenetic status of compact chromatin domains (chromomeres) of chicken lampbrush macrochromosomes. results: distribution of three epigenetic modifications – 5-methylcytosine, histone h3 trimethylated at lysine 9 and hyperacetylated histone h4 – along the axes of chicken lampbrush chromosomes 1-4, z and w was analyzed in details. enrichment of chromatin domains with the investigated epigenetic modifications was indicated on the cytological chromomere-loop maps for corresponding chicken lampbrush chromosomes. heterogeneity in the distribution of 5-methylcytosine and histone h3 trimethylated at lysine 9 along the chromosome axes was revealed. conclusions: on examples of certain chromomeres of chicken lampbrush chromosomes 1, 3, 4 and w we demonstrated that a combination of immunofluorescent staining and fluorescence in situ hybridization allows to relate the epigenetic status and a dna sequence context of individual chromomeres.”
Meyer, P.. (2015). Epigenetic variation and environmental change. Journal of Experimental Botany
Plain numerical DOI: 10.1093/jxb/eru502
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“Environmental conditions can change the activity of plant genes via epigenetic effects that alter the competence of genetic information to be expressed. this may provide a powerful strategy for plants to adapt to environmental change. however, as epigenetic changes do not modify dna sequences and are therefore reversible, only those epimutations that are transmitted through the germline can be expected to contribute to a long-term adaptive response. the major challenge for the investigation of epigenetic adaptation theories is therefore to identify genomic loci that undergo epigenetic changes in response to environmental conditions, which alter their expression in a heritable way and which improve the plant’s ability to adapt to the inducing conditions. this review focuses on the role of dna methylation as a prominent epigenetic mark that controls chromatin conformation, and on its potential in mediating expression changes in response to environmental signals.”
Silverman, B. R., & Shi, J.. (2016). Alterations of epigenetic regulators in pancreatic cancer and their clinical implications. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms17122138
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“Pancreatic cancer is one of the most aggressive human cancer types with a five-year survival less than 7%. emerging evidence revealed that many genetic alterations in pancreatic cancer target epigenetic regulators. some of these mutations are driver mutations in cancer development. several most important mechanisms of epigenetic regulations include dna methylation, histone modifications (methylation, acetylation, and ubiquitination), chromatin remodeling, and non-coding ribonucleic acids (rnas). these modifications can alter chromatin structure and promoter accessibility, and thus lead to aberrant gene expression. however, exactly how these alterations affect epigenetic reprogramming in pancreatic cancer cells and in different stages of tumor development is still not clear. this mini-review summarizes the current knowledge of epigenetic alterations in pancreatic cancer development and progression, and discusses the clinical applications of epigenetic regulators as diagnostic biomarkers and therapeutic targets in pancreatic cancer.”
Angermueller, C., Clark, S. J., Lee, H. J., Macaulay, I. C., Teng, M. J., Hu, T. X., … Reik, W.. (2016). Parallel single-cell sequencing links transcriptional and epigenetic heterogeneity. Nature Methods
Plain numerical DOI: 10.1038/nmeth.3728
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“We report scm&t-seq, a method for parallel single-cell genome-wide methylome and transcriptome sequencing that allows for the discovery of associations between transcriptional and epigenetic variation. profiling of 61 mouse embryonic stem cells confirmed known links between dna methylation and transcription. notably, the method revealed previously unrecognized associations between heterogeneously methylated distal regulatory elements and transcription of key pluripotency genes.”
Orozco-Solis, R., & Aguilar-Arnal, L.. (2020). Circadian Regulation of Immunity Through Epigenetic Mechanisms. Frontiers in Cellular and Infection Microbiology
Plain numerical DOI: 10.3389/fcimb.2020.00096
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“The circadian clock orchestrates daily rhythms in many physiological, behavioral and molecular processes, providing means to anticipate, and adapt to environmental changes. a specific role of the circadian clock is to coordinate functions of the immune system both at steady-state and in response to infectious threats. hence, time-of-day dependent variables are found in the physiology of immune cells, host-parasite interactions, inflammatory processes, or adaptive immune responses. interestingly, the molecular clock coordinates transcriptional-translational feedback loops which orchestrate daily oscillations in expression of many genes involved in cellular functions. this clock function is assisted by tightly controlled transitions in the chromatin fiber involving epigenetic mechanisms which determine how a when transcriptional oscillations occur. immune cells are no exception, as they also present a functional clock dictating transcriptional rhythms. hereby, the molecular clock and the chromatin regulators controlling rhythmicity represent a unique scaffold mediating the crosstalk between the circadian and the immune systems. certain epigenetic regulators are shared between both systems and uncovering them and characterizing their dynamics can provide clues to design effective chronotherapeutic strategies for modulation of the immune system.”
Mendizabal, I., Berto, S., Usui, N., Toriumi, K., Chatterjee, P., Douglas, C., … Yi, S. V.. (2019). Cell type-specific epigenetic links to schizophrenia risk in the brain. Genome Biology
Plain numerical DOI: 10.1186/s13059-019-1747-7
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“Background: the importance of cell type-specific epigenetic variation of non-coding regions in neuropsychiatric disorders is increasingly appreciated, yet data from disease brains are conspicuously lacking. we generate cell type-specific whole-genome methylomes (n = 95) and transcriptomes (n = 89) from neurons and oligodendrocytes obtained from brain tissue of patients with schizophrenia and matched controls. results: the methylomes of the two cell types are highly distinct, with the majority of differential dna methylation occurring in non-coding regions. dna methylation differences between cases and controls are subtle compared to cell type differences, yet robust against permuted data and validated in targeted deep-sequencing analyses. differential dna methylation between control and schizophrenia tends to occur in cell type differentially methylated sites, highlighting the significance of cell type-specific epigenetic dysregulation in a complex neuropsychiatric disorder. conclusions: our results provide novel and comprehensive methylome and transcriptome data from distinct cell populations within patient-derived brain tissues. this data clearly demonstrate that cell type epigenetic-differentiated sites are preferentially targeted by disease-associated epigenetic dysregulation. we further show reduced cell type epigenetic distinction in schizophrenia.”
Qureshi, I. A., & Mehler, M. F.. (2014). An evolving view of epigenetic complexity in the brain. Philosophical Transactions of the Royal Society B: Biological Sciences
Plain numerical DOI: 10.1098/rstb.2013.0506
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“Recent scientific advances have revolutionized our understanding of classical epigenetic mechanisms and the broader landscape of molecular interactions and cellular functions that are inextricably linked to these processes. our current view of epigenetics includes an increasing appreciation for the dynamic nature of dna methylation, active mechanisms for dna demethylation, differential functions of 5-methylcytosine and its oxidized derivatives, the intricate regulatory logic of histone post-translational modifications, the incorporation of histone variants into chromatin, nucleosome occupancy and dynamics, and direct links between cellular signalling pathways and the actions of chromatin ‘reader’, ‘writer’ and ‘eraser’ molecules. we also have an increasing awareness of the seemingly ubiquitous roles played by diverse classes of selectively expressed non-coding rnas in transcriptional, post-transcriptional, post-translational and local and higher order chromatin modulatory processes. these perspectives are still evolving with novel insights continuing to emerge rapidly (e.g. those related to epigenetic regulation of mobile genetic elements, epigenetic mechanisms in mitochondria, roles in nuclear architecture and ’rna epigenetics’). the precise functions of these epigenetic factors/phenomena are largely unknown. however, it is unequivocal that they serve as key mediators of brain complexity and flexibility, including neural development and aging, cellular differentiation, homeostasis, stress responses, and synaptic and neural network connectivity and plasticity. © 2014 the author(s) published by the royal society. all rights reserved.”
Qureshi, I. A., & Mehler, M. F.. (2014). An evolving view of epigenetic complexity in the brain. Philosophical Transactions of the Royal Society B: Biological Sciences
Plain numerical DOI: 10.1098/rstb.2013.0506
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“Recent scientific advances have revolutionized our understanding of classical epigenetic mechanisms and the broader landscape of molecular interactions and cellular functions that are inextricably linked to these processes. our current view of epigenetics includes an increasing appreciation for the dynamic nature of dna methylation, active mechanisms for dna demethylation, differential functions of 5-methylcytosine and its oxidized derivatives, the intricate regulatory logic of histone post-translational modifications, the incorporation of histone variants into chromatin, nucleosome occupancy and dynamics, and direct links between cellular signalling pathways and the actions of chromatin ‘reader’, ‘writer’ and ‘eraser’ molecules. we also have an increasing awareness of the seemingly ubiquitous roles played by diverse classes of selectively expressed non-coding rnas in transcriptional, post-transcriptional, post-translational and local and higher order chromatin modulatory processes. these perspectives are still evolving with novel insights continuing to emerge rapidly (e.g. those related to epigenetic regulation of mobile genetic elements, epigenetic mechanisms in mitochondria, roles in nuclear architecture and ’rna epigenetics’). the precise functions of these epigenetic factors/phenomena are largely unknown. however, it is unequivocal that they serve as key mediators of brain complexity and flexibility, including neural development and aging, cellular differentiation, homeostasis, stress responses, and synaptic and neural network connectivity and plasticity. © 2014 the author(s) published by the royal society. all rights reserved.”
Chin, C., Lunking, E. S., De La Fuente, M., & Ayad, N. G.. (2018). Immunotherapy and epigenetic pathway modulation in glioblastoma multiforme. Frontiers in Oncology
Plain numerical DOI: 10.3389/fonc.2018.00521
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“Glioblastoma multiforme (gbm) is the most common malignant primary brain tumor. despite aggressive multimodality treatment it remains one of the most challenging and intractable cancers (1). while current standard of care treatment for gbm is maximal safe surgical resection, systemic chemotherapy with temozolimide (tmz), and radiation therapy, the current prognosis of gbm patients remains poor, with a median overall survival of 12-15 months (2, 3). therefore, other treatments are needed to provide better outcomes for gbm patients. immunotherapy is one of the most promising new cancer treatment approaches. immunotherapy drugs have obtained regulatory approval in a variety of cancers including melanoma (4), hodgkin lymphoma (5), and non-small cell lung cancer (6). the basis of immunotherapy in cancer treatment is linked to stimulating the immune system to recognize cancer cells as foreign, thereby leading to the eventual elimination of the tumor. one form of immunotherapy utilizes vaccines that target tumor antigens (7), while other approaches utilize t-cells in patients to stimulate them to attack tumor cells (8). despite intensive efforts all approaches have not been overtly successful (9), suggesting that we need to better understand the underlying biology of tumor cells and their environment as they respond to immunotherapy. recent studies have elucidated epigenetic pathway regulation of gbm tumor expansion (10), suggesting that combined epigenetic pathway inhibition with immunotherapy may be feasible. in this review, we discuss current gbm clinical trials and how immune system interactions with epigenetic pathways and signaling nodes can be delineated to uncover potential combination therapies for this incurable disease.”
Jeong, P. S., Sim, B. W., Park, S. H., Kim, M. J., Kang, H. G., Nanjidsuren, T., … Kim, S. U.. (2020). Chaetocin improves pig cloning efficiency by enhancing epigenetic reprogramming and autophagic activity. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms21144836
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“Efficient epigenetic reprogramming is crucial for the in vitro development of mammalian somatic cell nuclear transfer (scnt) embryos. the aberrant levels of histone h3 lysine 9 trimethylation (h3k9me3) is an epigenetic barrier. in this study, we evaluated the effects of chaetocin, an h3k9me3-specific methyltransferase inhibitor, on the epigenetic reprogramming and developmental competence of porcine scnt embryos. the scnt embryos showed abnormal levels of h3k9me3 at the pronuclear, two-cell, and four-cell stages compared to in vitro fertilized embryos. moreover, the expression levels of h3k9me3-specific methyltransferases (suv39h1 and suv39h2) and dna methyltransferases (dnmt1, dnmt3a, and dnmt3b) were higher in scnt embryos. treatment with 0.5 nm chaetocin for 24 h after activation significantly increased the developmental competence of scnt embryos in terms of the cleavage rate, blastocyst formation rate, hatching rate, cell number, expression of pluripotency-related genes, and cell survival rate. in particular, chaetocin enhanced epigenetic reprogramming by reducing the h3k9me3 and 5-methylcytosine levels and restoring the abnormal expression of h3k9me3-specific methyltransferases and dna methyltransferases. chaetocin induced autophagic activity, leading to a significant reduction in maternal mrna levels in embryos at the pronuclear and two-cell stages. these findings revealed that chaetocin enhanced the developmental competence of porcine scnt embryos by regulating epigenetic reprogramming and autophagic activity and so could be used to enhance the production of transgenic pigs for biomedical research.”
Cacabelos, R., Carril, J., Sanmartín, A., & Cacabelos, P.. (
2019).
KRAS – an overview | ScienceDirect Topics. In Pharmacoepigenetics
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“The pharmacoepigenetic apparatus is integrated by gene clusters of different categories, including (i) pathogenic genes involved in disease pathogenesis, (ii) mechanistic genes encoding components of the epigenetic machinery serving as targets for epigenetic drugs, (iii) metabolic genes associated with the metabolism of drugs (phase i and phase ii enzymatic reactions), (iv) transporter genes encoding protein transporters acting as substrates, inhibitors, or inducers of drugs in association with metabolic enzymes, and (v) pleiotropic genes engaged in multiple metabolomic networks. all these genes, encoding pharmacoepigenetic processors, are under the control of the epigenetic machinery. according to their major targets, epigenetic drugs can be classified into the following categories: dna methyltransferase inhibitors, histone deacetylase inhibitors, histone acetyltransferase inhibitors, histone methyltransferase inhibitors, histone demethylase inhibitors, atp-dependent chromatin remodelers, polycomb repressive complex inhibitors, bromodomain inhibitors, and chromodomain inhibitors. most fda-approved epigenetic drugs have been developed for the treatment of different types of cancer; they are not devoid of severe side effects and many of them show limitations for brain penetration. structural and/or functional genomic defects in pharmacoepigenetic processors are responsible for drug resistance, and some epigenetic interventions are able to reverse this adverse phenomenon in experimental studies. some epigenetic signatures may also help to predict drug response or resistance in cancer. recent studies are contributing to consolidating the impact of toxicoepigenetics and nutriepigenetics in health and disease, reflecting bidirectional communication between environmental factors and the human genome. globally, epigenetic drugs are opening new avenues in molecular pharmacology, and pharmacoepigenetics is an upgraded version of what personalized medicine should be in the near future.”
Orozco-Solis, R., & Aguilar-Arnal, L.. (2020). Circadian Regulation of Immunity Through Epigenetic Mechanisms. Frontiers in Cellular and Infection Microbiology
Plain numerical DOI: 10.3389/fcimb.2020.00096
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“The circadian clock orchestrates daily rhythms in many physiological, behavioral and molecular processes, providing means to anticipate, and adapt to environmental changes. a specific role of the circadian clock is to coordinate functions of the immune system both at steady-state and in response to infectious threats. hence, time-of-day dependent variables are found in the physiology of immune cells, host-parasite interactions, inflammatory processes, or adaptive immune responses. interestingly, the molecular clock coordinates transcriptional-translational feedback loops which orchestrate daily oscillations in expression of many genes involved in cellular functions. this clock function is assisted by tightly controlled transitions in the chromatin fiber involving epigenetic mechanisms which determine how a when transcriptional oscillations occur. immune cells are no exception, as they also present a functional clock dictating transcriptional rhythms. hereby, the molecular clock and the chromatin regulators controlling rhythmicity represent a unique scaffold mediating the crosstalk between the circadian and the immune systems. certain epigenetic regulators are shared between both systems and uncovering them and characterizing their dynamics can provide clues to design effective chronotherapeutic strategies for modulation of the immune system.”
Khaled, N., & Bidet, Y.. (2019). New insights into the implication of epigenetic alterations in the EMT of triple negative breast cancer. Cancers
Plain numerical DOI: 10.3390/cancers11040559
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“Breast cancer is the most common cancer and leading cause of cancer death among women worldwide, encompassing a wide heterogeneity of subtypes with different clinical features. during the last two decades, the use of targeted therapies has emerged in clinical research in order to increase treatment efficiency, improve prognosis and reduce recurrence. however, the triple negative breast cancer (tnbc) subtype remains a clinical challenge, with poor prognosis since no therapeutic targets have been identified. this aggressive breast cancer entity lacks expression of oestrogen receptor (er) and progesterone receptor (pr), and it does not overexpress human epidermal growth factor receptor 2 (her2). the major reason for tnbc poor prognosis is early therapeutic escape from conventional treatments, leading to aggressive metastatic relapse. metastases occur after an epithelial-mesenchymal transition emt of epithelial cells, allowing them to break free from the primary tumour site and to colonize distant organs. cancer-associated emt consists not only of acquired migration and invasion ability, but involves complex and comprehensive reprogramming, including changes in metabolism, expression levels and epigenetic. recently, many studies have considered epigenetic alterations as the primary initiator of cancer development and metastasis. this review builds a picture of the epigenetic modifications implicated in the emt of breast cancer. it focuses on tnbc and allows comparisons with other subtypes. it emphasizes the role of the main epigenetic modifications lncrnas, mirnas, histone and dna- modifications in tumour invasion and appearance of metastases. these epigenetic alterations can be considered biomarkers representing potential diagnostic and prognostic factors in order to define a global metastatic signature for tnbc.”
Rando, T. A., & Chang, H. Y.. (2012). Aging, rejuvenation, and epigenetic reprogramming: Resetting the aging clock. Cell
Plain numerical DOI: 10.1016/j.cell.2012.01.003
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“The underlying cause of aging remains one of the central mysteries of biology. recent studies in several different systems suggest that not only may the rate of aging be modified by environmental and genetic factors, but also that the aging clock can be reversed, restoring characteristics of youthfulness to aged cells and tissues. this review focuses on the emerging biology of rejuvenation through the lens of epigenetic reprogramming. by defining youthfulness and senescence as epigenetic states, a framework for asking new questions about the aging process emerges. © 2012 elsevier inc.”
Skinner, M. K., Guerrero-Bosagna, C., & Haque, M. M.. (2015). Environmentally induced epigenetic transgenerational inheritance of sperm epimutations promote genetic mutations. Epigenetics
Plain numerical DOI: 10.1080/15592294.2015.1062207
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“A variety of environmental factors have been shown to induce the epigenetic transgenerational inheritance of disease and phenotypic variation. this involves the germline transmission of epigenetic information between generations. exposure specific transgenerational sperm epimutations have been previously observed. the current study was designed to investigate the potential role genetic mutations have in the process, using copy number variations (cnv). in the first (f1) generation following exposure, negligible cnv were identified; however, in the transgenerational f3 generation, a significant increase in cnv was observed in the sperm. the genome-wide locations of differential dna methylation regions (epimutations) and genetic mutations (cnv) were investigated. observations suggest the environmental induction of the epigenetic transgenerational inheritance of sperm epimutations promote genome instability, such that genetic cnv mutations are acquired in later generations. a combination of epigenetics and genetics is suggested to be involved in the transgenerational phenotypes. the ability of environmental factors to promote epigenetic inheritance that subsequently promotes genetic mutations is a significant advance in our understanding of how the environment impacts disease and evolution.”
Horvath, S., & Ritz, B. R.. (2015). Increased epigenetic age and granulocyte counts in the blood of Parkinson’s disease patients. Aging
Plain numerical DOI: 10.18632/aging.100859
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“It has been a long standing hypothesis that blood tissue of pd parkinson’s disease (pd) patients may exhibit signs of accelerated aging. here we use dna methylation based biomarkers of aging (‘epigenetic clock’) to assess the aging rate of blood in two ethnically distinct case-control data sets. using n=508 caucasian and n=84 hispanic blood samples, we assess a) the intrinsic epigenetic age acceleration of blood (ieaa), which is independent of blood cell counts, and b) the extrinsic epigenetic age acceleration rate of blood (eeaa) which is associated with age dependent changes in blood cell counts. blood of pd subjects exhibits increased age acceleration according to both ieaa (p=0.019) and eeaa (p=6.1×10-3). we find striking differences in imputed blood cell counts between pd cases and controls. compared to control subjects, pd subjects contains more granulocytes (p=1.0×10-9 in caucasians, p=0.00066 in hispanics) but fewer t helper cells (p=1.4×10-6 in caucasians, p=0.0024 in hispanics) and fewer b cells (p=1.6×10-5 in caucasians, p=4.5×10-5 in hispanics). overall, this study shows that the epigenetic age of the immune system is significantly increased in pd patients and that granulocytes play a significant role.”
Slotkin, R. K., & Martienssen, R.. (2007). Transposable elements and the epigenetic regulation of the genome. Nature Reviews Genetics
Plain numerical DOI: 10.1038/nrg2072
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“Overlapping epigenetic mechanisms have evolved in eukaryotic cells to silence the expression and mobility of transposable elements (tes). owing to their ability to recruit the silencing machinery, tes have served as building blocks for epigenetic phenomena, both at the level of single genes and across larger chromosomal regions. important progress has been made recently in understanding these silencing mechanisms. in addition, new insights have been gained into how this silencing has been co-opted to serve essential functions in ‘host’ cells, highlighting the importance of tes in the epigenetic regulation of the genome. © 2007 nature publishing group.”
Franco, F., Jaccard, A., Romero, P., Yu, Y. R., & Ho, P. C.. (2020). Metabolic and epigenetic regulation of T-cell exhaustion. Nature Metabolism
Plain numerical DOI: 10.1038/s42255-020-00280-9
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“Current immunotherapies yield remarkable clinical outcomes by boosting the power of host immunity in cancer cell elimination and viral clearance. however, after prolonged antigen exposure, cd8+ t cells differentiate into a special differentiation state known as t-cell exhaustion, which poses one of the major hurdles to antiviral and antitumor immunity during chronic viral infection and tumour development. growing evidence indicates that exhausted t cells undergo metabolic insufficiency with altered signalling cascades and epigenetic landscapes, which dampen effector immunity and cause poor responsiveness to immune-checkpoint-blockade therapies. how metabolic stress affects t-cell exhaustion remains unclear; therefore, in this review, we summarize current knowledge of how t-cell exhaustion occurs, and discuss how metabolic insufficiency and prolonged stress responses may affect signalling cascades and epigenetic reprogramming, thus locking t cells into an exhausted state via specialized differentiation programming.”
Yu, M., Hazelton, W. D., Luebeck, G. E., & Grady, W. M.. (2020). Epigenetic aging: More than just a clock when it comes to cancer. Cancer Research
Plain numerical DOI: 10.1158/0008-5472.CAN-19-0924
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“The incidence of cancer, adjusted for secular trends, is directly related to age, and advanced chronologic age is one of the most significant risk factors for cancer. organismal aging is associated with changes at the molecular, cellular, and tissue levels and is affected by both genetic and environmental factors. the specific mechanisms through which these age-associated molecular changes contribute to the increased risk of aging-related disease, such as cancer, are incompletely understood. dna methylation, a prominent epigenetic mark, also changes over a lifetime as part of an ‘epigenetic aging’ process. here, we give an update and review of epigenetic aging, in particular, the phenomena of epigenetic drift and epigenetic clock, with regard to its implication in cancer etiology. we discuss the discovery of the dna methylation–based biomarkers for biological tissue age and the construction of various epigenetic age estimators for human clinical outcomes and health/life span. recent studies in various types of cancer point to the significance of epigenetic aging in tumorigenesis and its potential use for cancer risk prediction. future studies are needed to assess the potential clinical impact of strategies focused on lowering cancer risk by preventing premature aging or promoting healthy aging.”
Hochedlinger, K., & Plath, K.. (2009). Epigenetic reprogramming and induced pluripotency. Development
Plain numerical DOI: 10.1242/dev.020867
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“The cloning of animals from adult cells has demonstrated that the developmental state of adult cells can be reprogrammed into that of embryonic cells by uncharacterized factors within the oocyte. more recently, transcription factors have been identified that can induce pluripotency in somatic cells without the use of oocytes, generating induced pluripotent stem (ips) cells. ips cells provide a unique platform to dissect the molecular mechanisms that underlie epigenetic reprogramming. moreover, ips cells can teach us about principles of normal development and disease, and might ultimately facilitate the treatment of patients by custom-tailored cell therapy.”
Mercer, T. R., & Mattick, J. S.. (2013). Structure and function of long noncoding RNAs in epigenetic regulation. Nature Structural and Molecular Biology
Plain numerical DOI: 10.1038/nsmb.2480
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“Genomes of complex organisms encode an abundance and diversity of long noncoding rnas (lncrnas) that are expressed throughout the cell and fulfill a wide variety of regulatory roles at almost every stage of gene expression. these roles, which encompass sensory, guiding, scaffolding and allosteric capacities, derive from folded modular domains in lncrnas. in this diverse functional repertoire, we focus on the well-characterized ability for lncrnas to function as epigenetic modulators. many lncrnas bind to chromatin-modifying proteins and recruit their catalytic activity to specific sites in the genome, thereby modulating chromatin states and impacting gene expression. considering this regulatory potential in combination with the abundance of lncrnas suggests that lncrnas may be part of a broad epigenetic regulatory network. copyright © 2013 nature america, inc.”
Matsuyama, M., WuWong, D. J., Horvath, S., & Matsuyama, S.. (2019). Epigenetic clock analysis of human fibroblasts in vitro: Effects of hypoxia, donor age, and expression of hTERT and SV40 largeT. Aging
Plain numerical DOI: 10.18632/aging.101955
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“Aging is associated with a genome-wide change of dna methylation (dnam). ‘dnam age’ is defined as the predicted chronological age by the age estimator based on dnam. the estimator is called the epigenetic clock. the molecular mechanism underlining the epigenetic clock is still unknown. here, we evaluated the effects of hypoxia and two immortalization factors, htert and sv40-larget (lt), on the dnam age of human fibroblasts in vitro. we detected the cell division-associated progression of dnam age after > 10 population doublings. moreover, the progression of dnam age was slower under hypoxia (1% oxygen) compared to normoxia (21% oxygen), suggesting that oxygen levels determine the speed of the epigenetic aging. we show that the speed of cell division-associated dnam age progression depends on the chronological age of the cell donor. htert expression did not arrest cell division-associated progression of dnam age in most cells. sv40lt expression produced inconsistent effects, including rejuvenation of dnam age. our results show that a) oxygen and the targets of sv40lt (e.g. p53) modulate epigenetic aging rates and b) the chronological age of donor cells determines the speed of mitosis-associated dnam age progression in daughter cells.”
Zhang, Q., Vallerga, C. L., Walker, R. M., Lin, T., Henders, A. K., Montgomery, G. W., … Visscher, P. M.. (2019). Improved precision of epigenetic clock estimates across tissues and its implication for biological ageing. Genome Medicine
Plain numerical DOI: 10.1186/s13073-019-0667-1
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“Background: dna methylation changes with age. chronological age predictors built from dna methylation are termed ‘epigenetic clocks’. the deviation of predicted age from the actual age (‘age acceleration residual’, aar) has been reported to be associated with death. however, it is currently unclear how a better prediction of chronological age affects such association. methods: in this study, we build multiple predictors based on training dna methylation samples selected from 13,661 samples (13,402 from blood and 259 from saliva). we use the lothian birth cohorts of 1921 (lbc1921) and 1936 (lbc1936) to examine whether the association between aar (from these predictors) and death is affected by (1) improving prediction accuracy of an age predictor as its training sample size increases (from 335 to 12,710) and (2) additionally correcting for confounders (i.e., cellular compositions). in addition, we investigated the performance of our predictor in non-blood tissues. results: we found that in principle, a near-perfect age predictor could be developed when the training sample size is sufficiently large. the association between aar and mortality attenuates as prediction accuracy increases. aar from our best predictor (based on elastic net, https://github.com/qzhang314/dnam-based-age-predictor) exhibits no association with mortality in both lbc1921 (hazard ratio = 1.08, 95% ci 0.91-1.27) and lbc1936 (hazard ratio = 1.00, 95% ci 0.79-1.28). predictors based on small sample size are prone to confounding by cellular compositions relative to those from large sample size. we observed comparable performance of our predictor in non-blood tissues with a multi-tissue-based predictor. conclusions: this study indicates that the epigenetic clock can be improved by increasing the training sample size and that its association with mortality attenuates with increased prediction of chronological age.”
Ross, K. M., Carroll, J., Horvath, S., Hobel, C. J., Coussons-Read, M. E., & Dunkel Schetter, C.. (2020). Immune epigenetic age in pregnancy and 1 year after birth: Associations with weight change. American Journal of Reproductive Immunology
Plain numerical DOI: 10.1111/aji.13229
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“Problem: epigenetic age indices are markers of biological aging determined from dna methylation patterns. accelerated epigenetic age predicts morbidity and mortality. women tend to demonstrate slower blood epigenetic aging compared to men, possibly due to female-specific hormones and reproductive milestones. pregnancy and the post-partum period are critical reproductive periods that have not been studied yet with respect to epigenetic aging. the purpose of this paper was to examine whether pregnancy itself and an important pregnancy-related variable, changes in body mass index (bmi) between pregnancy and the post-partum period, are associated with epigenetic aging. method of study: a pilot sample of 35 women was recruited as part of the healthy babies before birth (hb3) project. whole blood samples were collected at mid-pregnancy and 1 year post-partum. dna methylation at both time points was assayed using infinium 450k and epic chips. epigenetic age indices were calculated using an online calculator. results: paired-sample t-tests were used to test differences in epigenetic age indices from pregnancy to 1 year after birth. over this critical time span, women became younger with respect to phenotypic epigenetic age, grimage, dnam pai-1, and epigenetic age indices linked to aging-related shifts in immune cell populations, known as extrinsic epigenetic age. post-partum bmi retention, but not prenatal bmi increases, predicted accelerated epigenetic aging. conclusion: women appear to become younger from pregnancy to the post-partum period based on specific epigenetic age indices. further, bmi at 1 year after birth that reflects weight retention predicted greater epigenetic aging during this period.”
Li, H. T., Duymich, C. E., Weisenberger, D. J., & Liang, G.. (2016). Genetic and epigenetic alterations in bladder cancer. International Neurourology Journal
Plain numerical DOI: 10.5213/inj.1632752.376
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“Bladder cancer is one of the most common cancers worldwide, with a high rate of recurrence and poor outcomes as a result of relapse. bladder cancer patients require lifelong invasive monitoring and treatment, making bladder cancer one of the most expensive malignancies. lines of evidence increasingly point to distinct genetic and epigenetic alteration patterns in bladder cancer, even between the different stages and grades of disease. in addition, genetic and epigenetic alterations have been demonstrated to play important roles during bladder tumorigenesis. this review will focus on bladder cancer-associated genomic and epigenomic alterations, which are common in bladder cancer and provide potential diagnostic markers and therapeutic targets for bladder cancer treatment.”
Penas, C., & Navarro, X.. (2018). Epigenetic modifications associated to neuroinflammation and neuropathic pain after neural trauma. Frontiers in Cellular Neuroscience
Plain numerical DOI: 10.3389/fncel.2018.00158
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“Accumulating evidence suggests that epigenetic alterations lie behind the induction and maintenance of neuropathic pain. neuropathic pain is usually a chronic condition caused by a lesion, or pathological change, within the nervous system. neuropathic pain appears frequently after nerve and spinal cord injuries or diseases, producing a debilitation of the patient and a decrease of the quality of life. at the cellular level, neuropathic pain is the result of neuronal plasticity shaped by an increase in the sensitivity and excitability of sensory neurons of the central and peripheral nervous system. one of the mechanisms thought to contribute to hyperexcitability and therefore to the ontogeny of neuropathic pain is the altered expression, trafficking, and functioning of receptors and ion channels expressed by primary sensory neurons. besides, neuronal and glial cells, such as microglia and astrocytes, together with blood borne macrophages, play a critical role in the induction and maintenance of neuropathic pain by releasing powerful neuromodulators such as pro-inflammatory cytokines and chemokines, which enhance neuronal excitability. altered gene expression of neuronal receptors, ion channels, and pro-inflammatory cytokines and chemokines, have been associated to epigenetic adaptations of the injured tissue. within this review, we discuss the involvement of these epigenetic changes, including histone modifications, dna methylation, non-coding rnas, and alteration of chromatin modifiers, that have been shown to trigger modification of nociception after neural lesions. in particular, the function on these processes of ezh2, jmjd3, mecp2, several histone deacetylases (hdacs) and histone acetyl transferases (hats), g9a, dnmt, rest and diverse non-coding rnas, are described. despite the effort on developing new therapies, current treatments have only produced limited relief of this pain in a portion of patients. thus, the present review aims to contribute to find novel targets for chronic neuropathic pain treatment.”
Rohde, K., Keller, M., la Cour Poulsen, L., Blüher, M., Kovacs, P., & Böttcher, Y.. (2019). Genetics and epigenetics in obesity. Metabolism: Clinical and Experimental
Plain numerical DOI: 10.1016/j.metabol.2018.10.007
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“Obesity is among the most threatening health burdens worldwide and its prevalence has markedly increased over the last decades. obesity maybe considered a heritable trait. identifications of rare cases of monogenic obesity unveiled that hypothalamic circuits and the brain-adipose axis play an important role in the regulation of energy homeostasis, appetite, hunger and satiety. for example, mutations in the leptin gene cause obesity through almost unsuppressed overeating. common (multifactorial) obesity, most likely resulting from a concerted interplay of genetic, epigenetic and environmental factors, is clearly linked to genetic predisposition by multiple risk variants, which, however only account for a minor part of the general bmi variability. although gwas opened new avenues in elucidating the complex genetics behind common obesity, understanding the biological mechanisms relative to the specific risk contributing to obesity remains poorly understood. non-genetic factors such as eating behavior or physical activity strongly modulate the individual risk for developing obesity. these factors may interact with genetic predisposition for obesity through epigenetic mechanisms. thus, here, we review the current knowledge about monogenic and common (multifactorial) obesity highlighting the important recent advances in our knowledge on how epigenetic regulation is involved in the etiology of obesity.”
Piunti, A., & Shilatifard, A.. (2016). Epigenetic balance of gene expression by polycomb and compass families. Science
Plain numerical DOI: 10.1126/science.aad9780
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“Epigenetic regulation of gene expression in metazoans is central for establishing cellular diversity, and its deregulation can result in pathological conditions. although transcription factors are essential for implementing gene expression programs, they do not function in isolation and require the recruitment of various chromatin-modifying and -remodeling machineries. a classic example of developmental chromatin regulation is the balanced activities of the polycomb group (pcg) proteins within the prc1 and prc2 complexes, and the trithorax group (trxg) proteins within the compass family, which are highly mutated in a large number of human diseases. in this review, we will discuss the latest findings regarding the properties of the pcg and compass families and the insight they provide into the epigenetic control of transcription under physiological and pathological settings.”
Jones, P. A., & Baylin, S. B.. (2002). The fundamental role of epigenetic events in cancer. Nature Reviews Genetics
Plain numerical DOI: 10.1038/nrg816
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“Patterns of dna methylation and chromatin structure are profoundly altered in neoplasia and include genome-wide losses of, and regional gains in, dna methylation. the recent explosion in our knowledge of how chromatin organization modulates gene transcription has further highlighted the importance of epigenetic mechanisms in the initiation and progression of human cancer. these epigenetic changes – in particular, aberrant promoter hypermethylation that is associated with inappropriate gene silencing – affect virtually every step in tumour progression. in this review, we discuss these epigenetic events and the molecular alterations that might cause them and/or underlie altered gene expression in cancer.”
Michowski, W., Chick, J. M., Chu, C., Kolodziejczyk, A., Wang, Y., Suski, J. M., … Sicinski, P.. (2020). Cdk1 Controls Global Epigenetic Landscape in Embryonic Stem Cells. Molecular Cell
Plain numerical DOI: 10.1016/j.molcel.2020.03.010
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“The cyclin-dependent kinase 1 (cdk1) drives cell division. to uncover additional functions of cdk1, we generated knockin mice expressing an analog-sensitive version of cdk1 in place of wild-type cdk1. in our study, we focused on embryonic stem cells (escs), because this cell type displays particularly high cdk1 activity. we found that in escs, a large fraction of cdk1 substrates is localized on chromatin. cdk1 phosphorylates many proteins involved in epigenetic regulation, including writers and erasers of all major histone marks. consistent with these findings, inhibition of cdk1 altered histone-modification status of escs. high levels of cdk1 in escs phosphorylate and partially inactivate dot1l, the h3k79 methyltransferase responsible for placing activating marks on gene bodies. decrease of cdk1 activity during esc differentiation de-represses dot1l, thereby allowing coordinated expression of differentiation genes. these analyses indicate that cdk1 functions to maintain the epigenetic identity of escs.”
Du, H., & Che, G.. (2017). Genetic alterations and epigenetic alterations of cancer-associated fibroblasts (Review). Oncology Letters
Plain numerical DOI: 10.3892/ol.2016.5451
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“Cancer-associated fibroblasts (cafs) are one major type of component identified in the tumor microenvironment. studies have focused on the genetic and epigenetic status of cafs, since they are critical in tumor progression and differ phenotypically and functionally from normal fibroblasts. the present review summarizes the recent achievements in understanding the gene profiles of cafs and pays special attention to their possible epigenetic alterations. a total of 7 possible genetic alterations and epigenetic changes in cafs are discussed, including gene differential expression, karyotype analysis, gene copy number variation, loss of heterozygosis, allelic imbalance, microsatellite instability, post-transcriptional control and dna methylation. these genetic and epigenetic characteristics are hypothesized to provide a deep understanding of cafs and a perspective on their clinical significance.”
Krol, K. M., Moulder, R. G., Lillard, T. S., Grossmann, T., & Connelly, J. J.. (2019). Epigenetic dynamics in infancy and the impact of maternal engagement. Science Advances
Plain numerical DOI: 10.1126/sciadv.aay0680
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“The contribution of nature versus nurture to the development of human behavior has been debated for centuries. here, we offer a piece to this complex puzzle by identifying the human endogenous oxytocin system-known for its critical role in mammalian sociality-as a system sensitive to its early environment and subject to epigenetic change. recent animal work suggests that early parental care is associated with changes in dna methylation of conserved regulatory sites within the oxytocin receptor gene (oxtrm). through dyadic modeling of behavior and oxtrm status across the first year and a half of life, we translated these findings to 101 human mother-infant dyads. we show that oxtrm is dynamic in infancy and its change is predicted by maternal engagement and reflective of behavioral temperament. we provide evidence for an early window of environmental epigenetic regulation of the oxytocin system, facilitating the emergence of individual differences in human behavior.”
Rohde, K., Keller, M., la Cour Poulsen, L., Blüher, M., Kovacs, P., & Böttcher, Y.. (2019). Genetics and epigenetics in obesity. Metabolism: Clinical and Experimental
Plain numerical DOI: 10.1016/j.metabol.2018.10.007
DOI URL
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“Obesity is among the most threatening health burdens worldwide and its prevalence has markedly increased over the last decades. obesity maybe considered a heritable trait. identifications of rare cases of monogenic obesity unveiled that hypothalamic circuits and the brain-adipose axis play an important role in the regulation of energy homeostasis, appetite, hunger and satiety. for example, mutations in the leptin gene cause obesity through almost unsuppressed overeating. common (multifactorial) obesity, most likely resulting from a concerted interplay of genetic, epigenetic and environmental factors, is clearly linked to genetic predisposition by multiple risk variants, which, however only account for a minor part of the general bmi variability. although gwas opened new avenues in elucidating the complex genetics behind common obesity, understanding the biological mechanisms relative to the specific risk contributing to obesity remains poorly understood. non-genetic factors such as eating behavior or physical activity strongly modulate the individual risk for developing obesity. these factors may interact with genetic predisposition for obesity through epigenetic mechanisms. thus, here, we review the current knowledge about monogenic and common (multifactorial) obesity highlighting the important recent advances in our knowledge on how epigenetic regulation is involved in the etiology of obesity.”
Cortes, L. R., Cisternas, C. D., & Forger, N. G.. (2019). Does gender leave an epigenetic imprint on the brain?. Frontiers in Neuroscience
Plain numerical DOI: 10.3389/fnins.2019.00173
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“The words ‘sex’ and ‘gender’ are often used interchangeably in common usage. in fact, the merriam-webster dictionary offers ‘sex’ as the definition of gender. the authors of this review are neuroscientists, and the words ‘sex’ and ‘gender’ mean very different things to us: sex is based on biological factors such as sex chromosomes and gonads, whereas gender has a social component and involves differential expectations or treatment by conspecifics, based on an individual’s perceived sex. while we are accustomed to thinking about ‘sex’ and differences between males and females in epigenetic marks in the brain, we are much less used to thinking about the biological implications of gender. nonetheless, careful consideration of the field of epigenetics leads us to conclude that gender must also leave an epigenetic imprint on the brain. indeed, it would be strange if this were not the case, because all environmental influences of any import can epigenetically change the brain. in the following pages, we explain why there is now sufficient evidence to suggest that an epigenetic imprint for gender is a logical conclusion. we define our terms for sex, gender, and epigenetics, and describe research demonstrating sex differences in epigenetic mechanisms in the brain which, to date, is mainly based on work in non-human animals. we then give several examples of how gender, rather than sex, may cause the brain epigenome to differ in males and females, and finally consider the myriad of ways that sex and gender interact to shape gene expression in the brain.”
Miro-Blanch, J., & Yanes, O.. (2019). Epigenetic regulation at the interplay between gut microbiota and host metabolism. Frontiers in Genetics
Plain numerical DOI: 10.3389/fgene.2019.00638
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“Gut microbiota communities have coevolved for millions of years in a symbiotic relationship with their mammalian hosts. elucidating and understanding the molecular mechanisms by which microbiota interacts with its host and how this contributes to the homeostasis of the host is crucial. one of these molecular relationships is the so-called chemical crosstalk between microbiota and host metabolisms, including the poorly explored epigenetic regulation of host tissues by the metabolic activity of gut microbiota in response to changes in diet. dna methylation and histone modifications are epigenetic marks partly regulated by enzymes such as methylases and acetylases, whose activity depend on host and microbiota metabolites that act as substrates and cofactors for these reactions. however, providing a complete mechanistic description of the regulatory interactions between both metabolisms and the impact on the expression of host genes through an epigenetic modulation, remains elusive. this article presents our perspective on how metabolomic, metagenomic, transcriptomic, and epigenomic data can be used to investigate the ‘microbiota-nutrient metabolism-epigenetics axis.’ we also discuss the implications and opportunities this knowledge may have for basic and applied science, such as the impact on the way we structure future research, understand, and prevent diseases like type 2 diabetes or obesity.”
Cacabelos, R., Carril, J., Sanmartín, A., & Cacabelos, P.. (
2019).
KRAS – an overview | ScienceDirect Topics. In Pharmacoepigenetics
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“The pharmacoepigenetic apparatus is integrated by gene clusters of different categories, including (i) pathogenic genes involved in disease pathogenesis, (ii) mechanistic genes encoding components of the epigenetic machinery serving as targets for epigenetic drugs, (iii) metabolic genes associated with the metabolism of drugs (phase i and phase ii enzymatic reactions), (iv) transporter genes encoding protein transporters acting as substrates, inhibitors, or inducers of drugs in association with metabolic enzymes, and (v) pleiotropic genes engaged in multiple metabolomic networks. all these genes, encoding pharmacoepigenetic processors, are under the control of the epigenetic machinery. according to their major targets, epigenetic drugs can be classified into the following categories: dna methyltransferase inhibitors, histone deacetylase inhibitors, histone acetyltransferase inhibitors, histone methyltransferase inhibitors, histone demethylase inhibitors, atp-dependent chromatin remodelers, polycomb repressive complex inhibitors, bromodomain inhibitors, and chromodomain inhibitors. most fda-approved epigenetic drugs have been developed for the treatment of different types of cancer; they are not devoid of severe side effects and many of them show limitations for brain penetration. structural and/or functional genomic defects in pharmacoepigenetic processors are responsible for drug resistance, and some epigenetic interventions are able to reverse this adverse phenomenon in experimental studies. some epigenetic signatures may also help to predict drug response or resistance in cancer. recent studies are contributing to consolidating the impact of toxicoepigenetics and nutriepigenetics in health and disease, reflecting bidirectional communication between environmental factors and the human genome. globally, epigenetic drugs are opening new avenues in molecular pharmacology, and pharmacoepigenetics is an upgraded version of what personalized medicine should be in the near future.”
Ross, K. M., Carroll, J., Horvath, S., Hobel, C. J., Coussons-Read, M. E., & Dunkel Schetter, C.. (2020). Immune epigenetic age in pregnancy and 1 year after birth: Associations with weight change. American Journal of Reproductive Immunology
Plain numerical DOI: 10.1111/aji.13229
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“Problem: epigenetic age indices are markers of biological aging determined from dna methylation patterns. accelerated epigenetic age predicts morbidity and mortality. women tend to demonstrate slower blood epigenetic aging compared to men, possibly due to female-specific hormones and reproductive milestones. pregnancy and the post-partum period are critical reproductive periods that have not been studied yet with respect to epigenetic aging. the purpose of this paper was to examine whether pregnancy itself and an important pregnancy-related variable, changes in body mass index (bmi) between pregnancy and the post-partum period, are associated with epigenetic aging. method of study: a pilot sample of 35 women was recruited as part of the healthy babies before birth (hb3) project. whole blood samples were collected at mid-pregnancy and 1 year post-partum. dna methylation at both time points was assayed using infinium 450k and epic chips. epigenetic age indices were calculated using an online calculator. results: paired-sample t-tests were used to test differences in epigenetic age indices from pregnancy to 1 year after birth. over this critical time span, women became younger with respect to phenotypic epigenetic age, grimage, dnam pai-1, and epigenetic age indices linked to aging-related shifts in immune cell populations, known as extrinsic epigenetic age. post-partum bmi retention, but not prenatal bmi increases, predicted accelerated epigenetic aging. conclusion: women appear to become younger from pregnancy to the post-partum period based on specific epigenetic age indices. further, bmi at 1 year after birth that reflects weight retention predicted greater epigenetic aging during this period.”
Zhang, T., Pilko, A., & Wollman, R.. (2020). Loci specific epigenetic drug sensitivity. Nucleic Acids Research
Plain numerical DOI: 10.1093/nar/gkaa210
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“Therapeutic targeting of epigenetic modulators offers a novel approach to the treatment of multiple diseases. the cellular consequences of chemical compounds that target epigenetic regulators (epi-drugs) are complex. epi-drugs affect global cellular phenotypes and cause local changes to gene expression due to alteration of a gene chromatin environment. despite increasing use in the clinic, the mechanisms responsible for cellular changes are unclear. specifically, to what degree the effects are a result of cell-wide changes or disease related locus specific effects is unknown. here we developed a platform to systematically and simultaneously investigate the sensitivity of epi-drugs at hundreds of genomic locations by combining dna barcoding, unique split-pool encoding, and single cell expression measurements. internal controls are used to isolate locus specific effects separately from any global consequences these drugs have. using this platform we discovered wide-spread loci specific sensitivities to epi-drugs for three distinct epi-drugs that target histone deacetylase, dna methylation and bromodomain proteins. by leveraging encode data on chromatin modification, we identified features of chromatin environments that are most likely to be affected by epi-drugs. the measurements of loci specific epi-drugs sensitivities will pave the way to the development of targeted therapy for personalized medicine.”
Marczylo, E. L., Jacobs, M. N., & Gant, T. W.. (2016). Environmentally induced epigenetic toxicity: potential public health concerns. Critical Reviews in Toxicology
Plain numerical DOI: 10.1080/10408444.2016.1175417
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“Throughout our lives, epigenetic processes shape our development and enable us to adapt to a constantly changing environment. identifying and understanding environmentally induced epigenetic change(s) that may lead to adverse outcomes is vital for protecting public health. this review, therefore, examines the present understanding of epigenetic mechanisms involved in the mammalian life cycle, evaluates the current evidence for environmentally induced epigenetic toxicity in human cohorts and rodent models and highlights the research considerations and implications of this emerging knowledge for public health and regulatory toxicology. many hundreds of studies have investigated such toxicity, yet relatively few have demonstrated a mechanistic association among specific environmental exposures, epigenetic changes and adverse health outcomes in human epidemiological cohorts and/or rodent models. while this small body of evidence is largely composed of exploratory in vivo high-dose range studies, it does set a precedent for the existence of environmentally induced epigenetic toxicity. consequently, there is worldwide recognition of this phenomenon, and discussion on how to both guide further scientific research towards a greater mechanistic understanding of environmentally induced epigenetic toxicity in humans, and translate relevant research outcomes into appropriate regulatory policies for effective public health protection.”
Roth, T. L., Lubin, F. D., Sodhi, M., & Kleinman, J. E.. (2009). Epigenetic mechanisms in schizophrenia. Biochimica et Biophysica Acta – General Subjects
Plain numerical DOI: 10.1016/j.bbagen.2009.06.009
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“Epidemiological research suggests that both an individual’s genes and the environment underlie the pathophysiology of schizophrenia. molecular mechanisms mediating the interplay between genes and the environment are likely to have a significant role in the onset of the disorder. recent work indicates that epigenetic mechanisms, or the chemical markings of the dna and the surrounding histone proteins, remain labile through the lifespan and can be altered by environmental factors. thus, epigenetic mechanisms are an attractive molecular hypothesis for environmental contributions to schizophrenia. in this review, we first present an overview of schizophrenia and discuss the role of nature versus nurture in its pathology, where ‘nature’ is considered to be inherited or genetic vulnerability to schizophrenia, and ‘nurture’ is proposed to exert its effects through epigenetic mechanisms. second, we define dna methylation and discuss the evidence for its role in schizophrenia. third, we define posttranslational histone modifications and discuss their place in schizophrenia. this research is likely to lead to the development of epigenetic therapy, which holds the promise of alleviating cognitive deficits associated with schizophrenia. © 2009 elsevier b.v.”
Mulero-Navarro, S., & Esteller, M.. (2008). Epigenetic biomarkers for human cancer: The time is now. Critical Reviews in Oncology/Hematology
Plain numerical DOI: 10.1016/j.critrevonc.2008.03.001
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“The importance of epigenetic processes in the development of cancer is clear. the study of epigenetics is therefore bound to contribute to the improvement of human health. aberrations in dna methylation, post-translational modifications of histones, chromatin remodeling and micrornas patterns are the main epigenetic alterations, and these are associated with tumorigenesis. epigenetic technologies in cancer studies are helping increase the number of cancer candidate genes and allow us to examine changes in 5-methylcytosine dna and histone modifications at a genome-wide level. in fact, all the various cellular pathways contributing to the neoplastic phenotype are affected by epigenetic genes in cancer. they are being explored as biomarkers in clinical use for early detection of disease, tumor classification and response to treatment with classical chemotherapy agents, target compounds and epigenetic drugs. encouraging results have been obtained with histone deacetylase and dna methyltransferase inhibitors, leading the us food and drug administration to approve several of them for the treatment of hematological malignancies and lymphoproliferative disorders, such as myelodysplastic syndrome and cutaneous lymphoma. however, many tasks remains to be done, such as the clinical validation of epigenetic biomarkers to allow the accurate prediction of the outcome of cancer patients and their potential chemosensitivity to current pharmacological treatments. © 2008 elsevier ireland ltd. all rights reserved.”
Jeong, P. S., Sim, B. W., Park, S. H., Kim, M. J., Kang, H. G., Nanjidsuren, T., … Kim, S. U.. (2020). Chaetocin improves pig cloning efficiency by enhancing epigenetic reprogramming and autophagic activity. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms21144836
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“Efficient epigenetic reprogramming is crucial for the in vitro development of mammalian somatic cell nuclear transfer (scnt) embryos. the aberrant levels of histone h3 lysine 9 trimethylation (h3k9me3) is an epigenetic barrier. in this study, we evaluated the effects of chaetocin, an h3k9me3-specific methyltransferase inhibitor, on the epigenetic reprogramming and developmental competence of porcine scnt embryos. the scnt embryos showed abnormal levels of h3k9me3 at the pronuclear, two-cell, and four-cell stages compared to in vitro fertilized embryos. moreover, the expression levels of h3k9me3-specific methyltransferases (suv39h1 and suv39h2) and dna methyltransferases (dnmt1, dnmt3a, and dnmt3b) were higher in scnt embryos. treatment with 0.5 nm chaetocin for 24 h after activation significantly increased the developmental competence of scnt embryos in terms of the cleavage rate, blastocyst formation rate, hatching rate, cell number, expression of pluripotency-related genes, and cell survival rate. in particular, chaetocin enhanced epigenetic reprogramming by reducing the h3k9me3 and 5-methylcytosine levels and restoring the abnormal expression of h3k9me3-specific methyltransferases and dna methyltransferases. chaetocin induced autophagic activity, leading to a significant reduction in maternal mrna levels in embryos at the pronuclear and two-cell stages. these findings revealed that chaetocin enhanced the developmental competence of porcine scnt embryos by regulating epigenetic reprogramming and autophagic activity and so could be used to enhance the production of transgenic pigs for biomedical research.”
Lesch, B. J., Tothova, Z., Morgan, E. A., Liao, Z., Bronson, R. T., Ebert, B. L., & Page, D. C.. (2019). Intergenerational epigenetic inheritance of cancer susceptibility in mammals. ELife
Plain numerical DOI: 10.7554/eLife.39380
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“Susceptibility to cancer is heritable, but much of this heritability remains unexplained. some ‘missing’ heritability may be mediated by epigenetic changes in the parental germ line that do not involve transmission of genetic variants from parent to offspring. we report that deletion of the chromatin regulator kdm6a (utx) in the paternal germ line results in elevated tumor incidence in genetically wild type mice. this effect increases following passage through two successive generations of kdm6a male germline deletion, but is lost following passage through a wild type germ line. the h3k27me3 mark is redistributed in sperm of kdm6a mutants, and we define approximately 200 h3k27me3-marked regions that exhibit increased dna methylation, both in sperm of kdm6a mutants and in somatic tissue of progeny. hypermethylated regions in enhancers may alter regulation of genes involved in cancer initiation or progression. epigenetic changes in male gametes may therefore impact cancer susceptibility in adult offspring.”
Piunti, A., & Shilatifard, A.. (2016). Epigenetic balance of gene expression by polycomb and compass families. Science
Plain numerical DOI: 10.1126/science.aad9780
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“Epigenetic regulation of gene expression in metazoans is central for establishing cellular diversity, and its deregulation can result in pathological conditions. although transcription factors are essential for implementing gene expression programs, they do not function in isolation and require the recruitment of various chromatin-modifying and -remodeling machineries. a classic example of developmental chromatin regulation is the balanced activities of the polycomb group (pcg) proteins within the prc1 and prc2 complexes, and the trithorax group (trxg) proteins within the compass family, which are highly mutated in a large number of human diseases. in this review, we will discuss the latest findings regarding the properties of the pcg and compass families and the insight they provide into the epigenetic control of transcription under physiological and pathological settings.”
Sun, Y. C., Wang, Y. Y., Ge, W., Cheng, S. F., Dyce, P. W., & Shen, W.. (2017). Epigenetic regulation during the differentiation of stem cells to germ cells. Oncotarget
Plain numerical DOI: 10.18632/oncotarget.18444
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“Gametogenesis is an essential process to ensure the transfer of genetic information from one generation to the next. it also provides a mechanism by which genetic evolution can take place. although the genome of primordial germ cells (pgcs) is exactly the same with somatic cells within an organism, there are significant differences between their developments. for example, pgcs eventually undergo meiosis to become functional haploid gametes, and prior to that they undergo epigenetic imprinting which greatly alter their genetic regulation. epigenetic imprinting of pgcs involves the erasure of dna methylation and the reestablishment of them during sperm and oocyte formation. these processes are necessary and important during gametogenesis. also, histone modification and x-chromosome inactivation have important roles during germ cell development. recently, several studies have reported that functional sperm or oocytes can be derived from stem cells in vivo or in vitro. to produce functional germ cells, induction of germ cells from stem cells must recapitulate these processes similar to endogenous germ cells, such as epigenetic modifications. this review focuses on the epigenetic regulation during the process of germ cell development and discusses their importance during the differentiation from stem cells to germ cells.”
Samadani, A. A., Norollahi, S. E., Rashidy-Pour, A., Mansour-Ghanaei, F., Nemati, S., Joukar, F., … Gatei, M.. (2018). Cancer signaling pathways with a therapeutic approach: An overview in epigenetic regulations of cancer stem cells. Biomedicine and Pharmacotherapy
Plain numerical DOI: 10.1016/j.biopha.2018.09.048
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“One of the most important issues in cancer progression is caner stem cells (cscs) which have illustrated that the bulk tumors can arise from a special combination of cells. remarkably, it has been proposed to be a notable and strong factor in carcinogenesis and tumorogenesis and also is a key parameter of therapeutic resistance. in this way, recent findings have shown the key roles of epigenetic regulations in cancer development.considerably, epigenetic regulations of gene expression is an active and dynamic process including histone modification, dna methylation and chromatin remodeling with a reversible trait.meaningly, recent and novel findings have described the significance of epigenetic regulatory proteins from divers features comprising tumorogenesis,stem cell proliferation and carcinogenesis. evidently, abnormal epigenetic regulations is directly related with many serious disorders particularly different cancers. we here review a discussion of how the deregulation of eclectic pathways containing sonic hedgehog (shh), wnt, beta catenin and notch can help to carcinogenesis specially focusing to survival and maintenance of cscs in therapeutic approach.”
Cakouros, D. D., & Gronthos, S.. (2019). Epigenetic regulation of bone marrow stem cell aging: Revealing epigenetic signatures associated with hematopoietic and mesenchymal stem cell aging. Aging and Disease
Plain numerical DOI: 10.14336/AD.2017.1213
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“In this review we explore the importance of epigenetics as a contributing factor for aging adult stem cells. we summarize the latest findings of epigenetic factors deregulated as adult stem cells age and the consequence on stem cell self-renewal and differentiation, with a focus on adult stem cells in the bone marrow. with the latest whole genome bisulphite sequencing and chromatin immunoprecipitations we are able to decipher an emerging pattern common for adult stem cells in the bone marrow niche and how this might correlate to epigenetic enzymes deregulated during aging. we begin by briefly discussing the initial observations in yeast, drosophila and caenorhabditis elegans (c. elegans) that led to the breakthrough research that identified the role of epigenetic changes associated with lifespan and aging. we then focus on adult stem cells, specifically in the bone marrow, which lends strong support for the deregulation of dna methyltransferases, histone deacetylases, acetylates, methyltransferases and demethylases in aging stem cells, and how their corresponding epigenetic modifications influence gene expression and the aging phenotype. given the reversible nature of epigenetic modifications we envisage ‘epi’ targeted therapy as a means to reprogram aged stem cells into their younger counterparts.”
Hochedlinger, K., & Plath, K.. (2009). Epigenetic reprogramming and induced pluripotency. Development
Plain numerical DOI: 10.1242/dev.020867
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“The cloning of animals from adult cells has demonstrated that the developmental state of adult cells can be reprogrammed into that of embryonic cells by uncharacterized factors within the oocyte. more recently, transcription factors have been identified that can induce pluripotency in somatic cells without the use of oocytes, generating induced pluripotent stem (ips) cells. ips cells provide a unique platform to dissect the molecular mechanisms that underlie epigenetic reprogramming. moreover, ips cells can teach us about principles of normal development and disease, and might ultimately facilitate the treatment of patients by custom-tailored cell therapy.”
Casadesús, J., & Low, D.. (2006). Epigenetic Gene Regulation in the Bacterial World. Microbiology and Molecular Biology Reviews
Plain numerical DOI: 10.1128/mmbr.00016-06
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“Like many eukaryotes, bacteria make widespread use of postreplicative dna methylation for the epigenetic control of dna-protein interactions. unlike eukaryotes, however, bacteria use dna adenine methylation (rather than dna cytosine methylation) as an epigenetic signal. dna adenine methylation plays roles in the virulence of diverse pathogens of humans and livestock animals, including pathogenic escherichia coli, salmonella, vibrio, yersinia, haemophilus, and brucella. in alphaproteobacteria, methylation of adenine at gantc sites by the ccrm methylase regulates the cell cycle and couples gene transcription to dna replication. in gammaproteobacteria, adenine methylation at gatc sites by the dam methylase provides signals for dna replication, chromosome segregation, mismatch repair, packaging of bacteriophage genomes, transposase activity, and regulation of gene expression. transcriptional repression by dam methylation appears to be more common than transcriptional activation. certain promoters are active only during the hemimethylation interval that follows dna replication; repression is restored when the newly synthesized dna strand is methylated. in the e. coli genome, however, methylation of specific gatc sites can be blocked by cognate dna binding proteins. blockage of gatc methylation beyond cell division permits transmission of dna methylation patterns to daughter cells and can give rise to distinct epigenetic states, each propagated by a positive feedback loop. switching between alternative dna methylation patterns can split clonal bacterial populations into epigenetic lineages in a manner reminiscent of eukaryotic cell differentiation. inheritance of self-propagating dna methylation patterns governs phase variation in the e. coli pap operon, the agn43 gene, and other loci encoding virulence-related cell surface functions.”
Rando, O. J.. (2016). Intergenerational transfer of epigenetic information in sperm. Cold Spring Harbor Perspectives in Medicine
Plain numerical DOI: 10.1101/cshperspect.a022988
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“The inheritance of information beyonddnasequence, knownas epigenetic inheritance, has been implicated in a multitude of biological processes from control of plant flowering time to cancer in humans. in addition to epigenetic inheritance that occurs in dividing cells of a multicellular organism, it is also increasingly clear that at least some epigenetic information is transmitted via the gametes in a multitude of organisms, including mammals. here, i review the evidence for epigenetic information carriers in mammalian sperm, and explore the emerging field of intergenerational transfer of environmental information.”
Hayashi, S., Tamura, K., & Yokoyama, H.. (2020). Chromatin dynamics underlying the precise regeneration of a vertebrate limb – Epigenetic regulation and cellular memory. Seminars in Cell and Developmental Biology
Plain numerical DOI: 10.1016/j.semcdb.2019.04.006
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“Wound healing, tissue regeneration, and organ regrowth are all regeneration phenomena observed in vertebrates after an injury. however, the ability to regenerate differs greatly among species. mammals can undergo wound healing and tissue regeneration, but cannot regenerate an organ; for example, they cannot regrow an amputated limb. in contrast, amphibians and fish have much higher capabilities for organ-level regeneration. in addition to medical studies and those in conventional mammalian models such as mice, studies in amphibians and fish have revealed essential factors for and mechanisms of regeneration, including the regrowth of a limb, tail, or fin. however, the molecular nature of the cellular memory needed to precisely generate a new appendage from an amputation site is not fully understood. recent reports have indicated that organ regeneration is closely related to epigenetic regulation. for example, the methylation status of genomic dna is related to the expression of regeneration-related genes, and histone-modification enzymes are required to control the chromatin dynamics for regeneration. a proposed mechanism of cellular memory involving an inheritable system of epigenetic modification led us to hypothesize that epigenetic regulation forms the basis for cellular memory in organ regeneration. here we summarize the current understanding of the role of epigenetic regulation in organ regeneration and discuss the relationship between organ regeneration and epigenetic memory.”
Golbabapour, S., Abdulla, M. A., & Hajrezaei, M.. (2011). A concise review on epigenetic regulation: Insight into molecular mechanisms. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms12128661
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“Epigenetic mechanisms are responsible for the regulation of transcription of imprinted genes and those that induce a totipotent state. starting just after fertilization, dna methylation pattern undergoes establishment, reestablishment and maintenance. these modifications are important for normal embryo and placental developments. throughout life and passing to the next generation, epigenetic events establish, maintain, erase and reestablish. in the context of differentiated cell reprogramming, demethylation and activation of genes whose expressions contribute to the pluripotent state is the crux of the matter. in this review, firstly, regulatory epigenetic mechanisms related to somatic cell nuclear transfer (scnt) reprogramming are discussed, followed by embryonic development, and placental epigenetic issues. © 2011 by the authors; licensee mdpi, basel, switzerland.”
Pauken, K. E., Sammons, M. A., Odorizzi, P. M., Manne, S., Godec, J., Khan, O., … Wherry, E. J.. (2016). Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science
Plain numerical DOI: 10.1126/science.aaf2807
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“Blocking programmed death-1 (pd-1) can reinvigorate exhausted cd8 tcells (tex) and improve control of chronic infections and cancer. however, whether blocking pd-1 can reprogram tex into durable memory t cells (tmem) is unclear. we found that reinvigoration of tex in mice by pd-l1 blockade caused minimal memory development. after blockade, reinvigorated tex became reexhausted if antigen concentration remained high and failed to become tmem upon antigen clearance. tex acquired an epigenetic profile distinct from that of effector t cells (teff) and tmem cells that was minimally remodeled after pd-l1 blockade. this finding suggests that tex are a distinct lineage of cd8 t cells. nevertheless, pd-1 pathway blockade resulted in transcriptional rewiring and reengagement of effector circuitry in the tex epigenetic landscape. these data indicate that epigenetic fate inflexibility may limit current immunotherapies.”
Ryan, C. P.. (2021). “Epigenetic clocks”: Theory and applications in human biology. American Journal of Human Biology
Plain numerical DOI: 10.1002/ajhb.23488
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“All humans age, but how we age—and how fast—differs considerably from person to person. this deviation between apparent age and chronological age is often referred to as ‘biological age’ (ba) and until recently robust tools for studying ba have been scarce. ‘epigenetic clocks’ are starting to change this. epigenetic clocks use predictable changes in the epigenome, usually dna methylation, to estimate chronological age with unprecedented accuracy. more importantly, deviations between epigenetic age and chronological age predict a broad range of health outcomes and mortality risks better than chronological age alone. thus, epigenetic clocks appear to capture fundamental molecular processes tied to ba and can serve as powerful tools for studying health, development, and aging across the lifespan. in this article, i review epigenetic clocks, especially as they relate to key theoretical and applied issues in human biology. i first provide an overview of how epigenetic clocks are constructed and what we know about them. i then discuss emerging applications of particular relevance to human biologists—those related to reproduction, life-history, stress, and the environment. i conclude with an overview of the methods necessary for implementing epigenetic clocks, including considerations of study design, sample collection, and technical considerations for processing and interpreting epigenetic clocks. the goal of this review is to highlight some of the ways that epigenetic clocks can inform questions in human biology, and vice versa, and to provide human biologists with the foundational knowledge necessary to successfully incorporate epigenetic clocks into their research.”
Legoff, L., D’Cruz, S. C., Tevosian, S., Primig, M., & Smagulova, F.. (2019). Transgenerational Inheritance of Environmentally Induced Epigenetic Alterations during Mammalian Development. Cells
Plain numerical DOI: 10.3390/cells8121559
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“Genetic studies traditionally focus on dna as the molecule that passes information on from parents to their offspring. changes in the dna code alter heritable information and can more or less severely affect the progeny’s phenotype. while the idea that information can be inherited between generations independently of the dna’s nucleotide sequence is not new, the outcome of recent studies provides a mechanistic foundation for the concept. in this review, we attempt to summarize our current knowledge about the transgenerational inheritance of environmentally induced epigenetic changes. we focus primarily on studies using mice but refer to other species to illustrate salient points. some studies support the notion that there is a somatic component within the phenomenon of epigenetic inheritance. however, here, we will mostly focus on gamete-based processes and the primary molecular mechanisms that are thought to contribute to epigenetic inheritance: dna methylation, histone modifications, and non-coding rnas. most of the rodent studies published in the literature suggest that transgenerational epigenetic inheritance through gametes can be modulated by environmental factors. modification and redistribution of chromatin proteins in gametes is one of the major routes for transmitting epigenetic information from parents to the offspring. our recent studies provide additional specific cues for this concept and help better understand environmental exposure influences fitness and fidelity in the germline. in summary, environmental cues can induce parental alterations and affect the phenotypes of offspring through gametic epigenetic inheritance. consequently, epigenetic factors and their heritability should be considered during disease risk assessment.”
Guzman, F., Fazeli, Y., Khuu, M., Salcido, K., Singh, S., & Benavente, C. A.. (2020). Retinoblastoma tumor suppressor protein roles in epigenetic regulation. Cancers
Plain numerical DOI: 10.3390/cancers12102807
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“Mutations that result in the loss of function of prb were first identified in retinoblastoma and since then have been associated with the propagation of various forms of cancer. prb is best known for its key role as a transcriptional regulator during cell cycle exit. beyond the ability of prb to regulate transcription of cell cycle progression genes, prb can remodel chromatin to exert several of its other biological roles. in this review, we discuss the diverse functions of prb in epigenetic regulation including nucleosome mobilization, histone modifications, dna methylation and non-coding rnas.”
Fouad, A. F., Khan, A. A., Silva, R. M., & Kang, M. K.. (2020). Genetic and Epigenetic Characterization of Pulpal and Periapical Inflammation. Frontiers in Physiology
Plain numerical DOI: 10.3389/fphys.2020.00021
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“Pulpal and periapical diseases affect a large segment of the population. the role of microbial infections and host effector molecules in these diseases is well established. however, the interaction between host genes and environmental factors in disease susceptibility and progression is less well understood. studies of genetic polymorphisms in disease relevant genes have suggested that individual predisposition may contribute to susceptibility to pulpal and periapical diseases. other studies have explored the contribution of epigenetic mechanisms to these diseases. ongoing research expands the spectrum of non-coding rnas in pulpal disease to include viral micrornas as well. this review summarizes recent advances in the genetic and epigenetic characterization of pulpal and periapical disease, with special emphasis on recent data that address the pathogenesis of irreversible pulpal pathosis and apical periodontitis. specifically, proinflammatory and anti-inflammatory gene expression and gene polymorphism, as well as recent data on dna methylation and micrornas are reviewed. improved understanding of these mechanisms may aid in disease prevention as well as in improved treatment outcomes.”
Lee, J. E., & Ge, K.. (2014). Transcriptional and epigenetic regulation of PPARγ expression during adipogenesis. Cell and Bioscience
Plain numerical DOI: 10.1186/2045-3701-4-29
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“The nuclear receptor pparγ is a master regulator of adipogenesis. pparγ is highly expressed in adipose tissues and its expression is markedly induced during adipogenesis. in this review, we describe the current knowledge, as well as future directions, on transcriptional and epigenetic regulation of pparγ expression during adipogenesis. investigating the molecular mechanisms that control pparγ expression during adipogenesis is critical for understanding the development of white and brown adipose tissues, as well as pathological conditions such as obesity and diabetes. the robust induction of pparγ expression during adipogenesis also serves as an excellent model system for studying transcriptional and epigenetic regulation of cell-type-specific gene expression. © 2014 lee and ge; licensee biomed central ltd.”
Champagne, F. A.. (2020). Interplay between paternal germline and maternal effects in shaping development: The overlooked importance of behavioural ecology. Functional Ecology
Plain numerical DOI: 10.1111/1365-2435.13411
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“Environmental conditions can have a lasting epigenetic impact on development, and there is increasing evidence that these effects can be transmitted across generations. evidence for parental transmission of epigenetic variation to offspring has been primarily focused on paternal epigenetic influences induced by a male’s experience of nutritional, social and toxicological exposures. there is an assumption in the literature that paternal influence on offspring in non-biparental species is mediated exclusively through epigenetic transmission via the germline. however, integration of concepts from behavioural ecology into the study of parental transmission of environmental effects reveals the importance of mating tactics and maternal–paternal interplay in shaping resource allocation towards offspring in considering the mechanism(s) of epigenetic transmission. this paper describes the current state of knowledge regarding paternal epigenetic germline effects, the interplay between maternal and paternal influences and the importance of considering the complex nature of reproduction when predicting the transmission of phenotype across generations. further, this paper highlights how incorporating concepts from behavioural ecology into the study of epigenetic transmission can refine predictions of phenotypes that emerge and create a more integrated notion of development and inheritance. it is proposed that theoretical and methodological approaches that consider the impact of reproductive context, which include mating dynamics, fertility, variation in parental life history and assessment of maternal effects, could improve the predictions made within studies of paternal epigenetic effects on offspring development. a free plain language summary can be found within the supporting information of this article.”
Rando, O. J.. (2016). Intergenerational transfer of epigenetic information in sperm. Cold Spring Harbor Perspectives in Medicine
Plain numerical DOI: 10.1101/cshperspect.a022988
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“The inheritance of information beyonddnasequence, knownas epigenetic inheritance, has been implicated in a multitude of biological processes from control of plant flowering time to cancer in humans. in addition to epigenetic inheritance that occurs in dividing cells of a multicellular organism, it is also increasingly clear that at least some epigenetic information is transmitted via the gametes in a multitude of organisms, including mammals. here, i review the evidence for epigenetic information carriers in mammalian sperm, and explore the emerging field of intergenerational transfer of environmental information.”
Pollina, E. A., & Brunet, A.. (2011). Epigenetic regulation of aging stem cells. Oncogene
Plain numerical DOI: 10.1038/onc.2011.45
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“The function of adult tissue-specific stem cells declines with age, which may contribute to the physiological decline in tissue homeostasis and the increased risk of neoplasm during aging. old stem cells can be rejuvenated by environmental stimuli in some cases, raising the possibility that a subset of age-dependent stem cell changes is regulated by reversible mechanisms. epigenetic regulators are good candidates for such mechanisms, as they provide a versatile checkpoint to mediate plastic changes in gene expression and have recently been found to control organismal longevity. here, we review the importance of chromatin regulation in adult stem cell compartments. we particularly focus on the roles of chromatin-modifying complexes and transcription factors that directly impact chromatin in aging stem cells. understanding the regulation of chromatin states in adult stem cells is likely to have important implications for identifying avenues to maintain the homeostatic balance between sustained function and neoplastic transformation of aging stem cells. © 2011 macmillan publishers limited all rights reserved.”
Samarth, Kelly, D., Turnbull, M. H., & Jameson, P. E.. (2020). Molecular control of masting: An introduction to an epigenetic summer memory. Annals of Botany
Plain numerical DOI: 10.1093/AOB/MCAA004
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“• background mast flowering (‚masting’) is characterized by mass synchronized flowering at irregular intervals in populations of perennial plants over a wide geographical area, resulting in irregular high seed production. while masting is a global phenomenon, it is particularly prevalent in the alpine flora of new zealand. increases in global temperature may alter the masting pattern, affecting wider communities with a potential impact on plant-pollinator interactions, seed set and food availability for seed-consuming species. • scope this review summarizes an ecological temperature model (δt) that is being used to predict the intensity of a masting season. we introduce current molecular studies on flowering and the concept of an ‘epigenetic summer memory’ as a driver of mast flowering. we propose a hypothetical model based on temperature-associated epigenetic modifications of the floral integrator genes flowering locus t, flowering locus c and suppressor of overexpression of constans1. • conclusions genome-wide transcriptomic and targeted gene expression analyses are needed to establish the developmental and physiological processes associated with masting. such analyses may identify changes in gene expression that can be used to predict the intensity of a forthcoming masting season, as well as to determine the extent to which climate change will influence the mass synchronized flowering of masting species, with downstream impacts on their associated communities.”
Matsuyama, M., Søraas, A., Yu, S., Kim, K., Stavrou, E. X., Caimi, P. F., … Matsuyama, S.. (2020). Analysis of epigenetic aging in vivo and in vitro: Factors controlling the speed and direction. Experimental Biology and Medicine
Plain numerical DOI: 10.1177/1535370220947015
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“The mechanism of aging is not yet fully understood. it has been recognized that there are age-dependent changes in the dna methylation pattern of the whole genome. to date, there are several dna methylation-based estimators of the chronological age. a majority of the estimators use the dna methylation data from a single tissue type, such as blood. in 2013, for the first time, steve horvath reported the dna methylation-based age estimator (353 cpgs were used) that could be applied to multiple tissues. a refined, more sensitive version that uses 391 cpgs was subsequently developed and validated in human cells, including fibroblasts. in this review, the age predicted by dna methylation-based age estimator is referred to as dnamage, and the biological process controlling the progression of dnamage is referred to as the epigenetic aging in this minireview. the concepts of dnamage and epigenetic aging provide us opportunities to discover previously unrecognized biological events controlling aging. in this article, we discuss the frequently asked questions regarding dnamage and the epigenetic aging by introducing recent studies of ours and others. we focus on addressing the following questions: (1) is there any synchronization of dnamage between cells in a human body?, (2) can we use in vitro (cell culture) systems to study the epigenetic aging?, (3) is there an age limit of dnamage?, and (4) is it possible to change the speed and direction of the epigenetic aging? we describe our current understandings to these questions and outline potential future directions. impact statement: aging is associated with dna methylation (dnam) changes. recent advancement of the whole-genome dnam analysis technology allowed scientists to develop dnam-based age estimators. a majority of these estimators use dnam data from a single tissue type such as blood. in 2013, a multi-tissue age estimator using dnam pattern of 353 cpgs was developed by steve horvath. this estimator was named ‘epigenetic clock’, and the improved version using dnam pattern of 391 cpgs was developed in 2018. the estimated age by epigenetic clock is named dnamage. dnamage can be used as a biomarker of aging predicting the risk of age-associated diseases and mortality. although the dnam-based age estimators were developed, the mechanism of epigenetic aging is still enigmatic. the biological significance of epigenetic aging is not well understood, either. this minireview discusses the current understanding of th…”
Yelina, N., Diaz, P., Lambing, C., & Henderson, I. R.. (2015). Epigenetic control of meiotic recombination in plants. Science China Life Sciences
Plain numerical DOI: 10.1007/s11427-015-4811-x
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“Meiotic recombination is a deeply conserved process within eukaryotes that has a profound effect on patterns of natural genetic variation. during meiosis homologous chromosomes pair and undergo dna double strand breaks generated by the spo11 endonuclease. these breaks can be repaired as crossovers that result in reciprocal exchange between chromosomes. the frequency of recombination along chromosomes is highly variable, for example, crossovers are rarely observed in heterochromatin and the centromeric regions. recent work in plants has shown that crossover hotspots occur in gene promoters and are associated with specific chromatin modifications, including h2a.z. meiotic chromosomes are also organized in loop-base arrays connected to an underlying chromosome axis, which likely interacts with chromatin to organize patterns of recombination. therefore, epigenetic information exerts a major influence on patterns of meiotic recombination along chromosomes, genetic variation within populations and evolution of plant genomes.”
Khan, M. A., Tania, M., & Fu, J.. (2019). Epigenetic role of thymoquinone: impact on cellular mechanism and cancer therapeutics. Drug Discovery Today
Plain numerical DOI: 10.1016/j.drudis.2019.09.007
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“Thymoquinone is a natural product known for its anticancer activity. preclinical studies indicated numerous mechanisms of action by which thymoquinone exerts its effects on cancer cells. recent evidence has indicated that thymoquinone can modulate epigenetic machinery, like modifying histone acetylation and deacetylation, dna methylation and demethylation, which are among the major epigenetic changes that can contribute to carcinogenesis. moreover, thymoquinone can alter the genetic expression of various noncoding rnas, such as mirna and lncrna, which are the key parts of cellular epigenetics. this review focuses on cellular epigenetic systems, epigenetic changes responsible for cancer and the counteraction of thymoquinone to target epigenetic challenges, which might be among the mechanisms of the thymoquinone effect in cancer cells.”
Renani, P. G., Taheri, F., Rostami, D., Farahani, N., Abdolkarimi, H., Abdollahi, E., … Gheibi Hayat, S. M.. (2019). Involvement of aberrant regulation of epigenetic mechanisms in the pathogenesis of Parkinson’s disease and epigenetic-based therapies. Journal of Cellular Physiology
Plain numerical DOI: 10.1002/jcp.28622
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“Parkinson’s disease (pd) is known as a progressive neurodegenerative disorder associated with the reduction of dopamine-secreting neurons and the formation of lewy bodies in the substantia nigra and basal ganglia routes. aging, as well as environmental and genetic factors, are considered as disease risk factors that can make pd as a complex one. epigenetics means studying heritable changes in gene expression or function, without altering the underlying dna sequence. multiple studies have shown the association of epigenetic variations with onset or progression of various types of diseases. dna methylation, posttranslational modifications of histones and presence of microrna (mirna) are among epigenetic processes involved in regulating pathways related to the development of pd. unlike genetic mutations, most epigenetic variations may be reversible or preventable. therefore, the return of aberrant epigenetic events in different cells is a growing therapeutic approach to treatment or prevention. currently, there are several methods for treating pd patients, the most important of which are drug therapies. however, detection of genes and epigenetic mechanisms involved in the disease can develop appropriate diagnosis and treatment of the disease before the onset of disabilities and resulting complications. the main purpose of this study was to review the most important epigenetic molecular mechanisms, epigenetic variations in pd, and epigenetic-based therapies.”
Sun, Y. C., Wang, Y. Y., Ge, W., Cheng, S. F., Dyce, P. W., & Shen, W.. (2017). Epigenetic regulation during the differentiation of stem cells to germ cells. Oncotarget
Plain numerical DOI: 10.18632/oncotarget.18444
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“Gametogenesis is an essential process to ensure the transfer of genetic information from one generation to the next. it also provides a mechanism by which genetic evolution can take place. although the genome of primordial germ cells (pgcs) is exactly the same with somatic cells within an organism, there are significant differences between their developments. for example, pgcs eventually undergo meiosis to become functional haploid gametes, and prior to that they undergo epigenetic imprinting which greatly alter their genetic regulation. epigenetic imprinting of pgcs involves the erasure of dna methylation and the reestablishment of them during sperm and oocyte formation. these processes are necessary and important during gametogenesis. also, histone modification and x-chromosome inactivation have important roles during germ cell development. recently, several studies have reported that functional sperm or oocytes can be derived from stem cells in vivo or in vitro. to produce functional germ cells, induction of germ cells from stem cells must recapitulate these processes similar to endogenous germ cells, such as epigenetic modifications. this review focuses on the epigenetic regulation during the process of germ cell development and discusses their importance during the differentiation from stem cells to germ cells.”
Sharma, V., Wright, K. L., Epling-Burnette, P. K., & Reuther, G. W.. (2020). Metabolic Vulnerabilities and Epigenetic Dysregulation in Myeloproliferative Neoplasms. Frontiers in Immunology
Plain numerical DOI: 10.3389/fimmu.2020.604142
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“The janus kinase 2 (jak2)-driven myeloproliferative neoplasms (mpns) are associated with clonal myelopoiesis, elevated risk of death due to thrombotic complications, and transformation to acute myeloid leukemia (aml). jak2 inhibitors improve the quality of life for mpn patients, but these approved therapeutics do not readily reduce the natural course of disease or antagonize the neoplastic clone. an understanding of the molecular and cellular changes requisite for mpn development and progression are needed to develop improved therapies. recently, murine mpn models were demonstrated to exhibit metabolic vulnerabilities due to a high dependence on glucose. neoplastic hematopoietic progenitor cells in these mice express elevated levels of glycolytic enzymes and exhibit enhanced levels of glycolysis and oxidative phosphorylation, and the disease phenotype of these mpn model mice is antagonized by glycolytic inhibition. while all mpn-driving mutations lead to aberrant jak2 activation, these mutations often co-exist with mutations in genes that encode epigenetic regulators, including loss of function mutations known to enhance mpn progression. in this perspective we discuss how altered activity of epigenetic regulators (e.g., methylation and acetylation) in mpn-driving stem and progenitor cells may alter cellular metabolism and contribute to the mpn phenotype and progression of disease. specific metabolic changes associated with epigenetic deregulation may identify patient populations that exhibit specific metabolic vulnerabilities that are absent in normal hematopoietic cells, and thus provide a potential basis for the development of more effective personalized therapeutic approaches.”
Mimura, I., Tanaka, T., & Nangaku, M.. (2016). New insights into molecular mechanisms of epigenetic regulation in kidney disease. Clinical and Experimental Pharmacology and Physiology
Plain numerical DOI: 10.1111/1440-1681.12663
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“The number of patients with kidney failure has increased in recent years. different factors contribute to the progression of chronic kidney disease, including glomerular sclerosis, atherosclerosis of the renal arteries and tubulointerstitial fibrosis. tubulointerstitial injury is induced by hypoxia and other inflammatory signals, leading to fibroblast activation. technological advances using high-throughput sequencing has enabled the determination of the expression profile of almost all genes, revealing that gene expression is intricately regulated by dna methylation, histone modification, changes in chromosome conformation, long non-coding rnas and micrornas. these epigenetic modifications are stored as cellular epigenetic memory. epigenetic memory leads to adult-onset disease or ageing in the long term and may possibly play an important role in the kidney disease process. herein we emphasize the importance of clarifying the molecular mechanisms underlying epigenetic modifications because this may lead to the development of new therapeutic targets in kidney disease.”
Noguchi, H., Miyagi-Shiohira, C., & Nakashima, Y.. (2018). Induced tissue-specific stem cells and epigenetic memory in induced pluripotent stem cells. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms19040930
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“Induced pluripotent stem (ips) cells have significant implications for overcoming most of the ethical issues associated with embryonic stem (es) cells. the pattern of expressed genes, dna methylation, and covalent histone modifications in ips cells are very similar to those in es cells. however, it has recently been shown that, following the reprogramming of mouse/human ips cells, epigenetic memory is inherited from the parental cells. these findings suggest that the phenotype of ips cells may be influenced by their cells of origin and that their skewed differentiation potential may prove useful in the generation of differentiated cell types that are currently difficult to produce from es/ips cells for the treatment of human diseases. our recent study demonstrated the generation of induced tissue-specific stem (its) cells by transient overexpression of the reprogramming factors combined with tissue-specific selection. its cells are cells that inherit numerous components of epigenetic memory from donor tissue and acquire self-renewal potential. this review describes the ‘epigenetic memory’ phenomenon in ips and its cells and the possible clinical applications of these stem cells.”
Ruggero, K., Farran-Matas, S., Martinez-Tebar, A., & Aytes, A.. (2018). Epigenetic Regulation in Prostate Cancer Progression. Current Molecular Biology Reports
Plain numerical DOI: 10.1007/s40610-018-0095-9
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“Cancer is a disease arising from both genetic and epigenetic modifications of dna that contribute to changes in gene expression in the cell. genetic modifications include loss or amplification of dna, loss of heterozygosity (loh) as well as gene mutations. epigenetic changes in cancer are generally thought to be brought about by alterations in dna and histone modifications that lead to the silencing of tumour suppressor genes and the activation of oncogenic genes. other consequences that result from epigenetic changes, such as inappropriate expression or repression of some genes in the wrong cellular context, can also result in the alteration of control and physiological systems such that a normal cell becomes tumorigenic. excessive levels of the enzymes that act as epigenetic modifiers have been reported as markers of aggressive breast cancer and are associated with metastatic progression. it is likely that this is a common contributor to the recurrence and spread of the disease. the emphasis on genetic changes, for example in genome-wide association studies and increasingly in whole genome sequencing analyses of tumours, has resulted in the importance of epigenetic changes having less attention until recently. epigenetic alterations at both the dna and histone level are increasingly being recognised as playing a role in tumourigenesis. recent studies have found that distinct subgroups of poor-prognosis tumours lack genetic alterations but are epigenetically deregulated, pointing to the important role that epigenetic modifications and/or their modifiers may play in cancer. in this review, we highlight the multitude of epigenetic changes that can occur and will discuss how deregulation of epigenetic modifiers contributes to cancer progression. we also discuss the off-target effects that epigenetic modifiers may have, notably the effects that histone modifiers have on non-histone proteins that can modulate protein expression and activity, as well as the role of hypoxia in epigenetic regulation.”
Pauken, K. E., Sammons, M. A., Odorizzi, P. M., Manne, S., Godec, J., Khan, O., … Wherry, E. J.. (2016). Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science
Plain numerical DOI: 10.1126/science.aaf2807
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“Blocking programmed death-1 (pd-1) can reinvigorate exhausted cd8 tcells (tex) and improve control of chronic infections and cancer. however, whether blocking pd-1 can reprogram tex into durable memory t cells (tmem) is unclear. we found that reinvigoration of tex in mice by pd-l1 blockade caused minimal memory development. after blockade, reinvigorated tex became reexhausted if antigen concentration remained high and failed to become tmem upon antigen clearance. tex acquired an epigenetic profile distinct from that of effector t cells (teff) and tmem cells that was minimally remodeled after pd-l1 blockade. this finding suggests that tex are a distinct lineage of cd8 t cells. nevertheless, pd-1 pathway blockade resulted in transcriptional rewiring and reengagement of effector circuitry in the tex epigenetic landscape. these data indicate that epigenetic fate inflexibility may limit current immunotherapies.”
Rodriguez-Casanova, A., Costa-Fraga, N., Bao-Caamano, A., López-López, R., Muinelo-Romay, L., & Diaz-Lagares, A.. (2021). Epigenetic Landscape of Liquid Biopsy in Colorectal Cancer. Frontiers in Cell and Developmental Biology
Plain numerical DOI: 10.3389/fcell.2021.622459
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“Colorectal cancer (crc) is one of the most common malignancies and is a major cause of cancer-related deaths worldwide. thus, there is a clinical need to improve early detection of crc and personalize therapy for patients with this disease. in the era of precision oncology, liquid biopsy has emerged as a major approach to characterize the circulating tumor elements present in body fluids, including cell-free dna and rna, circulating tumor cells, and extracellular vesicles. this non-invasive tool has allowed the identification of relevant molecular alterations in crc patients, including some indicating the disruption of epigenetic mechanisms. epigenetic alterations found in solid and liquid biopsies have shown great utility as biomarkers for early detection, prognosis, monitoring, and evaluation of therapeutic response in crc patients. here, we summarize current knowledge of the most relevant epigenetic mechanisms associated with cancer development and progression, and the implications of their deregulation in cancer cells and liquid biopsy of crc patients. in particular, we describe the methodologies used to analyze these epigenetic alterations in circulating tumor material, and we focus on the clinical utility of epigenetic marks in liquid biopsy as tumor biomarkers for crc patients. we also discuss the great challenges and emerging opportunities of this field for the diagnosis and personalized management of crc patients.”
Ryan, C. P.. (2021). “Epigenetic clocks”: Theory and applications in human biology. American Journal of Human Biology
Plain numerical DOI: 10.1002/ajhb.23488
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“All humans age, but how we age—and how fast—differs considerably from person to person. this deviation between apparent age and chronological age is often referred to as ‘biological age’ (ba) and until recently robust tools for studying ba have been scarce. ‘epigenetic clocks’ are starting to change this. epigenetic clocks use predictable changes in the epigenome, usually dna methylation, to estimate chronological age with unprecedented accuracy. more importantly, deviations between epigenetic age and chronological age predict a broad range of health outcomes and mortality risks better than chronological age alone. thus, epigenetic clocks appear to capture fundamental molecular processes tied to ba and can serve as powerful tools for studying health, development, and aging across the lifespan. in this article, i review epigenetic clocks, especially as they relate to key theoretical and applied issues in human biology. i first provide an overview of how epigenetic clocks are constructed and what we know about them. i then discuss emerging applications of particular relevance to human biologists—those related to reproduction, life-history, stress, and the environment. i conclude with an overview of the methods necessary for implementing epigenetic clocks, including considerations of study design, sample collection, and technical considerations for processing and interpreting epigenetic clocks. the goal of this review is to highlight some of the ways that epigenetic clocks can inform questions in human biology, and vice versa, and to provide human biologists with the foundational knowledge necessary to successfully incorporate epigenetic clocks into their research.”
Cakouros, D. D., & Gronthos, S.. (2019). Epigenetic regulation of bone marrow stem cell aging: Revealing epigenetic signatures associated with hematopoietic and mesenchymal stem cell aging. Aging and Disease
Plain numerical DOI: 10.14336/AD.2017.1213
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“In this review we explore the importance of epigenetics as a contributing factor for aging adult stem cells. we summarize the latest findings of epigenetic factors deregulated as adult stem cells age and the consequence on stem cell self-renewal and differentiation, with a focus on adult stem cells in the bone marrow. with the latest whole genome bisulphite sequencing and chromatin immunoprecipitations we are able to decipher an emerging pattern common for adult stem cells in the bone marrow niche and how this might correlate to epigenetic enzymes deregulated during aging. we begin by briefly discussing the initial observations in yeast, drosophila and caenorhabditis elegans (c. elegans) that led to the breakthrough research that identified the role of epigenetic changes associated with lifespan and aging. we then focus on adult stem cells, specifically in the bone marrow, which lends strong support for the deregulation of dna methyltransferases, histone deacetylases, acetylates, methyltransferases and demethylases in aging stem cells, and how their corresponding epigenetic modifications influence gene expression and the aging phenotype. given the reversible nature of epigenetic modifications we envisage ‘epi’ targeted therapy as a means to reprogram aged stem cells into their younger counterparts.”
Fröhlich, J., & Grundhoff, A.. (2020). Epigenetic control in Kaposi sarcoma-associated herpesvirus infection and associated disease. Seminars in Immunopathology
Plain numerical DOI: 10.1007/s00281-020-00787-z
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“Kaposi sarcoma-associated herpesvirus (kshv) is the etiologic agent of several malignancies of endothelial and b-cell origin. the fact that latently infected tumor cells in these malignancies do not express classical viral oncogenes suggests that pathogenesis of kshv-associated disease results from multistep processes that, in addition to constitutive viral gene expression, may require accumulation of cellular alterations. heritable changes of the epigenome have emerged as an important co-factor that contributes to the pathogenesis of many non-viral cancers. since kshv encodes a number of factors that directly or indirectly manipulate host cell chromatin, it is an intriguing possibility that epigenetic reprogramming also contributes to the pathogenesis of kshv-associated tumors. the fact that heritable histone modifications have also been shown to regulate viral gene expression programs in kshv-infected tumor cells underlines the importance of epigenetic control during latency and tumorigenesis. we here review what is presently known about the role of epigenetic regulation of viral and host chromatin in kshv infection and discuss how viral manipulation of these processes may contribute to the development of kshv-associated disease.”
Yu, V. W. C., Yusuf, R. Z., Oki, T., Wu, J., Saez, B., Wang, X., … Scadden, D. T.. (2016). Epigenetic Memory Underlies Cell-Autonomous Heterogeneous Behavior of Hematopoietic Stem Cells. Cell
Plain numerical DOI: 10.1016/j.cell.2016.10.045
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“Stem cells determine homeostasis and repair of many tissues and are increasingly recognized as functionally heterogeneous. to define the extent of—and molecular basis for—heterogeneity, we overlaid functional, transcriptional, and epigenetic attributes of hematopoietic stem cells (hscs) at a clonal level using endogenous fluorescent tagging. endogenous hsc had clone-specific functional attributes over time in vivo. the intra-clonal behaviors were highly stereotypic, conserved under the stress of transplantation, inflammation, and genotoxic injury, and associated with distinctive transcriptional, dna methylation, and chromatin accessibility patterns. further, hsc function corresponded to epigenetic configuration but not always to transcriptional state. therefore, hematopoiesis under homeostatic and stress conditions represents the integrated action of highly heterogeneous clones of hsc with epigenetically scripted behaviors. this high degree of epigenetically driven cell autonomy among hscs implies that refinement of the concepts of stem cell plasticity and of the stem cell niche is warranted.”
Bors, E. K., Baker, C. S., Wade, P. R., O’Neill, K. B., Shelden, K. E. W., Thompson, M. J., … Horvath, S.. (2021). An epigenetic clock to estimate the age of living beluga whales. Evolutionary Applications
Plain numerical DOI: 10.1111/eva.13195
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“DNA methylation data facilitate the development of accurate molecular estimators of chronological age or ‘epigenetic clocks.’ we present a robust epigenetic clock for the beluga whale, delphinapterus leucas, developed for an endangered population in cook inlet, alaska, usa. we used a custom methylation array to measure methylation levels at 37,491 cytosine–guanine sites (cpgs) from skin samples of dead whales (n = 67) whose chronological ages were estimated based on tooth growth layer groups. using these calibration data, a penalized regression model selected 23 cpgs, providing an r2 = 0.92 for the training data; and an r2 = 0.74 and median absolute age error = 2.9 years for the leave one out cross-validation. we applied the epigenetic clock to an independent dataset of 38 skin samples collected with a biopsy dart from living whales between 2016 and 2018. age estimates ranged from 11 to 27 years. we also report sex correlations in cpg data and describe an approach of identifying the sex of an animal using dna methylation. the epigenetic estimators of age and sex presented here have broad applications for conservation and management of cook inlet beluga whales and potentially other cetaceans.”
Rajeevkumar, S., Anunanthini, P., & Sathishkumar, R.. (2015). Epigenetic silencing in transgenic plants. Frontiers in Plant Science
Plain numerical DOI: 10.3389/fpls.2015.00693
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“Epigenetic silencing is a natural phenomenon in which the expression of genes is regulated through modifications of dna, rna, or histone proteins. it is a mechanism for defending host genomes against the effects of transposable elements and viral infection, and acts as a modulator of expression of duplicated gene family members and as a silencer of transgenes. a major breakthrough in understanding the mechanism of epigenetic silencing was the discovery of silencing in transgenic tobacco plants due to the interaction between two homologous promoters. the molecular mechanism of epigenetic mechanism is highly complicated and it is not completely understood yet. two different molecular routes have been proposed for this, that is, transcriptional gene silencing, which is associated with heavy methylation of promoter regions and blocks the transcription of transgenes, and post-transcriptional gene silencing (ptgs), the basic mechanism is degradation of the cytosolic mrna of transgenes or endogenous genes. undesired transgene silencing is of major concern in the transgenic technologies used in crop improvement. a complete understanding of this phenomenon will be very useful for transgenic applications, where silencing of specific genes is required. the current status of epigenetic silencing in transgenic technology is discussed and summarized in this mini-review.”
Zhang, T., Pilko, A., & Wollman, R.. (2020). Loci specific epigenetic drug sensitivity. Nucleic Acids Research
Plain numerical DOI: 10.1093/nar/gkaa210
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“Therapeutic targeting of epigenetic modulators offers a novel approach to the treatment of multiple diseases. the cellular consequences of chemical compounds that target epigenetic regulators (epi-drugs) are complex. epi-drugs affect global cellular phenotypes and cause local changes to gene expression due to alteration of a gene chromatin environment. despite increasing use in the clinic, the mechanisms responsible for cellular changes are unclear. specifically, to what degree the effects are a result of cell-wide changes or disease related locus specific effects is unknown. here we developed a platform to systematically and simultaneously investigate the sensitivity of epi-drugs at hundreds of genomic locations by combining dna barcoding, unique split-pool encoding, and single cell expression measurements. internal controls are used to isolate locus specific effects separately from any global consequences these drugs have. using this platform we discovered wide-spread loci specific sensitivities to epi-drugs for three distinct epi-drugs that target histone deacetylase, dna methylation and bromodomain proteins. by leveraging encode data on chromatin modification, we identified features of chromatin environments that are most likely to be affected by epi-drugs. the measurements of loci specific epi-drugs sensitivities will pave the way to the development of targeted therapy for personalized medicine.”
Nowicka, A., Tokarz, B., Zwyrtková, J., Dvořák Tomaštíková, E., Procházková, K., Ercan, U., … Pecinka, A.. (2020). Comparative analysis of epigenetic inhibitors reveals different degrees of interference with transcriptional gene silencing and induction of DNA damage. Plant Journal
Plain numerical DOI: 10.1111/tpj.14612
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“Repetitive dna sequences and some genes are epigenetically repressed by transcriptional gene silencing (tgs). when genetic mutants are not available or problematic to use, tgs can be suppressed by chemical inhibitors. however, informed use of epigenetic inhibitors is partially hampered by the absence of any systematic comparison. in addition, there is emerging evidence that epigenetic inhibitors cause genomic instability, but the nature of this damage and its repair remain unclear. to bridge these gaps, we compared the effects of 5-azacytidine (ac), 2′-deoxy-5-azacytidine (dac), zebularine and 3-deazaneplanocin a (dznep) on tgs and dna damage repair. the most effective inhibitor of tgs was dac, followed by dznep, zebularine and ac. we confirmed that all inhibitors induce dna damage and suggest that this damage is repaired by multiple pathways with a critical role of homologous recombination and of the smc5/6 complex. a strong positive link between the degree of cytidine analog-induced dna demethylation and the amount of dna damage suggests that dna damage is an integral part of cytidine analog-induced dna demethylation. this helps us to understand the function of dna methylation in plants and opens the possibility of using epigenetic inhibitors in biotechnology.”
Duncan, E. J., Gluckman, P. D., & Dearden, P. K.. (2014). Epigenetics, plasticity, and evolution: How do we link epigenetic change to phenotype?. Journal of Experimental Zoology Part B: Molecular and Developmental Evolution
Plain numerical DOI: 10.1002/jez.b.22571
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“Epigenetic mechanisms are proposed as an important way in which the genome responds to the environment. epigenetic marks, including dna methylation and histone modifications, can be triggered by environmental effects, and lead to permanent changes in gene expression, affecting the phenotype of an organism. epigenetic mechanisms have been proposed as key in plasticity, allowing environmental exposure to shape future gene expression. while we are beginning to understand how these mechanisms have roles in human biology and disease, we have little understanding of their roles and impacts on ecology and evolution. in this review, we discuss different types of epigenetic marks, their roles in gene expression and plasticity, methods for assaying epigenetic changes, and point out the future advances we require to understand fully the impact of this field. © 2014 wiley periodicals, inc.”
Zhang, S., Gong, Y., Li, C., Yang, W., & Li, L.. (2021). Beyond regulations at DNA levels: A review of epigenetic therapeutics targeting cancer stem cells. Cell Proliferation
Plain numerical DOI: 10.1111/cpr.12963
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“In the past few years, the paramount role of cancer stem cells (cscs), in terms of cancer initiation, proliferation, metastasis, invasion and chemoresistance, has been revealed by accumulating studies. however, this level of cellular plasticity cannot be entirely explained by genetic mutations. research on epigenetic modifications as a complementary explanation for the properties of cscs has been increasing over the past several years. notably, therapeutic strategies are currently being developed in an effort to reverse aberrant epigenetic alterations using specific chemical inhibitors. in this review, we summarize the current understanding of cscs and their role in cancer progression, and provide an overview of epigenetic alterations seen in cscs. importantly, we focus on primary cancer therapies that target the epigenetic modification of cscs by the use of specific chemical inhibitors, such as histone deacetylase (hdac) inhibitors, dna methyltransferase (dnmt) inhibitors and microrna-based (mirna-based) therapeutics.”
Ruggero, K., Farran-Matas, S., Martinez-Tebar, A., & Aytes, A.. (2018). Epigenetic Regulation in Prostate Cancer Progression. Current Molecular Biology Reports
Plain numerical DOI: 10.1007/s40610-018-0095-9
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“Cancer is a disease arising from both genetic and epigenetic modifications of dna that contribute to changes in gene expression in the cell. genetic modifications include loss or amplification of dna, loss of heterozygosity (loh) as well as gene mutations. epigenetic changes in cancer are generally thought to be brought about by alterations in dna and histone modifications that lead to the silencing of tumour suppressor genes and the activation of oncogenic genes. other consequences that result from epigenetic changes, such as inappropriate expression or repression of some genes in the wrong cellular context, can also result in the alteration of control and physiological systems such that a normal cell becomes tumorigenic. excessive levels of the enzymes that act as epigenetic modifiers have been reported as markers of aggressive breast cancer and are associated with metastatic progression. it is likely that this is a common contributor to the recurrence and spread of the disease. the emphasis on genetic changes, for example in genome-wide association studies and increasingly in whole genome sequencing analyses of tumours, has resulted in the importance of epigenetic changes having less attention until recently. epigenetic alterations at both the dna and histone level are increasingly being recognised as playing a role in tumourigenesis. recent studies have found that distinct subgroups of poor-prognosis tumours lack genetic alterations but are epigenetically deregulated, pointing to the important role that epigenetic modifications and/or their modifiers may play in cancer. in this review, we highlight the multitude of epigenetic changes that can occur and will discuss how deregulation of epigenetic modifiers contributes to cancer progression. we also discuss the off-target effects that epigenetic modifiers may have, notably the effects that histone modifiers have on non-histone proteins that can modulate protein expression and activity, as well as the role of hypoxia in epigenetic regulation.”
Von Meyenn, F., & Reik, W.. (2015). Forget the parents: Epigenetic reprogramming in human germ cells. Cell
Plain numerical DOI: 10.1016/j.cell.2015.05.039
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“Epigenetic reprogramming in the germline resets genomic potential and erases epigenetic memory. three studies by gkountela et al., guo et al., and tang et al. analyze the transcriptional and epigenetic landscape of human primordial germ cells, revealing a unique transcriptional network and progressive and conserved global erasure of dna methylation.”
Erdel, F., & Greene, E. C.. (2016). Generalized nucleation and looping model for epigenetic memory of Histone modifications. Proceedings of the National Academy of Sciences of the United States of America
Plain numerical DOI: 10.1073/pnas.1605862113
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“Histone modifications can redistribute along the genome in a sequenceindependent manner, giving rise to chromatin position effects and epigenetic memory. the underlying mechanisms shape the endogenous chromatin landscape and determine its response to ectopically targeted histone modifiers. here, we simulate linear and loopingdriven spreading of histone modifications and compare bothmodels to recent experiments on histone methylation in fission yeast. we find that a generalized nucleation-and-looping mechanism describes key observations on engineered and endogenous methylation domains including intrinsic spatial confinement, independent regulation of domain size and memory, variegation in the absence of antagonists, and coexistence of short- and long-term memory at loci with weak and strong constitutive nucleation. these findings support a straightforward relationship between the biochemical properties of chromatin modifiers and the spatiotemporal modification pattern. the proposed mechanism gives rise to a phase diagram for cellular memory that may be generally applicable to explain epigenetic phenomena across different species.”
Kanwal, R., & Gupta, S.. (2012). Epigenetic modifications in cancer. Clinical Genetics
Plain numerical DOI: 10.1111/j.1399-0004.2011.01809.x
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“Cancer initiation and progression is controlled by both genetic and epigenetic events. the complexity of carcinogenesis cannot be accounted for by genetic alterations alone but also involves epigenetic changes. epigenetics refers to the study of mechanisms that alter gene expression without altering the primary dna sequence. epigenetic mechanisms are heritable and reversible, and include changes in dna methylation, histone modifications and small noncoding micrornas (mirna). disruption of epigenetic processes can lead to altered gene function and malignant cellular transformation. aberrant epigenetic modifications probably occur at a very early stage in neoplastic development, and they are widely described as essential players in cancer progression. recent advances in epigenetics offer a better understanding of the underlying mechanism(s) of carcinogenesis and provide insight into the discovery of putative cancer biomarkers for early detection, disease monitoring, prognosis, and risk assessment. in this review, we summarize the current literature on epigenetic changes causing genetic alterations that are thought to contribute to cancer, and discuss the potential impact of epigenetics future research. © 2011 john wiley & sons a/s.”
Peschansky, V. J., & Wahlestedt, C.. (2014). Non-coding RNAs as direct and indirect modulators of epigenetic regulation. Epigenetics
Plain numerical DOI: 10.4161/epi.27473
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“Epigenetic regulation of gene expression is an increasingly well-understood concept that explains much of the contribution of an organism’s environment and experience to its biology. however, discussion persists as to which mechanisms can be classified as epigenetic. ongoing research continues to uncover novel pathways, including the important role of non-protein coding rna transcripts in epigenetic gene regulation. we know that the majority of human and other mammalian transcripts are not translated but that many of these are nonetheless functional. these non-coding rnas (ncrnas) can be short (< 200 nt) or long (< 200 nt) and are further classified by genomic origin and mechanism of action. we discuss examples of ncrnas that interact with histone modifying complexes or dna methyltransferases to regulate gene expression, others that are targets of these epigenetic mechanisms, and propose a model in which such transcripts feed back into an epigenetic regulatory network. © 2014 landes bioscience.”
Yu, V. W. C., Yusuf, R. Z., Oki, T., Wu, J., Saez, B., Wang, X., … Scadden, D. T.. (2016). Epigenetic Memory Underlies Cell-Autonomous Heterogeneous Behavior of Hematopoietic Stem Cells. Cell
Plain numerical DOI: 10.1016/j.cell.2016.10.045
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“Stem cells determine homeostasis and repair of many tissues and are increasingly recognized as functionally heterogeneous. to define the extent of—and molecular basis for—heterogeneity, we overlaid functional, transcriptional, and epigenetic attributes of hematopoietic stem cells (hscs) at a clonal level using endogenous fluorescent tagging. endogenous hsc had clone-specific functional attributes over time in vivo. the intra-clonal behaviors were highly stereotypic, conserved under the stress of transplantation, inflammation, and genotoxic injury, and associated with distinctive transcriptional, dna methylation, and chromatin accessibility patterns. further, hsc function corresponded to epigenetic configuration but not always to transcriptional state. therefore, hematopoiesis under homeostatic and stress conditions represents the integrated action of highly heterogeneous clones of hsc with epigenetically scripted behaviors. this high degree of epigenetically driven cell autonomy among hscs implies that refinement of the concepts of stem cell plasticity and of the stem cell niche is warranted.”
Achrem, M., Szućko, I., & Kalinka, A.. (2020). The epigenetic regulation of centromeres and telomeres in plants and animals. Comparative Cytogenetics
Plain numerical DOI: 10.3897/COMPCYTOGEN.V14I2.51895
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“The centromere is a chromosomal region where the kinetochore is formed, which is the attachment point of spindle fibers. thus, it is responsible for the correct chromosome segregation during cell division. telomeres protect chromosome ends against enzymatic degradation and fusions, and localize chromosomes in the cell nucleus. for this reason, centromeres and telomeres are parts of each linear chromosome that are necessary for their proper functioning. more and more research results show that the identity and functions of these chromosomal regions are epigenetically determined. telomeres and centromeres are both usually described as highly condensed heterochromatin regions. however, the epigenetic nature of centromeres and telomeres is unique, as epigenetic modifications characteristic of both eu-and heterochromatin have been found in these areas. this specificity allows for the proper functioning of both regions, thereby affecting chromosome homeostasis. this review focuses on demonstrating the role of epigenetic mechanisms in the functioning of centromeres and telomeres in plants and animals.”
Daniel, M., & Tollefsbol, T. O.. (2015). Epigenetic linkage of aging, cancer and nutrition. Journal of Experimental Biology
Plain numerical DOI: 10.1242/jeb.107110
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“Epigenetic mechanisms play a pivotal role in the expression of genes and can be influenced by both the quality and quantity of diet. dietary compounds such as sulforaphane (sfn) found in cruciferous vegetables and epigallocatechin-3-gallate (egcg) in green tea exhibit the ability to affect various epigenetic mechanisms such as dna methyltransferase (dnmt) inhibition, histone modifications via histone deacetylase (hdac), histone acetyltransferase (hat) inhibition, or noncoding rna expression. regulation of these epigenetic mechanisms has been shown to have notable influences on the formation and progression of various neoplasms. we have shown that an epigenetic diet can influence both cellular longevity and carcinogenesis through the modulation of certain key genes that encode telomerase and p16. caloric restriction (cr) can also play a crucial role in aging and cancer. reductions in caloric intake have been shown to increase both the life- and health-span in a variety of animal models. moreover, restriction of glucose has been demonstrated to decrease the incidence of age-related diseases such as cancer and diabetes. a diet rich in compounds such as genistein, sfn and egcg can positively modulate the epigenome and lead to many health benefits. also, reducing the quantity of calories and glucose in the diet can confer an increased health-span, including reduced cancer incidence.”
Lestari, S. W., & Rizki, M. D.. (2016). Epigenetic: A new approach to etiology of infertility. Medical Journal of Indonesia
Plain numerical DOI: 10.13181/mji.v25i4.1504
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“Infertility is a complex disease which could be caused by male and female factors. the etiology from both factors needs further study. there are some approaches to understanding the etiology of infertility, one of them is epigenetic. epigenetic modifications consist of dna methylation, histone modifications, and chromatin remodelling. male and female germinal cells undergo epigenetic modifications dynamically during differentiation into matured sperm and oocyte cells. in a male, the alteration of dna methylation in spermatogenesis will cause oligo/asthenozoospermia. in addition, the histone methylation, acetylation, or other histone modification may lead sperm lose its ability to fertilize oocyte. similarly, in a female, the alteration of dna methylation and histone modification affects oogenesis, created aneuploidy in fertilized oocytes and resulted in embryonic death in the uterus. alteration of these epigenetic modification patterns will cause infertility, both in male and female.”
Mayran, A., & Drouin, J.. (2018). Pioneer transcription factors shape the epigenetic landscape. Journal of Biological Chemistry
Plain numerical DOI: 10.1074/jbc.R117.001232
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“Pioneer transcription factors have the unique and important role of unmasking chromatin domains during development to allow the implementation of new cellular programs. compared with those of other transcription factors, this activity implies that pioneer factors can recognize their target dna sequences in so-called compacted or ‘closed’ heterochromatin and can trigger remodeling of the adjoining chromatin landscape to provide accessibility to nonpioneer transcription factors. recent studies identified several steps of pioneer action, namely rapid but weak initial binding to heterochromatin and stabilization of binding followed by chromatin opening and loss of cytosine-phosphate-guanine (cpg) methylation that provides epigenetic memory. whereas cpg demethylation depends on replication, chromatin opening does not. in this minireview, we highlight the unique properties of this transcription factor class and the challenges of understanding their mechanism of action.”
Fröhlich, J., & Grundhoff, A.. (2020). Epigenetic control in Kaposi sarcoma-associated herpesvirus infection and associated disease. Seminars in Immunopathology
Plain numerical DOI: 10.1007/s00281-020-00787-z
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“Kaposi sarcoma-associated herpesvirus (kshv) is the etiologic agent of several malignancies of endothelial and b-cell origin. the fact that latently infected tumor cells in these malignancies do not express classical viral oncogenes suggests that pathogenesis of kshv-associated disease results from multistep processes that, in addition to constitutive viral gene expression, may require accumulation of cellular alterations. heritable changes of the epigenome have emerged as an important co-factor that contributes to the pathogenesis of many non-viral cancers. since kshv encodes a number of factors that directly or indirectly manipulate host cell chromatin, it is an intriguing possibility that epigenetic reprogramming also contributes to the pathogenesis of kshv-associated tumors. the fact that heritable histone modifications have also been shown to regulate viral gene expression programs in kshv-infected tumor cells underlines the importance of epigenetic control during latency and tumorigenesis. we here review what is presently known about the role of epigenetic regulation of viral and host chromatin in kshv infection and discuss how viral manipulation of these processes may contribute to the development of kshv-associated disease.”
Hanif, E. A. M., & Shah, S. A.. (2018). Overview on epigenetic re-programming: A potential therapeutic intervention in triple negative breast cancers. Asian Pacific Journal of Cancer Prevention
Plain numerical DOI: 10.31557/APJCP.2018.19.12.3341
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“Breast cancer treatments leads to variable responses. hormonal therapy is beneficial to receptor positive breast cancer subtypes and display better clinical outcome than triple negative breast cancers (tnbcs) with fec (5-fluorouracil, epirubicin and cyclophosphamide) the mainstay chemotherapy regiment. owning to their negative expressions of estrogen (er), progesterone (pr) and her2 receptors, disease recurrence and metastasis befalls some patients indicating resistance to fec. involvement of epigenetic silencing through dna methylation, histone methylation, acetylation and sumoylation may be the key player in fec chemoresistance. epigenetic and molecular profiling successfully classified breast cancer subtypes, indicating potential driver mechanisms to the progression of tnbcs but functional mechanisms behind chemoresistance of these molecular markers are not well defined. several epigenetic inhibitors and drugs have been used in the management of cancers but these attempts are mainly beneficial in hematopoietic cancers and not specifically favourable in solid tumours. hypothetically, upon administration of epigenetic drugs, recovery of tumour suppressor genes is expected. however, high tendency of switching on global metastatic genes is predicted. polycomb repressive complex (prc) such as ezh2, setd1a, dnmt, is known to have repressive effects in gene regulation and shown to inhibit cell proliferation and invasion in breast cancers. individual epigenetic regulators may be an option to improve chemo-drug delivery in cancers. this review discussed on molecular signatures of various breast cancer subtypes and on-going attempts in understanding underlying molecular mechanisms of epigenetic regulators as well as providing insights on possible ways to utilize epigenetic enzymes/inhibitors with responses to chemotherapeutic drugs to re-program cellular and biological outcome in tnbcs.”
Kwon, M. J., & Shin, Y. K.. (2011). Epigenetic regulation of cancer-associated genes in ovarian cancer. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms12020983
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“The involvement of epigenetic aberrations in the development and progression of tumors is now well established. however, most studies have focused on the epigenetic inactivation of tumor suppressor genes during tumorigenesis and little is known about the epigenetic activation of cancer-associated genes, except for the dna hypomethylation of some genes. recently, we reported that the overexpression of cancer-promoting genes in ovarian cancer is associated with the loss of repressive histone modifications. this discovery suggested that epigenetic derepression may contribute to ovarian tumorigenesis by constituting a possible mechanism for the overexpression of oncogenes or cancer-promoting genes in tumors. the emerging importance of epigenetic aberrations in tumor initiation and in the regulation of cancer-initiating cells, suggests that epigenetically regulated genes may be promising therapeutic targets and biomarkers. given that the current challenges in ovarian cancer include the identification of biomarkers for early cancer detection and the discovery of novel therapeutic targets for patients with recurrent malignancies undergoing chemotherapy, understanding the epigenetic changes that occur in ovarian cancer is crucial. this review looks at epigenetic mechanisms involved in the regulation of cancer-associated genes, including the contribution of epigenetic derepression to the activation of cancer-associated genes in ovarian cancer. in addition, possible epigenetic therapies targeting epigenetically dysregulated genes are discussed. a better understanding of the epigenetic changes in ovarian cancer will contribute to the improvement of patient outcomes. © 2011 by the authors; licensee mdpi, basel, switzerland.”
Kular, L., & Jagodic, M.. (2020). Epigenetic insights into multiple sclerosis disease progression. Journal of Internal Medicine
Plain numerical DOI: 10.1111/joim.13045
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“Multiple sclerosis (ms), a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system, is today a leading cause of unpredictable lifelong disability in young adults. the treatment of patients in progressive stages remains highly challenging, alluding to our limited understanding of the underlying pathological processes. in this review, we provide insights into the mechanisms underpinning ms progression from a perspective of epigenetics, that refers to stable and mitotically heritable, yet reversible, changes in the genome activity and gene expression. we first recapitulate findings from epigenetic studies examining the brain tissue of progressive ms patients, which support a contribution of dna and histone modifications in impaired oligodendrocyte differentiation, defective myelination/remyelination and sustained neuro-axonal vulnerability. we next explore possibilities for identifying factors affecting progression using easily accessible tissues such as blood by comparing epigenetic signatures in peripheral immune cells and brain tissue. despite minor overlap at individual methylation sites, nearly 30% of altered genes reported in peripheral immune cells of progressive ms patients were found in brain tissue, jointly converging on alterations of neuronal functions. we further speculate about the mechanisms underlying shared epigenetic patterns between blood and brain, which likely imply the influence of internal (genetic control) and/or external (e.g. smoking and ageing) factors imprinting a common signature in both compartments. overall, we propose that epigenetics might shed light on clinically relevant mechanisms involved in disease progression and open new avenues for the treatment of progressive ms patients in the future.”
Hayano, M., Yang, J.-H., Bonkowski, M., Amorim, J., Ross, J., Coppotelli, G., … Sinclair, D.. (2019). DNA Break-Induced Epigenetic Drift as a Cause of Mammalian Aging. SSRN Electronic Journal
Plain numerical DOI: 10.1101/808659
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“DNA breaks induce epigenomic changes that accelerate the aging clock in mammals there are numerous hallmarks of aging in mammals, but no unifying cause has been identified. in budding yeast, aging is associated with a loss of epigenetic information that occurs in response to genome instability, particularly dna double-strand breaks (dsbs). mammals also undergo predictable epigenetic changes with age, including alterations to dna methylation patterns that serve as epigenetic ‘age’ clocks, but what drives these changes is not known. using a transgenic mouse system called ‘ice’ (for inducible changes to the epigenome), we show that a tissue’s response to non-mutagenic dsbs reorganizes the epigenome and accelerates physiological, cognitive, and molecular changes normally seen in older mice, including advancement of the epigenetic clock. these findings implicate dsb-induced epigenetic drift as a conserved cause of aging from yeast to mammals.”
Griñán-Ferré, C., Bellver-Sanchis, A., Izquierdo, V., Corpas, R., Roig-Soriano, J., Chillón, M., … Pallàs, M.. (2021). The pleiotropic neuroprotective effects of resveratrol in cognitive decline and Alzheimer’s disease pathology: From antioxidant to epigenetic therapy. Ageing Research Reviews
Plain numerical DOI: 10.1016/j.arr.2021.101271
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“While the elderly segment of the population continues growing in importance, neurodegenerative diseases increase exponentially. lifestyle factors such as nutrition, exercise, and education, among others, influence ageing progression, throughout life. notably, the central nervous system (cns) can benefit from nutritional strategies and dietary interventions that prevent signs of senescence, such as cognitive decline or neurodegenerative diseases such as alzheimer’s disease and parkinson’s disease. the dietary polyphenol resveratrol (rv) possesses antioxidant and cytoprotective effects, producing neuroprotection in several organisms. the oxidative stress (os) occurs because of reactive oxygen species (ros) accumulation that has been proposed to explain the cause of the ageing. one of the most harmful effects of ros in the cell is dna damage. nevertheless, there is also evidence demonstrating that os can produce other molecular changes such as mitochondrial dysfunction, inflammation, apoptosis, and epigenetic modifications, among others. interestingly, the dietary polyphenol rv is a potent antioxidant and possesses pleiotropic actions, exerting its activity through various molecular pathways. in addition, recent evidence has shown that rv mediates epigenetic changes involved in ageing and the function of the cns that persists across generations. furthermore, it has been demonstrated that rv interacts with gut microbiota, showing modifications in bacterial composition associated with beneficial effects. in this review, we give a comprehensive overview of the main mechanisms of action of rv in different experimental models, including clinical trials and discuss how the interconnection of these molecular events could explain the neuroprotective effects induced by rv.”
Rehman, M., & Tanti, B.. (2020). Understanding epigenetic modifications in response to abiotic stresses in plants. Biocatalysis and Agricultural Biotechnology
Plain numerical DOI: 10.1016/j.bcab.2020.101673
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“Plants have to cope up with environmental stresses during different developmental stages of their life cycle. to overcome the stresses, epigenetic regulations play a significant role in their adaptation. epigenetic modification has already been well understood. in fact, there are numerous reports related to an epigenetic modification in plants under abiotic stresses. however, there is still a gap in understanding the correlation among different epigenetic phenomena occurring under various abiotic stresses in plants. therefore, in this review, an attempt has been made to correlate the various epigenetic modifications in the plant under abiotic stresses. further, recent high-throughput technologies that are being used in the epigenetic analysis have also been highlighted. various aspects of epigenetic modification in plants have been studied giving emphasis towards abiotic stresses. dna methylation and histone modification have been focused including the rddm pathway, atp-dependent chromatin remodeling, and methylation-sensitive amplified polymorphism (msap). with the advancement of technology, various techniques have been applied to detect dna methylation patterns in plants. these may include bisulfite sequencing, combined bisulfite restriction analysis (cobra), chromatin immunoprecipitation (chip), methylation-sensitive single nucleotide primer extension (ms-snupe), cytosine assay and many more, of which bisulfite genomic sequencing, is the most commonly used. in this report, bisulfite sequencing and chromatin immunoprecipitation were described in detail. moreover, with the advent of various bioinformatics tools and techniques, epigenetic research has been facilitated, few of which were discussed in this review.”
De Boni, L., & Wüllner, U.. (2019). Epigenetic analysis in human neurons: Considerations for disease modeling in PD. Frontiers in Neuroscience
Plain numerical DOI: 10.3389/fnins.2019.00276
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“Parkinson’s disease (pd) is the second most common neurodegenerative disorder next to alzheimer’s disease. most pd cases are considered to be sporadic and despite considerable scientific effort, the underlying cause(s) still remain(s) enigmatic. in particular, it is unknown to which extent epigenetic alterations contribute to the pathophysiology of this devastating disorder. this is partly due to the fact that appropriate pd models are not yet available. moreover, epigenetic patterns and mechanisms are species specific and murine systems reflect only a few of the idiosyncrasies of human neurons. for several years now, patient-specific stem cell-derived neural and non-neural cells have been employed to overcome this limitation allowing the analysis and establishment of humanized disease models for pd. thus, several studies tried to dissect epigenetic alterations such as aberrant dna methylation or microrna patterns using lund human mesencephalic cell lines or neurons derived from (patient-specific) induced pluripotent stem cells. these studies demonstrate that human neurons have the potential to be used as model systems for the study of epigenetic modifications in pd such as characterizing epigenetic changes, correlating epigenetic changes to gene expression alterations and hopefully using these insights for the development of novel therapeutics. however, more research is required to define the epigenetic (age-associated) landscape of human in vitro neurons and compare these to native neurons before they can be established as suitable models for epigenetic studies in pd. in this review, we summarize the knowledge about epigenetic studies performed on human neuronal pd models, and we discuss advantages and current limitations of these (stem cell-derived) neuronal models for the study of epigenetic alterations in pd.”
Kanherkar, R. R., Stair, S. E., Bhatia-Dey, N., Mills, P. J., Chopra, D., & Csoka, A. B.. (2017). Epigenetic mechanisms of integrative medicine. Evidence-Based Complementary and Alternative Medicine
Plain numerical DOI: 10.1155/2017/4365429
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“Since time immemorial humans have utilized natural products and therapies for their healing properties. even now, in the age of genomics and on the cusp of regenerative medicine, the use of complementary and alternative medicine (cam) approaches represents a popular branch of health care. furthermore, there is a trend towards a unified medical philosophy referred to as integrative medicine (im) that represents the convergence of cam and conventional medicine. the im model not only considers the holistic perspective of the physiological components of the individual, but also includes psychological and mind-body aspects. justification for and validation of such a whole-systems approach is in part dependent upon identification of the functional pathways governing healing, and new data is revealing relationships between therapies and biochemical effects that have long defied explanation. we review this data and propose a unifying theme: im’s ability to affect healing is due at least in part to epigenetic mechanisms.this hypothesis is based on a mounting body of evidence that demonstrates a correlation between the physical and mental effects of im and modulation of gene expression and epigenetic state. emphasis on mapping, deciphering, and optimizing these effects will facilitate therapeutic delivery and create further benefits.”
Renaude, E., Kroemer, M., Loyon, R., Binda, D., Borg, C., Guittaut, M., … Peixoto, P.. (2020). The fate of Th17 cells is shaped by epigenetic modifications and remodeled by the tumor microenvironment. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms21051673
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“Th17 cells represent a subset of cd4+ t cells characterized by the master transcription factor rorγt and the production of il-17. epigenetic modifications such as post-translational histone modifications and dna methylation play a key role in th17 cell differentiation and high plasticity. th17 cells are highly recruited in many types of cancer and can be associated with good or bad prognosis. here, we will review the remodeling of the epigenome induced by the tumor microenvironment, which may explain th17 cell predominance. we will also discuss the promising treatment perspectives of molecules targeting epigenetic enzymes to remodel a th17-enriched tumor microenvironment.”
Feinberg, A. P., Koldobskiy, M. A., & Göndör, A.. (2016). Epigenetic modulators, modifiers and mediators in cancer aetiology and progression. Nature Reviews Genetics
Plain numerical DOI: 10.1038/nrg.2016.13
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“This year is the tenth anniversary of the publication in this journal of a model suggesting the existence of ‘tumour progenitor genes’. these genes are epigenetically disrupted at the earliest stages of malignancies, even before mutations, and thus cause altered differentiation throughout tumour evolution. the past decade of discovery in cancer epigenetics has revealed a number of similarities between cancer genes and stem cell reprogramming genes, widespread mutations in epigenetic regulators, and the part played by chromatin structure in cellular plasticity in both development and cancer. in the light of these discoveries, we suggest here a framework for cancer epigenetics involving three types of genes: ‘epigenetic mediators’, corresponding to the tumour progenitor genes suggested earlier; ‘epigenetic modifiers’ of the mediators, which are frequently mutated in cancer; and ‘epigenetic modulators’ upstream of the modifiers, which are responsive to changes in the cellular environment and often linked to the nuclear architecture. we suggest that this classification is helpful in framing new diagnostic and therapeutic approaches to cancer.”
Van Ouwerkerk, A. F., Hall, A. W., Kadow, Z. A., Lazarevic, S., Reyat, J. S., Tucker, N. R., … Christoffels, V. M.. (2020). Epigenetic and Transcriptional Networks Underlying Atrial Fibrillation. Circulation Research
Plain numerical DOI: 10.1161/CIRCRESAHA.120.316574
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“Genome-wide association studies have uncovered over a 100 genetic loci associated with atrial fibrillation (af), the most common arrhythmia. many of the top af-associated loci harbor key cardiac transcription factors, including pitx2, tbx5, prrx1, and zfhx3. moreover, the vast majority of the af-associated variants lie within noncoding regions of the genome where causal variants affect gene expression by altering the activity of transcription factors and the epigenetic state of chromatin. in this review, we discuss a transcriptional regulatory network model for af defined by effector genes in genome-wide association studies loci. we describe the current state of the field regarding the identification and function of af-relevant gene regulatory networks, including variant regulatory elements, dose-sensitive transcription factor functionality, target genes, and epigenetic states. we illustrate how altered transcriptional networks may impact cardiomyocyte function and ionic currents that impact af risk. last, we identify the need for improved tools to identify and functionally test transcriptional components to define the links between genetic variation, epigenetic gene regulation, and atrial function.”
Samarth, Kelly, D., Turnbull, M. H., & Jameson, P. E.. (2020). Molecular control of masting: An introduction to an epigenetic summer memory. Annals of Botany
Plain numerical DOI: 10.1093/AOB/MCAA004
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“• background mast flowering (‚masting’) is characterized by mass synchronized flowering at irregular intervals in populations of perennial plants over a wide geographical area, resulting in irregular high seed production. while masting is a global phenomenon, it is particularly prevalent in the alpine flora of new zealand. increases in global temperature may alter the masting pattern, affecting wider communities with a potential impact on plant-pollinator interactions, seed set and food availability for seed-consuming species. • scope this review summarizes an ecological temperature model (δt) that is being used to predict the intensity of a masting season. we introduce current molecular studies on flowering and the concept of an ‘epigenetic summer memory’ as a driver of mast flowering. we propose a hypothetical model based on temperature-associated epigenetic modifications of the floral integrator genes flowering locus t, flowering locus c and suppressor of overexpression of constans1. • conclusions genome-wide transcriptomic and targeted gene expression analyses are needed to establish the developmental and physiological processes associated with masting. such analyses may identify changes in gene expression that can be used to predict the intensity of a forthcoming masting season, as well as to determine the extent to which climate change will influence the mass synchronized flowering of masting species, with downstream impacts on their associated communities.”
Kim, J. A., & Yeom, Y. Il. (2018). Metabolic signaling to epigenetic alterations in cancer. Biomolecules and Therapeutics
Plain numerical DOI: 10.4062/biomolther.2017.185
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“Cancer cells reprogram cellular metabolism to support the malignant features of tumors, such as rapid growth and proliferation. the cancer promoting effects of metabolic reprogramming are found in many aspects: generating additional energy, providing more anabolic molecules for biosynthesis, and rebalancing cellular redox states in cancer cells. metabolic pathways are considered the pipelines to supply metabolic cofactors of epigenetic modifiers. in this regard, cancer metabolism, whereby cellular metabolite levels are greatly altered compared to normal levels, is closely associated with cancer epigenetics, which is implicated in many stages of tumorigenesis. in this review, we provide an overview of cancer metabolism and its involvement in epigenetic modifications and suggest that the metabolic adaptation leading to epigenetic changes in cancer cells is an important non-genetic factor for tumor progression, which cooperates with genetic causes. understanding the interaction of metabolic reprogramming with epigenetics in cancers may help to develop novel or highly improved therapeutic strategies that target cancer metabolism.”
Kular, L., & Jagodic, M.. (2020). Epigenetic insights into multiple sclerosis disease progression. Journal of Internal Medicine
Plain numerical DOI: 10.1111/joim.13045
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“Multiple sclerosis (ms), a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system, is today a leading cause of unpredictable lifelong disability in young adults. the treatment of patients in progressive stages remains highly challenging, alluding to our limited understanding of the underlying pathological processes. in this review, we provide insights into the mechanisms underpinning ms progression from a perspective of epigenetics, that refers to stable and mitotically heritable, yet reversible, changes in the genome activity and gene expression. we first recapitulate findings from epigenetic studies examining the brain tissue of progressive ms patients, which support a contribution of dna and histone modifications in impaired oligodendrocyte differentiation, defective myelination/remyelination and sustained neuro-axonal vulnerability. we next explore possibilities for identifying factors affecting progression using easily accessible tissues such as blood by comparing epigenetic signatures in peripheral immune cells and brain tissue. despite minor overlap at individual methylation sites, nearly 30% of altered genes reported in peripheral immune cells of progressive ms patients were found in brain tissue, jointly converging on alterations of neuronal functions. we further speculate about the mechanisms underlying shared epigenetic patterns between blood and brain, which likely imply the influence of internal (genetic control) and/or external (e.g. smoking and ageing) factors imprinting a common signature in both compartments. overall, we propose that epigenetics might shed light on clinically relevant mechanisms involved in disease progression and open new avenues for the treatment of progressive ms patients in the future.”
Leso, V., Macrini, M. C., Russo, F., & Iavicoli, I.. (2020). Formaldehyde exposure and epigenetic effects: A systematic review. Applied Sciences (Switzerland)
Plain numerical DOI: 10.3390/app10072319
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“Formaldehyde (fa) is a general living and occupational pollutant, classified as carcinogenic for humans. although genotoxicity is recognized as a famechanism of action, a potential contribution of epigenetic effects cannot be excluded. therefore, aim of this review is to comprehensively assess possible epigenetic alterations induced by fa exposure in humans, animals, and cellular models. asystematic review of pubmed, scopus, and isiweb of science databases was performed. dnaglobal methylation changes were demonstrated in workers exposed to fa, and also in human bronchial cells. histone alterations, i.e., the reduction in acetylation of histone lysine residues, in human lung cells were induced by fa. moreover, a dysregulation of microrna expression in human lung adenocarcinoma cells as well as in the nose, olfactory bulb and white blood cells of rodents and nonhuman primates was reported. although preliminary, these findings suggest the role of epigenetic modifications as possible fa mechanisms of action that need deeper qualitative and quantitative investigation. this may allow to define the role of such alterations as indicators of early biological effect and the opportunity to include such information in future risk assessment and management strategies for public and occupationally fa-exposed populations.”
Kumar, R., Mary Paul, A., Rameshwar, P., & Pillai, M. R.. (2019). Epigenetic dysregulation at the crossroad of women’s cancer. Cancers
Plain numerical DOI: 10.3390/cancers11081193
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“An increasingly number of women of all age groups are affected by cancer, despite substantial progress in our understanding of cancer pathobiology, the underlying genomic alterations and signaling cascades, and cellular-environmental interactions. though our understanding of women’s cancer is far more complete than ever before, there is no comprehensive model to explain the reasons behind the increased incidents of certain reproductive cancer among older as well as younger women. it is generally suspected that environmental and life-style factors affecting hormonal and growth control pathways might help account for the rise of women’s cancers in younger age, as well, via epigenetic mechanisms. epigenetic regulators play an important role in orchestrating an orderly coordination of cellular signals in gene activity in response to upstream signaling and/or epigenetic modifiers present in a dynamic extracellular milieu. here we will discuss the broad principles of epigenetic regulation of dna methylation and demethylation, histone acetylation and deacetylation, and rna methylation in women’s cancers in the context of gene expression, hormonal action, and the egfr family of cell surface receptor tyrosine kinases. we anticipate that a better understanding of the epigenetics of women’s cancers may provide new regulatory leads and further fuel the development of new epigenetic biomarkers and therapeutic approaches.”
Delgado-Morales, R., Agís-Balboa, R. C., Esteller, M., & Berdasco, M.. (2017). Epigenetic mechanisms during ageing and neurogenesis as novel therapeutic avenues in human brain disorders. Clinical Epigenetics
Plain numerical DOI: 10.1186/s13148-017-0365-z
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“Ageing is the main risk factor for human neurological disorders. among the diverse molecular pathways that govern ageing, epigenetics can guide age-associated decline in part by regulating gene expression and also through the modulation of genomic instability and high-order chromatin architecture. epigenetic mechanisms are involved in the regulation of neural differentiation as well as in functional processes related to memory consolidation, learning or cognition during healthy lifespan. on the other side of the coin, many neurodegenerative diseases are associated with epigenetic dysregulation. the reversible nature of epigenetic factors and, especially, their role as mediators between the genome and the environment make them exciting candidates as therapeutic targets. rather than providing a broad description of the pathways epigenetically deregulated in human neurological disorders, in this review, we have focused on the potential use of epigenetic enzymes as druggable targets to ameliorate neural decline during normal ageing and especially in neurological disorders. we will firstly discuss recent progress that supports a key role of epigenetic regulation during healthy ageing with an emphasis on the role of epigenetic regulation in adult neurogenesis. then, we will focus on epigenetic alterations associated with ageing-related human disorders of the central nervous system. we will discuss examples in the context of psychiatric disorders, including schizophrenia and posttraumatic stress disorders, and also dementia or alzheimer’s disease as the most frequent neurodegenerative disease. finally, methodological limitations and future perspectives are discussed.”
Ferrer, A. I., Trinidad, J. R., Sandiford, O., Etchegaray, J. P., & Rameshwar, P.. (2020). Epigenetic dynamics in cancer stem cell dormancy. Cancer and Metastasis Reviews
Plain numerical DOI: 10.1007/s10555-020-09882-x
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“Cancer remains one of the most challenging diseases despite significant advances of early diagnosis and therapeutic treatments. cancerous tumors are composed of various cell types including cancer stem cells capable of self-renewal, proliferation, differentiation, and invasion of distal tumor sites. most notably, these cells can enter a dormant cellular state that is resistant to conventional therapies. thereby, cancer stem cells have the intrinsic potential for tumor initiation, tumor growth, metastasis, and tumor relapse after therapy. both genetic and epigenetic alterations are attributed to the formation of multiple tumor types. this review is focused on how epigenetic dynamics involving dna methylation and dna oxidations are implicated in breast cancer and glioblastoma multiforme. the emergence and progression of these cancer types rely on cancer stem cells with the capacity to enter quiescence also known as a dormant cellular state, which dictates the distinct tumorigenic aggressiveness between breast cancer and glioblastomas.”
Surace, A. E. A., & Hedrich, C. M.. (2019). The role of epigenetics in autoimmune/inflammatory disease. Frontiers in Immunology
Plain numerical DOI: 10.3389/fimmu.2019.01525
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“Historically, systemic self-inflammatory conditions were classified as either autoinflammatory and caused by the innate immune system or autoimmune and driven by adaptive immune responses. however, it became clear that reality is much more complex and that autoimmune/inflammatory conditions range along an ‘inflammatory spectrum’ with primarily autoinflammatory vs. autoimmune conditions resembling extremes at either end. epigenetic modifications influence gene expression and alter cellular functions without modifying the genomic sequence. methylation of cpg dna dinucleotides and/or their hydroxymethylation, post-translational modifications to amino termini of histone proteins, and non-coding rna expression are main epigenetic events. the pathophysiology of autoimmune/inflammatory diseases has been closely linked with disease causing gene mutations (rare) or a combination of genetic susceptibility and epigenetic modifications arising from exposure to the environment (more common). over recent years, progress has been made in understanding molecular mechanisms involved in systemic inflammation and the contribution of innate and adaptive immune responses. epigenetic events have been identified as (i) central pathophysiological factors in addition to genetic disease predisposition and (ii) as co-factors determining clinical pictures and outcomes in individuals with monogenic disease. thus, a complete understanding of epigenetic contributors to autoimmune/inflammatory disease will result in approaches to predict individual disease outcomes and the introduction of effective, target-directed, and tolerable therapies. here, we summarize recent findings that signify the importance of epigenetic modifications in autoimmune/inflammatory disorders along the inflammatory spectrum choosing three examples: the autoinflammatory bone condition chronic nonbacterial osteomyelitis (cno), the ‘mixed pattern’ disorder psoriasis, and the autoimmune disease systemic lupus erythematosus (sle).”
Jiang, Z., Wang, Y., Lin, J., Xu, J., Ding, G., & Huang, H.. (2017). Genetic and epigenetic risks of assisted reproduction. Best Practice and Research: Clinical Obstetrics and Gynaecology
Plain numerical DOI: 10.1016/j.bpobgyn.2017.07.004
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“Assisted reproductive technology (art) is used primarily for infertility treatments to achieve pregnancy and involves procedures such as in vitro fertilization (ivf), intracytoplasmic sperm injection (icsi), and cryopreservation. moreover, preimplantation genetic diagnosis (pgd) of art is used in couples for genetic reasons. in art treatments, gametes and zygotes are exposed to a series of non-physiological processes and culture media. although the majority of children born with this treatment are healthy, some concerns remain regarding the safety of this technology. animal studies and follow-up studies of art-borne children suggested that art was associated with an increased incidence of genetic, physical, or developmental abnormalities, although there are also observations that contradict these findings. as ivf, icsi, frozen-thawed embryo transfer, and pgd manipulate gametes and embryo at a time that is important for reprogramming, they may affect epigenetic stability, leading to gamete/embryo origins of adult diseases. in fact, art offspring have been reported to have an increased risk of gamete/embryo origins of adult diseases, such as early-onset diabetes, cardiovascular disease, and so on. in this review, we will discuss evidence related to genetic, especially epigenetic, risks of assisted reproduction.”
Taufiqul Arif, K. M., Elliot, E. K., Haupt, L. M., & Griffiths, L. R.. (2020). Regulatory mechanisms of epigenetic mirna relationships in human cancer and potential as therapeutic targets. Cancers
Plain numerical DOI: 10.3390/cancers12102922
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“Initiation and progression of cancer are under both genetic and epigenetic regulation. epigenetic modifications including alterations in dna methylation, rna and histone modifications can lead to microrna (mirna) gene dysregulation and malignant cellular transformation and are hereditary and reversible. mirnas are small non-coding rnas which regulate the expression of specific target genes through degradation or inhibition of translation of the target mrna. mirnas can target epigenetic modifier enzymes involved in epigenetic modulation, establishing a trilateral regulatory ‘epi–mir–epi’ feedback circuit. the intricate association between mirnas and the epigenetic architecture is an important feature through which to monitor gene expression profiles in cancer. this review summarises the involvement of epigenetically regulated mirnas and mirna-mediated epigenetic modulations in various cancers. in addition, the application of bioinformatics tools to study these networks and the use of therapeutic mirnas for the treatment of cancer are also reviewed. a comprehensive interpretation of these mechanisms and the interwoven bond between mirnas and epigenetics is crucial for understanding how the human epigenome is maintained, how aberrant mirna expression can contribute to tumorigenesis and how knowledge of these factors can be translated into diagnostic and therapeutic tool development.”
Suarez, A., Lahti, J., Czamara, D., Lahti-Pulkkinen, M., Knight, A. K., Girchenko, P., … Räikkönen, K.. (2018). The Epigenetic Clock at Birth: Associations With Maternal Antenatal Depression and Child Psychiatric Problems. Journal of the American Academy of Child and Adolescent Psychiatry
Plain numerical DOI: 10.1016/j.jaac.2018.02.011
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“Objective: maternal antenatal depression may compromise the fetal developmental milieu and contribute to individual differences in aging and disease trajectories in later life. we evaluated the association between maternal antenatal depression and a novel biomarker of aging at birth, namely epigenetic gestational age (ga) based on fetal cord blood methylation data. we also examined whether this biomarker prospectively predicts and mediates maternal effects on early childhood psychiatric problems. method: a total of 694 mothers from the prediction and prevention of preeclampsia and intrauterine growth restriction (predo) study provided information on history of depression diagnosed before pregnancy; 581 completed the center for epidemiological studies depression scale throughout pregnancy, and 407 completed the child behavior checklist at child’s age 3.7 years (sd = 0.75 year). dna methylation (dnam) ga of fetal cord blood dna was based on the methylation profile of 148 selected cytosine linked to guanine by phosphate (cpg) sites. epigenetic ga was calculated as the arithmetic difference between dnam ga and chronological ga and adjusted for chronological ga. results: maternal history of depression diagnosed before pregnancy (mean difference = −0.25 sd units, 95% ci = −0.46 to −0.03) and greater antenatal depressive symptoms (−0.08 sd unit per 1-sd unit increase, 95% ci = −0.16 to −0.004) were associated with child’s lower epigenetic ga. child’s lower epigenetic ga, in turn, prospectively predicted total and internalizing problems and partially mediated the effects of maternal antenatal depression on internalizing problems in boys. conclusion: maternal antenatal depression is associated with lower epigenetic ga in offspring. this lower epigenetic ga seems to be associated with a developmental disadvantage for boys, who, in early childhood, show greater psychiatric problems.”
Alamer, E., Zhong, C., Hajnik, R., Soong, L., & Hu, H.. (2021). Modulation of BRD4 in HIV epigenetic regulation: implications for finding an HIV cure. Retrovirology
Plain numerical DOI: 10.1186/s12977-020-00547-9
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“Following reverse transcription, hiv viral dna is integrated into host cell genomes and establishes a stable latent infection, which has posed a major obstacle for obtaining a cure for hiv. hiv proviral transcription is regulated in cellular reservoirs by complex host epigenetic and transcriptional machineries. the bromodomain (bd) and extra-terminal domain (et) protein, brd4, is an important epigenetic reader that interacts with acetyl-histones and a variety of chromatin and transcriptional regulators to control gene expression, including hiv. modulation of brd4 by a pan bet inhibitor (jq1) has been shown to activate hiv transcription. recent studies by my group and others indicate that the function of brd4 is versatile and its effects on hiv transcription may depend on the partner proteins or pathways engaged by brd4. our studies have reported a novel class of small-molecule modulators that are distinct from jq1 but induce hiv transcriptional suppression through brd4. herein, we reviewed recent research on the modulation of brd4 in hiv epigenetic regulation and discussed their potential implications for finding an hiv cure.”
Kumari, N., Karmakar, A., & Ganesan, S. kumar. (2020). Targeting epigenetic modifications as a potential therapeutic option for diabetic retinopathy. Journal of Cellular Physiology
Plain numerical DOI: 10.1002/jcp.29180
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“Diabetic retinopathy (dr) is the leading cause of visual impairment in adults of working age (20–65 years) in developed countries. the metabolic memory phenomena (persistent effect of a glycemic insult even after retrieved) associated with it has increased the risk of developing the complication even after the termination of the glycemic insult. hence, the need for finding early diagnosis and treatment options has been of great concern. epigenetic modifications which generally occur during the beginning stages of the disease are responsible for the metabolic memory effect. therefore, the therapy based on the reversal of the associated epigenetic mechanism can bring new insight in the area of early diagnosis and treatment mechanism. this review discusses the diabetic retinopathy, its pathogenesis, current treatment options, need of finding novel treatment options, and different epigenetic alterations associated with dr. however, the main focus is emphasized on various epigenetic modifications particularly dna methylation which are responsible for the initiation and progression of diabetic retinopathy and the use of different epigenetic inhibitors as a novel therapeutic option for dr.”
Yahara, I.. (2019). A role for epigenetic adaption in evolution. Genes to Cells
Plain numerical DOI: 10.1111/gtc.12709
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“The outcome of epigenetic responses to stress depends strictly on genetic background, suggesting that altered phenotypes, when induced, are created by a combination of induced epigenetic factors and pre-existing allelic ones. when individuals with altered phenotypes are selected and subjected to successive breeding, alleles that potentiate epigenetic responses could accumulate in offspring populations. it is reasonable to suppose that many, if not all, of these allelic genes could also be involved in creating new phenotypes under nonstressful conditions. in this review, i discuss the possibility that the accumulation of such alleles in selected individuals with an epigenetic phenotype could give rise to individuals that exhibit the same phenotype even in the absence of stress.”
Guo, Y., Su, Z. Y., & Kong, A. N. T.. (2015). Current Perspectives on Epigenetic Modifications by Dietary Chemopreventive and Herbal Phytochemicals. Current Pharmacology Reports
Plain numerical DOI: 10.1007/s40495-015-0023-0
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“Studies during the last two decades have revealed the involvement of epigenetic modifications in the development of human cancer. it is now recognized that the interplay of dna methylation, posttranslational histone modification, and non-coding rnas can interact with genetic defects to drive tumorigenesis. the early onset, reversibility, and dynamic nature of such epigenetic modifications enable them to be developed as promising cancer biomarkers and preventive/therapeutic targets. in addition to the recent approval of several epigenetic therapies in the treatment of human cancer, emerging studies have indicated that dietary phytochemicals might exert cancer chemopreventive effects by targeting epigenetic mechanisms. in this review, we will present the current understanding of the epigenetic alterations in carcinogenesis and highlight the potential of targeting these mechanisms to treat/prevent cancer. the latest findings, published in the past 3 years regarding the effects of dietary phytochemicals in modulating epigenetic mechanisms, will also be discussed.”
Okazaki, S., Otsuka, I., Horai, T., Hirata, T., Takahashi, M., Ueno, Y., … Hishimoto, A.. (2020). Accelerated extrinsic epigenetic aging and increased natural killer cells in blood of suicide completers. Progress in Neuro-Psychopharmacology and Biological Psychiatry
Plain numerical DOI: 10.1016/j.pnpbp.2019.109805
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“Background: studies suggest aberrant dna methylation in victims of suicide. recently, dna methylation profiles have been developed for determining ‘epigenetic age,’ which is the most accurate estimate of biological age. subsequently, two refined measures of epigenetic age acceleration have been expanded for blood samples as intrinsic and extrinsic epigenetic age acceleration (ieaa and eeaa, respectively). ieaa involves pure epigenetic aging independent of blood cell composition, whereas eeaa involves immunosenescence in association with blood cell composition. methods: we investigated epigenetic age acceleration using two independent dna methylation datasets: a brain dataset from 16 suicide completers and 15 non-psychiatric controls and a blood dataset compiled using economical dna pooling technique from 56 suicide completers and 60 living healthy controls. in the blood dataset, we considered ieaa and eeaa, as well as dna methylation-based blood cell composition. results: there was no significant difference in universal epigenetic age acceleration between suicide completers and controls in both brain and blood datasets. blood of suicide completers exhibited an increase in eeaa, but not in ieaa. we additionally found that suicide completers had more natural killer cells but fewer granulocytes compared to controls. conclusion: this study provides novel evidence for accelerated extrinsic epigenetic aging in suicide completers and for the potential application of natural killer cells as a biomarker for suicidal behavior.”
Karakaidos, P., Karagiannis, D., & Rampias, T.. (2020). Resolving DNA damage: Epigenetic regulation of DNA repair. Molecules
Plain numerical DOI: 10.3390/molecules25112496
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“Epigenetic research has rapidly evolved into a dynamic field of genome biology. chromatin regulation has been proved to be an essential aspect for all genomic processes, including dna repair. chromatin structure is modified by enzymes and factors that deposit, erase, and interact with epigenetic marks such as dna and histone modifications, as well as by complexes that remodel nucleosomes. in this review we discuss recent advances on how the chromatin state is modulated during this multi-step process of damage recognition, signaling, and repair. moreover, we examine how chromatin is regulated when different pathways of dna repair are utilized. furthermore, we review additional modes of regulation of dna repair, such as through the role of global and localized chromatin states in maintaining expression of dna repair genes, as well as through the activity of epigenetic enzymes on non-nucleosome substrates. finally, we discuss current and future applications of the mechanistic interplays between chromatin regulation and dna repair in the context cancer treatment.”
Mayran, A., & Drouin, J.. (2018). Pioneer transcription factors shape the epigenetic landscape. Journal of Biological Chemistry
Plain numerical DOI: 10.1074/jbc.R117.001232
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“Pioneer transcription factors have the unique and important role of unmasking chromatin domains during development to allow the implementation of new cellular programs. compared with those of other transcription factors, this activity implies that pioneer factors can recognize their target dna sequences in so-called compacted or ‘closed’ heterochromatin and can trigger remodeling of the adjoining chromatin landscape to provide accessibility to nonpioneer transcription factors. recent studies identified several steps of pioneer action, namely rapid but weak initial binding to heterochromatin and stabilization of binding followed by chromatin opening and loss of cytosine-phosphate-guanine (cpg) methylation that provides epigenetic memory. whereas cpg demethylation depends on replication, chromatin opening does not. in this minireview, we highlight the unique properties of this transcription factor class and the challenges of understanding their mechanism of action.”
Perri, F., Longo, F., Giuliano, M., Sabbatino, F., Favia, G., Ionna, F., … Pisconti, S.. (2017). Epigenetic control of gene expression: Potential implications for cancer treatment. Critical Reviews in Oncology/Hematology
Plain numerical DOI: 10.1016/j.critrevonc.2017.01.020
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“Epigenetic changes are defined as inherited modifications that are not present in dna sequence. gene expression is regulated at various levels and not only in response to dna modifications. examples of epigenetic control are dna methylation, histone deacetylation and mi-rna expression. methylation of several tumor suppressor gene promoters is responsible for their silencing and thus potentially sustain cancerogenesis. similarly, histone deacetylation can lead to oncogene activation. mi-rna are small (18–20 nucleotides) non-coding rna fragments capable of inhibiting other m-rna, ultimately altering the balance in oncogene and tumor suppressor gene expression. it has been shown that growth of several tumor types can be stimulated by epigenetic changes in various phases of cancerogenesis, and drugs able to interfere with these mechanisms can have a positive impact on tumor progression. as matter of fact, epigenetic changes are dynamic and can be reversed by epigenetic inhibitors. recently, methyltransferase and histone deacetylase inhibitors have attracted the attention of researchers and clinicians as they potentially provide alternative therapeutic options in some cancers. drugs that inhibit dna methylation or histone deacetylation have been studied for the reactivation of tumor suppressor genes and repression of cancer cell growth. epigenetic inhibitors work alone or in combination with other therapeutic agents. to date, a number of epigenetic inhibitors have been approved for cancer treatment. the main challenge in the field of epigenetic inhibitors is their lack of specificity. in this review article we describe their mechanisms of action and potential in cancer treatment.”
Hanif, E. A. M., & Shah, S. A.. (2018). Overview on epigenetic re-programming: A potential therapeutic intervention in triple negative breast cancers. Asian Pacific Journal of Cancer Prevention
Plain numerical DOI: 10.31557/APJCP.2018.19.12.3341
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“Breast cancer treatments leads to variable responses. hormonal therapy is beneficial to receptor positive breast cancer subtypes and display better clinical outcome than triple negative breast cancers (tnbcs) with fec (5-fluorouracil, epirubicin and cyclophosphamide) the mainstay chemotherapy regiment. owning to their negative expressions of estrogen (er), progesterone (pr) and her2 receptors, disease recurrence and metastasis befalls some patients indicating resistance to fec. involvement of epigenetic silencing through dna methylation, histone methylation, acetylation and sumoylation may be the key player in fec chemoresistance. epigenetic and molecular profiling successfully classified breast cancer subtypes, indicating potential driver mechanisms to the progression of tnbcs but functional mechanisms behind chemoresistance of these molecular markers are not well defined. several epigenetic inhibitors and drugs have been used in the management of cancers but these attempts are mainly beneficial in hematopoietic cancers and not specifically favourable in solid tumours. hypothetically, upon administration of epigenetic drugs, recovery of tumour suppressor genes is expected. however, high tendency of switching on global metastatic genes is predicted. polycomb repressive complex (prc) such as ezh2, setd1a, dnmt, is known to have repressive effects in gene regulation and shown to inhibit cell proliferation and invasion in breast cancers. individual epigenetic regulators may be an option to improve chemo-drug delivery in cancers. this review discussed on molecular signatures of various breast cancer subtypes and on-going attempts in understanding underlying molecular mechanisms of epigenetic regulators as well as providing insights on possible ways to utilize epigenetic enzymes/inhibitors with responses to chemotherapeutic drugs to re-program cellular and biological outcome in tnbcs.”
Silverman, B. R., & Shi, J.. (2016). Alterations of epigenetic regulators in pancreatic cancer and their clinical implications. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms17122138
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“Pancreatic cancer is one of the most aggressive human cancer types with a five-year survival less than 7%. emerging evidence revealed that many genetic alterations in pancreatic cancer target epigenetic regulators. some of these mutations are driver mutations in cancer development. several most important mechanisms of epigenetic regulations include dna methylation, histone modifications (methylation, acetylation, and ubiquitination), chromatin remodeling, and non-coding ribonucleic acids (rnas). these modifications can alter chromatin structure and promoter accessibility, and thus lead to aberrant gene expression. however, exactly how these alterations affect epigenetic reprogramming in pancreatic cancer cells and in different stages of tumor development is still not clear. this mini-review summarizes the current knowledge of epigenetic alterations in pancreatic cancer development and progression, and discusses the clinical applications of epigenetic regulators as diagnostic biomarkers and therapeutic targets in pancreatic cancer.”
Baron, U., Werner, J., Schildknecht, K., Schulze, J. J., Mulu, A., Liebert, U. G., … Olek, S.. (2018). Epigenetic immune cell counting in human blood samples for immunodiagnostics. Science Translational Medicine
Plain numerical DOI: 10.1126/scitranslmed.aan3508
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“Immune cell profiles provide valuable diagnostic information for hematologic and immunologic diseases. although it is the most widely applied analytical approach, flow cytometry is limited to liquid blood. moreover, either analysis must be performed with fresh samples or cell integrity needs to be guaranteed during storage and transport. we developed epigenetic real-time quantitative polymerase chain reaction (qpcr) assays for analysis of human leukocyte subpopulations. after method establishment, whole blood from 25 healthy donors and 97 hiv+ patients as well as dried spots from 250 healthy newborns and 24 newborns with primary immunodeficiencies were analyzed. concordance between flow cytometric and epigenetic data for neutrophils and b, natural killer, cd3+ t, cd8+ t, cd4+ t, and foxp3+ regulatory t cells was evaluated, demonstrating substantial equivalence between epigenetic qpcr analysis and flow cytometry. epigenetic qpcr achieves both relative and absolute quantifications. applied to dried blood spots, epigenetic immune cell quantification was shown to identify newborns suffering from various primary immunodeficiencies. using epigenetic qpcr not only provides a precise means for immune cell counting in fresh-frozen blood but also extends applicability to dried blood spots. this method could expand the ability for screening immune defects and facilitates diagnostics of unobservantly collected samples, for example, in underdeveloped areas, where logistics are major barriers to screening.”
Lappalainen, T., & Greally, J. M.. (2017). Associating cellular epigenetic models with human phenotypes. Nature Reviews Genetics
Plain numerical DOI: 10.1038/nrg.2017.32
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“Epigenetic association studies have been carried out to test the hypothesis that environmental perturbations trigger cellular reprogramming, with downstream effects on cellular function and phenotypes. there have now been numerous studies of the potential molecular mediators of epigenetic changes by epigenome-wide association studies (ewas). however, a challenge for the field is the interpretation of the results obtained. we describe a second-generation ewas approach, which focuses on the possible cellular models of epigenetic perturbations, studied by rigorous analysis and interpretation of genomic data. thus refocused, epigenetics research aligns with the field of functional genomics to provide insights into environmental and genetic influences on phenotypic variation in humans.”
Zughaier, S. M., Rouquette-Loughlin, C. E., & Shafer, W. M.. (2020). Identification of a neisseria gonorrhoeae histone deacetylase: Epigenetic impact on host gene expression. Pathogens
Plain numerical DOI: 10.3390/pathogens9020132
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“Epigenetic reprogramming in macrophages is termed trained innate immunity, which regulates immune tolerance and limits tissue damage during infection. neisseria gonorrhoeae is a strict human pathogen that causes the sexually transmitted infection termed gonorrhea. here, we report that this pathogen harbors a gene that encodes a histone deacetylase-like enzyme (gc-hdac) that shares high 3d-homology to human hdac1, hdac2 and hdac8. a gc-hdac null mutant was constructed to determine the biologic significance of this gene. the results showed that wt gonococci reduced the expression of host defense peptides ll-37, hbd-1 and slpi in macrophages when compared to its gc-hdac-deficient isogenic strain. the enrichment of epigenetic marks in histone tails control gene expression and are known to change during bacterial infections. to investigate whether gonococci exert epigenetic modifications on host chromatin, the enrichment of acetylated lysine 9 in histone 3 (h3k9ac) was investigated using the tlr-focused chip array system. the data showed that infection with wt gonococci led to higher h3k9ac enrichment at the promoters of pro-inflammatory mediators’ genes, many tlrs, adaptor proteins and transcription factors, suggesting gene activation when compared to infection with the gc-hdac-deficient mutant. taken together, the data suggest that gonococci can exert epigenetic modifications on host cells to modulate certain macrophage defense genes, leading to a maladaptive state of trained immunity.”
Zhu, B., & Reinberg, D.. (2011). Epigenetic inheritance: Uncontested?. Cell Research
Plain numerical DOI: 10.1038/cr.2011.26
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“Epigenetics is currently defined as the inheritance of variation (-genetics) above and beyond (epi-) changes in the dna sequence. despite the fact that histones are believed to carry important epigenetic information, little is known about the molecular mechanisms of the inheritance of histone-based epigenetic information, including histone modifications and histone variants. here we review recent progress and discuss potential models for the mitotic inheritance of histone modifications-based epigenetic information. © 2011 ibcb, sibs, cas all rights reserved.”
Goldman, S. L., Hassan, C., Khunte, M., Soldatenko, A., Jong, Y., Afshinnekoo, E., & Mason, C. E.. (2019). Epigenetic modifications in acute myeloid leukemia: Prognosis, treatment, and heterogeneity. Frontiers in Genetics
Plain numerical DOI: 10.3389/fgene.2019.00133
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“Leukemia, specifically acute myeloid leukemia (aml), is a common malignancy that can be differentiated into multiple subtypes based on leukemogenic history and etiology. although genetic aberrations, particularly cytogenetic abnormalities and mutations in known oncogenes, play an integral role in aml development, epigenetic processes have been shown as a significant and sometimes independent dynamic in aml pathophysiology. here, we summarize how tumors evolve and describe aml through an epigenetic lens, including discussions on recent discoveries that include prognostics from epialleles, changes in rna function for hematopoietic stem cells and the epitranscriptome, and novel epigenetic treatment options. we further describe the limitations of treatment in the context of the high degree of heterogeneity that characterizes acute myeloid leukemia.”
Jiang, S., & Guo, Y.. (2020). Epigenetic Clock: DNA Methylation in Aging. Stem Cells International
Plain numerical DOI: 10.1155/2020/1047896
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“Aging, which is accompanied by decreased organ function and increased disease incidence, limits human lifespan and has attracted investigators for thousands of years. in recent decades, with the rapid development of biology, scientists have shown that epigenetic modifications, especially dna methylation, are key regulators involved in this process. regular fluctuations in global dna methylation levels have been shown to accurately estimate biological age and disease prognosis. in this review, we discuss recent findings regarding the relationship between variations in dna methylation level patterns and aging. in addition, we introduce the known mechanisms by which dna methylation regulators affect aging and related diseases. as more studies uncover the mechanisms by which dna methylation regulates aging, antiaging interventions and treatments for related diseases may be developed that enable human life extension.”
Yang, J.-H., Griffin, P., Vera, D., Apostolides, J., Hayano, M., Meer, M., … Sinclair, D.. (2019). Erosion of the Epigenetic Landscape and Loss of Cellular Identity as a Cause of Aging in Mammals. SSRN Electronic Journal
Plain numerical DOI: 10.1101/808642
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“All living things experience entropy, manifested as a loss of inherited genetic and epigenetic information over time. as budding yeast cells age, epigenetic changes result in a loss of cell identity and sterility, both hallmarks of yeast aging. in mammals, epigenetic information is also lost over time, but what causes it to be lost and whether it is a cause or a consequence of aging is not known. here we show that the transient induction of genomic instability, in the form of a low number of non-mutagenic dna breaks, accelerates many of the chromatin and tissue changes seen during aging, including the erosion of the epigenetic landscape, a loss of cellular identity, advancement of the dna methylation clock and cellular senescence. these data support a model in which a loss of epigenetic information is a cause of aging in mammals.one sentence summary the act of repairing dna breaks induces chromatin reorganization and a loss of cell identity that may contribute to mammalian aging”
Rehman, M., & Tanti, B.. (2020). Understanding epigenetic modifications in response to abiotic stresses in plants. Biocatalysis and Agricultural Biotechnology
Plain numerical DOI: 10.1016/j.bcab.2020.101673
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“Plants have to cope up with environmental stresses during different developmental stages of their life cycle. to overcome the stresses, epigenetic regulations play a significant role in their adaptation. epigenetic modification has already been well understood. in fact, there are numerous reports related to an epigenetic modification in plants under abiotic stresses. however, there is still a gap in understanding the correlation among different epigenetic phenomena occurring under various abiotic stresses in plants. therefore, in this review, an attempt has been made to correlate the various epigenetic modifications in the plant under abiotic stresses. further, recent high-throughput technologies that are being used in the epigenetic analysis have also been highlighted. various aspects of epigenetic modification in plants have been studied giving emphasis towards abiotic stresses. dna methylation and histone modification have been focused including the rddm pathway, atp-dependent chromatin remodeling, and methylation-sensitive amplified polymorphism (msap). with the advancement of technology, various techniques have been applied to detect dna methylation patterns in plants. these may include bisulfite sequencing, combined bisulfite restriction analysis (cobra), chromatin immunoprecipitation (chip), methylation-sensitive single nucleotide primer extension (ms-snupe), cytosine assay and many more, of which bisulfite genomic sequencing, is the most commonly used. in this report, bisulfite sequencing and chromatin immunoprecipitation were described in detail. moreover, with the advent of various bioinformatics tools and techniques, epigenetic research has been facilitated, few of which were discussed in this review.”
Ramos-Lopez, O., Milagro, F. I., Riezu-Boj, J. I., & Martinez, J. A.. (2021). Epigenetic signatures underlying inflammation: an interplay of nutrition, physical activity, metabolic diseases, and environmental factors for personalized nutrition. Inflammation Research
Plain numerical DOI: 10.1007/s00011-020-01425-y
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“Aim and objective: emerging translational evidence suggests that epigenetic alterations (dna methylation, mirna expression, and histone modifications) occur after external stimuli and may contribute to exacerbated inflammation and the risk of suffering several diseases including diabetes, cardiovascular diseases, cancer, and neurological disorders. this review summarizes the current knowledge about the harmful effects of high-fat/high-sugar diets, micronutrient deficiencies (folate, manganese, and carotenoids), obesity and associated complications, bacterial/viral infections, smoking, excessive alcohol consumption, sleep deprivation, chronic stress, air pollution, and chemical exposure on inflammation through epigenetic mechanisms. additionally, the epigenetic phenomena underlying the anti-inflammatory potential of caloric restriction, n-3 pufa, mediterranean diet, vitamin d, zinc, polyphenols (i.e., resveratrol, gallic acid, epicatechin, luteolin, curcumin), and the role of systematic exercise are discussed. methods: original and review articles encompassing epigenetics and inflammation were screened from major databases (including pubmed, medline, science direct, scopus, etc.) and analyzed for the writing of the review paper. conclusion: although caution should be exercised, research on epigenetic mechanisms is contributing to understand pathological processes involving inflammatory responses, the prediction of disease risk based on the epigenotype, as well as the putative design of therapeutic interventions targeting the epigenome.”
Kanherkar, R. R., Stair, S. E., Bhatia-Dey, N., Mills, P. J., Chopra, D., & Csoka, A. B.. (2017). Epigenetic mechanisms of integrative medicine. Evidence-Based Complementary and Alternative Medicine
Plain numerical DOI: 10.1155/2017/4365429
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“Since time immemorial humans have utilized natural products and therapies for their healing properties. even now, in the age of genomics and on the cusp of regenerative medicine, the use of complementary and alternative medicine (cam) approaches represents a popular branch of health care. furthermore, there is a trend towards a unified medical philosophy referred to as integrative medicine (im) that represents the convergence of cam and conventional medicine. the im model not only considers the holistic perspective of the physiological components of the individual, but also includes psychological and mind-body aspects. justification for and validation of such a whole-systems approach is in part dependent upon identification of the functional pathways governing healing, and new data is revealing relationships between therapies and biochemical effects that have long defied explanation. we review this data and propose a unifying theme: im’s ability to affect healing is due at least in part to epigenetic mechanisms.this hypothesis is based on a mounting body of evidence that demonstrates a correlation between the physical and mental effects of im and modulation of gene expression and epigenetic state. emphasis on mapping, deciphering, and optimizing these effects will facilitate therapeutic delivery and create further benefits.”
Kim, J. A., & Yeom, Y. Il. (2018). Metabolic signaling to epigenetic alterations in cancer. Biomolecules and Therapeutics
Plain numerical DOI: 10.4062/biomolther.2017.185
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“Cancer cells reprogram cellular metabolism to support the malignant features of tumors, such as rapid growth and proliferation. the cancer promoting effects of metabolic reprogramming are found in many aspects: generating additional energy, providing more anabolic molecules for biosynthesis, and rebalancing cellular redox states in cancer cells. metabolic pathways are considered the pipelines to supply metabolic cofactors of epigenetic modifiers. in this regard, cancer metabolism, whereby cellular metabolite levels are greatly altered compared to normal levels, is closely associated with cancer epigenetics, which is implicated in many stages of tumorigenesis. in this review, we provide an overview of cancer metabolism and its involvement in epigenetic modifications and suggest that the metabolic adaptation leading to epigenetic changes in cancer cells is an important non-genetic factor for tumor progression, which cooperates with genetic causes. understanding the interaction of metabolic reprogramming with epigenetics in cancers may help to develop novel or highly improved therapeutic strategies that target cancer metabolism.”
Koch, C. M., & Wagner, W.. (2011). Epigenetic-aging-signature to determine age in different tissues. Aging
Plain numerical DOI: 10.18632/aging.100395
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“All tissues of the organism are affected by aging. this process is associated with epigenetic modifications such as methylation changes at specific cytosine residues in the dna (cpg sites). here, we have identified an epigenetic-aging- signature which is applicable for many tissues to predict donor age. dna-methylation profiles of various cell types were retrieved from public data depositories – all using the humanmethylation27 beadchip platform which represents 27,578 cpg sites. five datasets from dermis, epidermis, cervical smear, t-cells and monocytes were used for pavlidis template matching to identify 19 cpg sites that are continuously hypermethylated upon aging (r > 0.6; p-value <10-13). four of these cpg sites (associated with the genes nptx2, trim58, gria2 and kcnq1dn) and an additional hypomethylated cpg site (birc4bp) were implemented in a model to predict donor age. this epigenetic-aging-signature was tested on a validation group of eight independent datasets corresponding to several cell types from different tissues. overall, the five cpg sites revealed age-associated dna-methylation changes in all tissues. the average absolute difference between predicted and real chronological age was about 11 years. this method can be used to predict donor age in various cell preparations - for example in forensic analysis. © koch and wagner.”
Barrero, M. J.. (2017). Epigenetic strategies to boost cancer immunotherapies. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms18061108
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“Recently, immunotherapeutic approaches have shown impressive responses in a subset of cancer patients. however, the rate of success is low and a large percentage of treated patients do not experience clinical benefits. therefore, additional strategies are needed to improve responses and select responsive patients. emerging data suggest that epigenetic drugs can improve the responses to immunotherapy. understanding the mechanisms of resistance to immunotherapy and the epigenetic events that take place during immune evasion is critical to providing a rational combined use of immunotherapies and epigenetic drugs. this review focuses in the epigenetic mechanisms involved in the responses to immunotherapy and how current drugs that target epigenetic regulators impact on them.”
Daniel, M., & Tollefsbol, T. O.. (2015). Epigenetic linkage of aging, cancer and nutrition. Journal of Experimental Biology
Plain numerical DOI: 10.1242/jeb.107110
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“Epigenetic mechanisms play a pivotal role in the expression of genes and can be influenced by both the quality and quantity of diet. dietary compounds such as sulforaphane (sfn) found in cruciferous vegetables and epigallocatechin-3-gallate (egcg) in green tea exhibit the ability to affect various epigenetic mechanisms such as dna methyltransferase (dnmt) inhibition, histone modifications via histone deacetylase (hdac), histone acetyltransferase (hat) inhibition, or noncoding rna expression. regulation of these epigenetic mechanisms has been shown to have notable influences on the formation and progression of various neoplasms. we have shown that an epigenetic diet can influence both cellular longevity and carcinogenesis through the modulation of certain key genes that encode telomerase and p16. caloric restriction (cr) can also play a crucial role in aging and cancer. reductions in caloric intake have been shown to increase both the life- and health-span in a variety of animal models. moreover, restriction of glucose has been demonstrated to decrease the incidence of age-related diseases such as cancer and diabetes. a diet rich in compounds such as genistein, sfn and egcg can positively modulate the epigenome and lead to many health benefits. also, reducing the quantity of calories and glucose in the diet can confer an increased health-span, including reduced cancer incidence.”
Feinberg, A. P., Koldobskiy, M. A., & Göndör, A.. (2016). Epigenetic modulators, modifiers and mediators in cancer aetiology and progression. Nature Reviews Genetics
Plain numerical DOI: 10.1038/nrg.2016.13
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“This year is the tenth anniversary of the publication in this journal of a model suggesting the existence of ‘tumour progenitor genes’. these genes are epigenetically disrupted at the earliest stages of malignancies, even before mutations, and thus cause altered differentiation throughout tumour evolution. the past decade of discovery in cancer epigenetics has revealed a number of similarities between cancer genes and stem cell reprogramming genes, widespread mutations in epigenetic regulators, and the part played by chromatin structure in cellular plasticity in both development and cancer. in the light of these discoveries, we suggest here a framework for cancer epigenetics involving three types of genes: ‘epigenetic mediators’, corresponding to the tumour progenitor genes suggested earlier; ‘epigenetic modifiers’ of the mediators, which are frequently mutated in cancer; and ‘epigenetic modulators’ upstream of the modifiers, which are responsive to changes in the cellular environment and often linked to the nuclear architecture. we suggest that this classification is helpful in framing new diagnostic and therapeutic approaches to cancer.”
Hu, L., Xiao, P., Jiang, Y., Dong, M., Chen, Z., Li, H., … Wang, J.. (2018). Transgenerational epigenetic inheritance under environmental stress by genome-wide DNA methylation profiling in cyanobacterium. Frontiers in Microbiology
Plain numerical DOI: 10.3389/fmicb.2018.01479
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“Epigenetic modifications such as dna methylation are well known as connected with many important biological processes. rapid accumulating evidence shows environmental stress can generate particular defense epigenetic changes across generations in eukaryotes. this transgenerational epigenetic inheritance in animals and plants has gained interest over the last years. cyanobacteria play very crucial role in the earth, and as the primary producer they can adapt to nearly all diverse environments. however, few knowledge about the genome wide epigenetic information such as methylome information in cyanobacteria, especially under any environment stress, was reported so far. in this study we profiled the genome-wide cytosine methylation from a model cyanobacterium synechocystis sp. pcc 6803, and explored the possibility of transgenerational epigenetic process in this ancient single-celled prokaryote by comparing the dna methylomes among normal nitrogen medium cultivation, nitrogen starvation for 72 h and nitrogen recovery for about 12 generations. our results shows that dna methylation patterns in nitrogen starvation and nitrogen recovery are much more similar with each other, significantly different from that of the normal nitrogen. this study reveals the difference in global dna methylation pattern of cyanobacteria between normal and nutrient stress conditions and reports the evidence of transgenerational epigenetic process in cyanobacteria. the results of this study may contribute to a better understanding of epigenetic regulation in prokaryotic adaptation to and survive in the ever changing environment.”
Wang, X., & Moazed, D.. (2017). DNA sequence-dependent epigenetic inheritance of gene silencing and histone H3K9 methylation. Science
Plain numerical DOI: 10.1126/science.aaj2114
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“Epigenetic inheritance mechanisms play fundamental roles in maintaining cellular memory of gene expression states. in fission yeast, histone h3 lysine 9 (h3k9) is methylated (h3k9me) at heterochromatic domains. these domains can be epigenetically inherited when epe1+, encoding an enzyme that promotes h3k9 demethylation, is deleted. how native epigenetic states are stably maintained in epe1+ cells remains unknown. here, we developed a system to examine the role of dna sequence and genomic context in propagation of a cis-heritable h3k9medependent silenced state. we show that in epe1+ cells, in addition to sequenceindependent mechanisms that propagate h3k9me, epigenetic inheritance of silencing requires binding sites for sequence-dependent activating transcription factor (atf)-adenosine 3’,5’-monophosphate (camp) response element-binding protein (creb) family transcription factors within their native chromosomal context. thus, specific dna sequences contribute to cis inheritance of h3k9me and silent epigenetic states.”
Durinck, K., & Speleman, F.. (2018). Epigenetic regulation of neuroblastoma development. Cell and Tissue Research
Plain numerical DOI: 10.1007/s00441-017-2773-y
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“In recent years, technological advances have enabled a detailed landscaping of the epigenome and the mechanisms of epigenetic regulation that drive normal cell function, development and cancer. rather than merely a structural entity to support genome compaction, we now look at chromatin as a very dynamic and essential constellation that is actively participating in the tight orchestration of transcriptional regulation as well as dna replication and repair. the unique feature of chromatin flexibility enabling fast switches towards more or less restricted epigenetic cellular states is, not surprisingly, intimately connected to cancer development and treatment resistance, and the central role of epigenetic alterations in cancer is illustrated by the finding that up to 50% of all mutations across cancer entities affect proteins controlling the chromatin status. we summarize recent insights into epigenetic rewiring underlying neuroblastoma (nb) tumor formation ranging from changes in dna methylation patterns and mutations in epigenetic regulators to global effects on transcriptional regulatory circuits that involve key players in nb oncogenesis. insights into the disruption of the homeostatic epigenetic balance contributing to developmental arrest of sympathetic progenitor cells and subsequent nb oncogenesis are rapidly growing and will be exploited towards the development of novel therapeutic strategies to increase current survival rates of patients with high-risk nb.”
Lestari, S. W., & Rizki, M. D.. (2016). Epigenetic: A new approach to etiology of infertility. Medical Journal of Indonesia
Plain numerical DOI: 10.13181/mji.v25i4.1504
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“Infertility is a complex disease which could be caused by male and female factors. the etiology from both factors needs further study. there are some approaches to understanding the etiology of infertility, one of them is epigenetic. epigenetic modifications consist of dna methylation, histone modifications, and chromatin remodelling. male and female germinal cells undergo epigenetic modifications dynamically during differentiation into matured sperm and oocyte cells. in a male, the alteration of dna methylation in spermatogenesis will cause oligo/asthenozoospermia. in addition, the histone methylation, acetylation, or other histone modification may lead sperm lose its ability to fertilize oocyte. similarly, in a female, the alteration of dna methylation and histone modification affects oogenesis, created aneuploidy in fertilized oocytes and resulted in embryonic death in the uterus. alteration of these epigenetic modification patterns will cause infertility, both in male and female.”
Suvà, M. L., Riggi, N., & Bernstein, B. E.. (2013). Epigenetic reprogramming in cancer. Science
Plain numerical DOI: 10.1126/science.1230184
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“The demonstration of induced pluripotency and direct lineage conversion has led to remarkable insights regarding the roles of transcription factors and chromatin regulators in mediating cell state transitions. beyond its considerable implications for regenerative medicine, this body of work is highly relevant to multiple stages of oncogenesis, from the initial cellular transformation to the hierarchical organization of established malignancies. here, we review conceptual parallels between the respective biological phenomena, highlighting important interrelationships among transcription factors, chromatin regulators, and preexisting epigenetic states. the shared mechanisms provide insights into oncogenic transformation, tumor heterogeneity, and cancer stem cell models.”
Li, H. X., Xiao, L., Wang, C., Gao, J. L., & Zhai, Y. G.. (2010). Epigenetic regulation of adipocyte differentiation and adipogenesis. Journal of Zhejiang University: Science B
Plain numerical DOI: 10.1631/jzus.B0900401
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“It is generally agreed that adipocytes originate from mesenchymal stem cells in what can be divided into two processes: determination and differentiation. in the past decade, many factors associated with epigenetic signals have been proved to be pivotal for the appropriate timing of adipogenesis progression. a large number of coregulators at critical gene promoters set up specific patterns of dna methylation, histone acetylation and methylation, and nucleosome rearrangement, that act as an epigenetic code to modulate the correct progress of adipocyte differentiation and adipogenesis during adipogenesis. in this review, we focus on the functions and roles of epigenetic processes in preadipocyte differentiation and adipogenesis. © 2010 zhejiang university and springer-verlag berlin heidelberg.”
Egger, G., Liang, G., Aparicio, A., & Jones, P. A.. (2004). Epigenetics in human disease and prospects for epigenetic therapy. Nature
Plain numerical DOI: 10.1038/nature02625
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“Epigenetic mechanisms, which involve dna and histone modifications, result in the heritable silencing of genes without a change in their coding sequence. the study of human disease has focused on genetic mechanisms, but disruption of the balance of epigenetic networks can cause several major pathologies, including cancer, syndromes involving chromosomal instabilities, and mental retardation. the development of new diagnostic tools might reveal other diseases that are caused by epigenetic alterations. great potential lies in the development of ‘epigenetic therapies’ – several inhibitors of enzymes controlling epigenetic modifications, specifically dna methyltransferases and histone deacetylases, have shown promising antitumorigenic effects for some malignancies.”
Van Ouwerkerk, A. F., Hall, A. W., Kadow, Z. A., Lazarevic, S., Reyat, J. S., Tucker, N. R., … Christoffels, V. M.. (2020). Epigenetic and Transcriptional Networks Underlying Atrial Fibrillation. Circulation Research
Plain numerical DOI: 10.1161/CIRCRESAHA.120.316574
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“Genome-wide association studies have uncovered over a 100 genetic loci associated with atrial fibrillation (af), the most common arrhythmia. many of the top af-associated loci harbor key cardiac transcription factors, including pitx2, tbx5, prrx1, and zfhx3. moreover, the vast majority of the af-associated variants lie within noncoding regions of the genome where causal variants affect gene expression by altering the activity of transcription factors and the epigenetic state of chromatin. in this review, we discuss a transcriptional regulatory network model for af defined by effector genes in genome-wide association studies loci. we describe the current state of the field regarding the identification and function of af-relevant gene regulatory networks, including variant regulatory elements, dose-sensitive transcription factor functionality, target genes, and epigenetic states. we illustrate how altered transcriptional networks may impact cardiomyocyte function and ionic currents that impact af risk. last, we identify the need for improved tools to identify and functionally test transcriptional components to define the links between genetic variation, epigenetic gene regulation, and atrial function.”
Alcalà-Vida, R., Awada, A., Boutillier, A. L., & Merienne, K.. (2021). Epigenetic mechanisms underlying enhancer modulation of neuronal identity, neuronal activity and neurodegeneration. Neurobiology of Disease
Plain numerical DOI: 10.1016/j.nbd.2020.105155
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“Neurodegenerative diseases, including huntington’s disease (hd) and alzheimer’s disease (ad), are progressive conditions characterized by selective, disease-dependent loss of neuronal regions and/or subpopulations. neuronal loss is preceded by a long period of neuronal dysfunction, during which glial cells also undergo major changes, including neuroinflammatory response. those dramatic changes affecting both neuronal and glial cells associate with epigenetic and transcriptional dysregulations, characterized by defined cell-type-specific signatures. notably, increasing studies support the view that altered regulation of transcriptional enhancers, which are distal regulatory regions of the genome capable of modulating the activity of promoters through chromatin looping, play a critical role in transcriptional dysregulation in hd and ad. we review current knowledge on enhancers in hd and ad, and highlight challenging issues to better decipher the epigenetic code of neurodegenerative diseases.”
Kwon, M. J., & Shin, Y. K.. (2011). Epigenetic regulation of cancer-associated genes in ovarian cancer. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms12020983
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“The involvement of epigenetic aberrations in the development and progression of tumors is now well established. however, most studies have focused on the epigenetic inactivation of tumor suppressor genes during tumorigenesis and little is known about the epigenetic activation of cancer-associated genes, except for the dna hypomethylation of some genes. recently, we reported that the overexpression of cancer-promoting genes in ovarian cancer is associated with the loss of repressive histone modifications. this discovery suggested that epigenetic derepression may contribute to ovarian tumorigenesis by constituting a possible mechanism for the overexpression of oncogenes or cancer-promoting genes in tumors. the emerging importance of epigenetic aberrations in tumor initiation and in the regulation of cancer-initiating cells, suggests that epigenetically regulated genes may be promising therapeutic targets and biomarkers. given that the current challenges in ovarian cancer include the identification of biomarkers for early cancer detection and the discovery of novel therapeutic targets for patients with recurrent malignancies undergoing chemotherapy, understanding the epigenetic changes that occur in ovarian cancer is crucial. this review looks at epigenetic mechanisms involved in the regulation of cancer-associated genes, including the contribution of epigenetic derepression to the activation of cancer-associated genes in ovarian cancer. in addition, possible epigenetic therapies targeting epigenetically dysregulated genes are discussed. a better understanding of the epigenetic changes in ovarian cancer will contribute to the improvement of patient outcomes. © 2011 by the authors; licensee mdpi, basel, switzerland.”
ENGINEERS. (
2019).
व ा र ् ष ि क प ् रत ि व े दन Annual Report Annual Report.
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“A growing body of evidence points towards epigenetic mechanisms being responsible for a wide range of biological phenomena, from the plasticity of plant growth and development to the nutritional control of caste determination in honeybees and the etiology of human disease (e.g., cancer). with the (partial) elucidation of the molecular basis of epigenetic variation and the heritability of certain of these changes, the field of evolutionary epigenetics is flourishing. despite this, the role of epigenetics in shaping host–pathogen interactions has received comparatively little attention. yet there is plenty of evidence supporting the implication of epigenetic mechanisms in the modulation of the biological interaction between hosts and pathogens. the phenotypic plasticity of many key parasite life-history traits appears to be under epigenetic control. moreover, pathogen-induced effects in host phenotype may have transgenerational consequences, and the bases of these changes and their heritability probably have an epigenetic component. the significance of epigenetic modifications may, however, go beyond providing a mechanistic basis for host and pathogen plasticity. epigenetic epidemiology has recently emerged as a promising area for future research on infectious diseases. in addition, the incorporation of epigenetic inheritance and epigenetic plasticity mechanisms to evolutionary models and empirical studies of host–pathogen interactions will provide new insights into the evolution and coevolution of these associations. here, we review the evidence available for the role epigenetics on host–pathogen interactions, and the utility and versatility of the epigenetic technologies available that can be cross-applied to host–pathogen studies. we conclude with recommendations and directions for future research on the burgeoning field of epigenetics as applied to host–pathogen interactions.”
Zampieri, M., Ciccarone, F., Calabrese, R., Franceschi, C., Bürkle, A., & Caiafa, P.. (2015). Reconfiguration of DNA methylation in aging. Mechanisms of Ageing and Development
Plain numerical DOI: 10.1016/j.mad.2015.02.002
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“A complex interplay between multiple biological effects shapes the aging process. the advent of genome-wide quantitative approaches in the epigenetic field has highlighted the effective impact of epigenetic deregulation, particularly of dna methylation, on aging. age-associated alterations in dna methylation are commonly grouped in the phenomenon known as ‘epigenetic drift’ which is characterized by gradual extensive demethylation of genome and hypermethylation of a number of promoter-associated cpg islands. surprisingly, specific dna regions show directional epigenetic changes in aged individuals suggesting the importance of these events for the aging process. however, the epigenetic information obtained until now in aging needs a re-consideration due to the recent discovery of 5-hydroxymethylcytosine, a new dna epigenetic mark present on genome. a recapitulation of the factors involved in the regulation of dna methylation and the changes occurring in aging will be described in this review also considering the data available on 5hmc.”
El Hajj, N., Dittrich, M., & Haaf, T.. (2017). Epigenetic dysregulation of protocadherins in human disease. Seminars in Cell and Developmental Biology
Plain numerical DOI: 10.1016/j.semcdb.2017.07.007
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“Protocadherins (pcdhs) are a group of cell-cell adhesion molecules that are highly expressed in the nervous system and have a major function in dendrite development and neural circuit formation. however, the role protocadherins play in human health and disease remains unclear. several recent studies have associated epigenetic dysregulation of protocadherins with possible implications for disease pathogenesis. in this review, we briefly recap the various epigenetic mechanisms regulating protocadherin genes, particularly the clustered pcdhs. we further outline research describing altered epigenetic regulation of protocadherins in neurological and psychiatric disorders, as well as in cancer and during aging. we additionally present preliminary data on dna methylation dynamics of clustered protocadherins during fetal brain development, as well as the epigenetic differences distinguishing adult neuronal and glial cells. a deeper understanding of the role of protocadherins in disease is crucial for designing novel diagnostic tools and therapies targeting brain disorders.”
Wiese, M., & Bannister, A. J.. (2020). Two genomes, one cell: Mitochondrial-nuclear coordination via epigenetic pathways. Molecular Metabolism
Plain numerical DOI: 10.1016/j.molmet.2020.01.006
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“Background: virtually all eukaryotic cells contain spatially distinct genomes, a single nuclear genome that harbours the vast majority of genes and much smaller genomes found in mitochondria present at thousands of copies per cell. to generate a coordinated gene response to various environmental cues, the genomes must communicate with each another. much of this bi-directional crosstalk relies on epigenetic processes, including dna, rna, and histone modification pathways. crucially, these pathways, in turn depend on many metabolites generated in specific pools throughout the cell, including the mitochondria. they also involve the transport of metabolites as well as the enzymes that catalyse these modifications between nuclear and mitochondrial genomes. scope of review: this study examines some of the molecular mechanisms by which metabolites influence the activity of epigenetic enzymes, ultimately affecting gene regulation in response to metabolic cues. we particularly focus on the subcellular localisation of metabolite pools and the crosstalk between mitochondrial and nuclear proteins and rnas. we consider aspects of mitochondrial-nuclear communication involving histone proteins, and potentially their epigenetic marks, and discuss how nuclear-encoded enzymes regulate mitochondrial function through epitranscriptomic pathways involving various classes of rna molecules within mitochondria. major conclusions: epigenetic communication between nuclear and mitochondrial genomes occurs at multiple levels, ultimately ensuring a coordinated gene expression response between different genetic environments. metabolic changes stimulated, for example, by environmental factors, such as diet or physical activity, alter the relative abundances of various metabolites, thereby directly affecting the epigenetic machinery. these pathways, coupled to regulated protein and rna transport mechanisms, underpin the coordinated gene expression response. their overall importance to the fitness of a cell is highlighted by the identification of many mutations in the pathways we discuss that have been linked to human disease including cancer.”
Philibert, R., Beach, S. R. H., Lei, M. K., Gibbons, F. X., Gerrard, M., Simons, R. L., & Dogan, M. V.. (2020). Array-based epigenetic aging indices may be racially biased. Genes
Plain numerical DOI: 10.3390/genes11060685
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“Epigenetic aging (ea) indices are frequently used as predictors of mortality and other important health outcomes. however, each of the commonly used array-based indices has significant heritable components which could tag ethnicity and potentially confound comparisons across racial and ethnic groups. to determine if this was possible, we examined the relationship of dna methylation in cord blood from 203 newborns (112 african american (aa) and 91 white) at the 513 probes from the levine phenoage epigenetic aging index to ethnicity. then, we examined all sites significantly associated with race in the newborn sample to determine if they were also associated with an index of ethnic genetic heritage in a cohort of 505 aa adults. after bonferroni correction, methylation at 50 cpg sites was significantly associated with ethnicity in the newborn cohort. the five most significant sites predicted ancestry with a receiver operator characteristic area under the curve of 0.97. examination of the top 50 sites in the aa adult cohort showed that methylation status at 11 of those sites was also associated with percentage european ancestry. we conclude that the levine phenoage index is influenced by cryptic ethnic-specific genetic influences. this influence may extend to similarly constructed ea indices and bias cross-race comparisons.”
Pan, D., Rampal, R., & Mascarenhas, J.. (2020). Clinical developments in epigenetic-directed therapies in acute myeloid leukemia. Blood Advances
Plain numerical DOI: 10.1182/bloodadvances.2019001245
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“Acute myeloid leukemia (aml) is a highly heterogeneous disease arising from acquired genetic and epigenetic aberrations which stifle normal development and differentiation of hematopoietic precursors. despite the complex and varied biological underpinnings, induction therapy foramlhas remained fairly uniform over 4 decades and outcomes remain poor for most patients. recently, enhanced understanding of the leukemic epigenome has resulted in the translational investigation of a number of epigenetic modifying agents currently in various stages of clinical development. these novel therapies are based on mechanistic rationale and offer the potential to improve aml patient outcomes. in light of many recent advances in this field, we provide an updated, clinically oriented review of the evolving landscape of epigenetic modifying agents for the treatment of aml.”
Ishidate, T., Ozturk, A. R., Durning, D. J., Sharma, R., Shen, E. zhi, Chen, H., … Mello, C. C.. (2018). ZNFX-1 Functions within Perinuclear Nuage to Balance Epigenetic Signals. Molecular Cell
Plain numerical DOI: 10.1016/j.molcel.2018.04.009
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“Animal cells have a remarkable capacity to adopt durable and heritable gene expression programs or epigenetic states that define the physical properties and diversity of somatic cell types. the maintenance of epigenetic programs depends on poorly understood pathways that prevent gain or loss of inherited signals. in the germline, epigenetic factors are enriched in liquid-like perinuclear condensates called nuage. here, we identify the deeply conserved helicase-domain protein, znfx-1, as an epigenetic regulator and component of nuage that interacts with argonaute systems to balance epigenetic inheritance. our findings suggest that znfx-1 promotes the 3′ recruitment of machinery that propagates the small rna epigenetic signal and thus counteracts a tendency for argonaute targeting to shift 5′ along the mrna. these functional insights support the idea that recently identified subdomains of nuage, including znfx-1 granules or ‘z-granules,’ may define spatial and temporal zones of molecular activity during epigenetic regulation. ishidate et al. identify znfx-1, a highly conserved helicase protein, as a factor required for epigenetic inheritance in c. elegans. their findings indicate that znfx-1 localizes within nuage, where it interacts with argonaute systems and rna-dependent rna polymerase (rdrp) to ensure balanced amplification of small rna signals along germline mrnas.”
Puri, D., Dhawan, J., & Mishra, R. K.. (2010). The paternal hidden agenda: Epigenetic inheritance through sperm chromatin. Epigenetics
Plain numerical DOI: 10.4161/epi.5.5.12005
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“Epigenetic modifications play a crucial role in developmental gene regulation. these modifications, being reversible, provide a layer of information over and above the dna sequence, that has plasticity and leads to the generation of cell type-specific epigenomes during cellular differentiation. in almost all higher eukaryotes, the oocyte provides not only its cytoplasm, mitochondria, maternally deposited rna and proteins but also an epigenetic component in the form of dna and histone-modifications. during spermeiogenesis however, most of the histones are replaced by protamines, leading to a loss of the epigenetic component. the sperm is, therefore, viewed as a passive carrier of the paternal genome with a disproportionate, lower epigenetic contribution except for dna methylation, to the next generation. a recent study overturns this view by demonstrating a locus-specific retention of histones, with specific modifications in the sperm chromatin at the promoters of developmentally important genes. this programmed retention of epigenetic marks with a role in embryonic development is suggested to offset, in some measure, the dominant maternal effect. this new finding helps in addressing the question of epigenetic transmission of environmental and ‘lifestyle’ experiences across generations and raises the question of ‘parental conflict’ at the loci that may be differentially marked. © 2010 landes bioscience.”
Peixoto, P., Etcheverry, A., Aubry, M., Missey, A., Lachat, C., Perrard, J., … Hervouet, E.. (2019). EMT is associated with an epigenetic signature of ECM remodeling genes. Cell Death and Disease
Plain numerical DOI: 10.1038/s41419-019-1397-4
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“Type iii epithelial–mesenchymal transition (emt) has been previously associated with increased cell migration, invasion, metastasis, and therefore cancer aggressiveness. this reversible process is associated with an important gene expression reprogramming mainly due to epigenetic plasticity. nevertheless, most of the studies describing the central role of epigenetic modifications during emt were performed in a single-cell model and using only one mode of emt induction. in our study, we studied the overall modulations of gene expression and epigenetic modifications in four different emt-induced cell models issued from different tissues and using different inducers of emt. pangenomic analysis (transcriptome and chip–sequencing) validated our hypothesis that gene expression reprogramming during emt is largely regulated by epigenetic modifications of a wide range of genes. indeed, our results confirmed that each emt model is unique and can be associated with a specific transcriptome profile and epigenetic program. however, we could select some genes or pathways that are similarly regulated in the different models and that could therefore be used as a common signature of all emt models and become new biomarkers of the emt phenotype. as an example, we can cite the regulation of gene-coding proteins involved in the degradation of the extracellular matrix (ecm), which are highly induced in all emt models. based on our investigations and results, we identified adam19 as a new biomarker of in vitro and in vivo emt and we validated this biological new marker in a cohort of non-small lung carcinomas.”
Shorter, K. R., & Miller, B. H.. (2015). Epigenetic mechanisms in schizophrenia. Progress in Biophysics and Molecular Biology
Plain numerical DOI: 10.1016/j.pbiomolbio.2015.04.008
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“Epigenetic modifications, including dna methylation, histone modifications, and non-coding rnas, have been implicated in a number of complex diseases. schizophrenia and other major psychiatric and neurodevelopmental disorders are associated with abnormalities in multiple epigenetic mechanisms, resulting in altered gene expression during development and adulthood. polymorphisms and copy number variants in schizophrenia risk genes contribute to the high heritability of the disease, but environmental factors that lead to epigenetic modifications may either reduce or exacerbate the expression of molecular and behavioral phenotypes associated with schizophrenia and related disorders. in the present paper, we will review the current understanding of molecular dysregulation in schizophrenia, including disruption of the dopamine, nmda, and gaba signaling pathways, and discuss the role of epigenetic factors underlying disease pathology.”
Jovanovic, T., Vance, L. A., Cross, D., Knight, A. K., Kilaru, V., Michopoulos, V., … Smith, A. K.. (2017). Exposure to Violence Accelerates Epigenetic Aging in Children. Scientific Reports
Plain numerical DOI: 10.1038/s41598-017-09235-9
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“Epigenetic processes, including dna methylation, change reliably with age across the lifespan, such that dna methylation can be used as an ‘epigenetic clock’. this epigenetic clock can be used to predict age and age acceleration, which occurs when methylation-based prediction of age exceeds chronological age and has been associated with increased mortality. in the current study we examined epigenetic age acceleration using saliva samples collected from children between ages 6-13 (n = 101). children’s exposure to neighborhood violence and heart rate during a stressful task were assessed. age acceleration was associated with children’s direct experience of violence (p = 0.004) and with decreased heart rate (p = 0.002). children who were predicted to be older than their chronological age had twice as much violence exposure as other children and their heart rate was similar to that of adults. the results remained significant after controlling for demographic variables, such as sex, income and education. this is the first study to show the effects of direct violence exposure on epigenetic aging in children using salivary dna. although longitudinal studies are needed to determine whether accelerated epigenetic aging leads to adverse health outcomes later in life, these data point to dna methylation during childhood as a putative biological mechanism.”
Manukyan, M., & Singh, P. B.. (2012). Epigenetic rejuvenation. Genes to Cells
Plain numerical DOI: 10.1111/j.1365-2443.2012.01595.x
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“Induced pluripotent stem (ips) cells have provided a rational means of obtaining histo-compatible tissues for ‘patient-specific’ regenerative therapies (hanna 2010; yamanaka & blau 2010). despite the obvious potential of ips cell-based therapies, there are certain problems that must be overcome before these therapies can become safe and routine (ohi 2011; pera 2011). as an alternative, we have recently explored the possibility of using ‘epigenetic rejuvenation’, where the specialized functions of an old cell are rejuvenated in the absence of any change in its differentiated state (singh & zacouto 2010). the mechanism(s) that underpin ‘epigenetic rejuvenation’ are unknown and here we discuss model systems, using key epigenetic modifiers, which might shed light on the processes involved. epigenetic rejuvenation has advantages over ips cell techniques that are currently being pursued. first, the genetic and epigenetic abnormalities that arise through the cycle of dedifferentiation of somatic cells to ips cells followed by redifferentiation of ips cells into the desired cell type are avoided (gore 2011; hussein 2011; pera 2011): epigenetic rejuvenation does not require passage through the de-/redifferentiation cycle. second, because the aim of epigenetic rejuvenation is to ensure that the differentiated cell type retains its specialized function it makes redundant the question of transcriptional memory that is inimical to ips cell-based therapies (ohi 2011). third, to produce unrelated cell types using the ips technology takes a long time, around three weeks, whereas epigenetic rejuvenation of old cells will take only a matter of days. epigenetic rejuvenation provides the most safe, rapid and cheap route to successful regenerative medicine. © 2012 the authors. journal compilation © 2012 by the molecular biology society of japan/blackwell publishing ltd.”
Huang, X. A., Yin, H., Sweeney, S., Raha, D., Snyder, M., & Lin, H.. (2013). A Major Epigenetic Programming Mechanism Guided by piRNAs. Developmental Cell
Plain numerical DOI: 10.1016/j.devcel.2013.01.023
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“A central enigma in epigenetics is how epigenetic factors are guided to specific genomic sites for their function. previously, we reported that a piwi-pirna complex associates with the pirna-complementary site in the drosophila genome and regulates its epigenetic state. here, we report that piwi-pirna complexes bind to numerous pirna-complementary sequences throughout the genome, implicating pirnas as a major mechanism that guides piwi and piwi-associated epigenetic factors to program the genome. to test this hypothesis, we demonstrate that inserting pirna-complementary sequences to an ectopic site leads to piwi, hp1a, and su(var)3-9 recruitment to the site as well as h3k9me2/3 enrichment and reduced rna polymerase ii association, indicating that pirna is both necessary and sufficient to recruit piwi and epigenetic factors to specific genomic sites. piwi deficiency drastically changed the epigenetic landscape and polymerase ii profile throughout the genome, revealing the piwi-pirna mechanism as a major epigenetic programming mechanism in drosophila.”
Sermer, D., Pasqualucci, L., Wendel, H. G., Melnick, A., & Younes, A.. (2019). Emerging epigenetic-modulating therapies in lymphoma. Nature Reviews Clinical Oncology
Plain numerical DOI: 10.1038/s41571-019-0190-8
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“Despite considerable advances in the treatment of lymphoma, the prognosis of patients with relapsed and/or refractory disease continues to be poor; thus, a continued need exists for the development of novel approaches and therapies. epigenetic dysregulation might drive and/or promote tumorigenesis in various types of malignancies and is prevalent in both b cell and t cell lymphomas. over the past decade, a large number of epigenetic-modifying agents have been developed and introduced into the clinical management of patients with haematological malignancies. in this review, we provide a concise overview of the most promising epigenetic therapies for the treatment of lymphomas, including inhibitors of histone deacetylases (hdacs), dna methyltransferases (dnmts), enhancer of zeste homologue 2 (ezh2), bromodomain and extra-terminal domain proteins (bets), protein arginine n-methyltransferases (prmts) and isocitrate dehydrogenases (idhs), and highlight the most promising future directions of research in this area.”
Aydin, C., & Kalkan, R.. (2020). Cancer Treatment: An Epigenetic View. Global Medical Genetics
Plain numerical DOI: 10.1055/s-0040-1713610
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“Cancer can be identified as an uncontrolled growth and reproduction of cell. accumulation of genetic aberrations (mutations of oncogenes and tumor-suppressor genes and epigenetic modifications) is one of the characteristics of cancer cell. increasing number of studies highlighted importance of the epigenetic alterations in cancer treatment and prognosis. now, cancer epigenetics have a huge importance for developing novel biomarkers and therapeutic target for cancer. in this review, we will provide a summary of the major epigenetic changes involved in cancer and preclinical results of epigenetic therapeutics.”
Borrelli, E., Nestler, E. J., Allis, C. D., & Sassone-Corsi, P.. (2008). Decoding the Epigenetic Language of Neuronal Plasticity. Neuron
Plain numerical DOI: 10.1016/j.neuron.2008.10.012
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“Neurons are submitted to an exceptional variety of stimuli and are able to convert these into high-order functions, such as storing memories, controlling behavior, and governing consciousness. these unique properties are based on the highly flexible nature of neurons, a characteristic that can be regulated by the complex molecular machinery that controls gene expression. epigenetic control, which largely involves events of chromatin remodeling, appears to be one way in which transcriptional regulation of gene expression can be modified in neurons. this review will focus on how epigenetic control in the mature nervous system may guide dynamic plasticity processes and long-lasting cellular neuronal responses. we outline the molecular pathways underlying chromatin transitions, propose the presence of an ‘epigenetic indexing code,’ and discuss how central findings accumulating at an exponential pace in the field of epigenetics are conceptually changing our perspective of adult brain function. © 2008 elsevier inc. all rights reserved.”
Ramos-Lopez, O., Milagro, F. I., Riezu-Boj, J. I., & Martinez, J. A.. (2021). Epigenetic signatures underlying inflammation: an interplay of nutrition, physical activity, metabolic diseases, and environmental factors for personalized nutrition. Inflammation Research
Plain numerical DOI: 10.1007/s00011-020-01425-y
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“Aim and objective: emerging translational evidence suggests that epigenetic alterations (dna methylation, mirna expression, and histone modifications) occur after external stimuli and may contribute to exacerbated inflammation and the risk of suffering several diseases including diabetes, cardiovascular diseases, cancer, and neurological disorders. this review summarizes the current knowledge about the harmful effects of high-fat/high-sugar diets, micronutrient deficiencies (folate, manganese, and carotenoids), obesity and associated complications, bacterial/viral infections, smoking, excessive alcohol consumption, sleep deprivation, chronic stress, air pollution, and chemical exposure on inflammation through epigenetic mechanisms. additionally, the epigenetic phenomena underlying the anti-inflammatory potential of caloric restriction, n-3 pufa, mediterranean diet, vitamin d, zinc, polyphenols (i.e., resveratrol, gallic acid, epicatechin, luteolin, curcumin), and the role of systematic exercise are discussed. methods: original and review articles encompassing epigenetics and inflammation were screened from major databases (including pubmed, medline, science direct, scopus, etc.) and analyzed for the writing of the review paper. conclusion: although caution should be exercised, research on epigenetic mechanisms is contributing to understand pathological processes involving inflammatory responses, the prediction of disease risk based on the epigenotype, as well as the putative design of therapeutic interventions targeting the epigenome.”
He, S., Chen, J., Gao, H., Yang, G., Zhang, F., Ding, Y., & Zhu, H.. (2020). Extended transcriptome analysis reveals genome-wide lncRNA-mediated epigenetic dysregulation in colorectal cancer. Computational and Structural Biotechnology Journal
Plain numerical DOI: 10.1016/j.csbj.2020.11.004
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“It is estimated that the rate of epigenetic changes may be orders of magnitude higher than that of genetic changes and that purely epigenetic mechanisms may explain why cancers arise with few or no recurrent mutations. however, supporting evidence remains limited, partly due to the cost of experimentally studying genome-wide epigenetic dysregulation. since genome modification enzymes are recruited by long noncoding rnas (lncrnas) to specific genomic sites, analyzing differentially expressed genes and differentially methylated regions (dmrs) at the dna binding sites of differentially expressed lncrnas is important for uncovering epigenetic dysregulation. we performed rna-seq and medip-seq on a set of colorectal cancer (crc) and normal colon samples and developed an analysis pipeline for combined analyses of gene expression, dna methylation, and lncrna/dna binding. the genes identified in our data and important for crc agree with widely reported findings. we found that aberrantly transcribed noncoding transcripts may epigenetically dysregulate genes, that correlated gene expression is significantly determined by epigenetic dysregulation, that differentially expressed noncoding transcripts and their epigenetic targets form distinct modules in different cancer cells, and that many hub lncrnas in these modules are primate-specific. these results suggest that lncrna-mediated epigenetic dysregulation greatly determines aberrant gene expression and that epigenetic dysregulation is highly species-specific. the analysis pipeline can effectively unveil cancer- and cell-specific modules of epigenetic dysregulation, and such modules may provide novel clues for identifying diagnostic, therapeutic, and prognostic targets for epigenetic dysregulation.”
Lio, C. W. J., & Huang, S. C. C.. (2020). Circles of Life: linking metabolic and epigenetic cycles to immunity. Immunology
Plain numerical DOI: 10.1111/imm.13207
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“Metabolites are the essential substrates for epigenetic modification enzymes to write or erase the epigenetic blueprint in cells. hence, the availability of nutrients and activity of metabolic pathways strongly influence the enzymatic function. recent studies have shed light on the choreography between metabolome and epigenome in the control of immune cell differentiation and function, with a major focus on histone modifications. yet, despite its importance in gene regulation, dna methylation and its relationship with metabolism is relatively unclear. in this review, we will describe how the metabolic flux can influence epigenetic networks in innate and adaptive immune cells, with a focus on the dna methylation cycle and the metabolites s-adenosylmethionine and α-ketoglutarate. future directions will be discussed for this rapidly emerging field.”
Barrero, M. J.. (2017). Epigenetic strategies to boost cancer immunotherapies. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms18061108
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“Recently, immunotherapeutic approaches have shown impressive responses in a subset of cancer patients. however, the rate of success is low and a large percentage of treated patients do not experience clinical benefits. therefore, additional strategies are needed to improve responses and select responsive patients. emerging data suggest that epigenetic drugs can improve the responses to immunotherapy. understanding the mechanisms of resistance to immunotherapy and the epigenetic events that take place during immune evasion is critical to providing a rational combined use of immunotherapies and epigenetic drugs. this review focuses in the epigenetic mechanisms involved in the responses to immunotherapy and how current drugs that target epigenetic regulators impact on them.”
Hu, L., Xiao, P., Jiang, Y., Dong, M., Chen, Z., Li, H., … Wang, J.. (2018). Transgenerational epigenetic inheritance under environmental stress by genome-wide DNA methylation profiling in cyanobacterium. Frontiers in Microbiology
Plain numerical DOI: 10.3389/fmicb.2018.01479
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“Epigenetic modifications such as dna methylation are well known as connected with many important biological processes. rapid accumulating evidence shows environmental stress can generate particular defense epigenetic changes across generations in eukaryotes. this transgenerational epigenetic inheritance in animals and plants has gained interest over the last years. cyanobacteria play very crucial role in the earth, and as the primary producer they can adapt to nearly all diverse environments. however, few knowledge about the genome wide epigenetic information such as methylome information in cyanobacteria, especially under any environment stress, was reported so far. in this study we profiled the genome-wide cytosine methylation from a model cyanobacterium synechocystis sp. pcc 6803, and explored the possibility of transgenerational epigenetic process in this ancient single-celled prokaryote by comparing the dna methylomes among normal nitrogen medium cultivation, nitrogen starvation for 72 h and nitrogen recovery for about 12 generations. our results shows that dna methylation patterns in nitrogen starvation and nitrogen recovery are much more similar with each other, significantly different from that of the normal nitrogen. this study reveals the difference in global dna methylation pattern of cyanobacteria between normal and nutrient stress conditions and reports the evidence of transgenerational epigenetic process in cyanobacteria. the results of this study may contribute to a better understanding of epigenetic regulation in prokaryotic adaptation to and survive in the ever changing environment.”
Tripathi, S. K., & Lahesmaa, R.. (2014). Transcriptional and epigenetic regulation of T-helper lineage specification. Immunological Reviews
Plain numerical DOI: 10.1111/imr.12204
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“Summary: combined with tcr stimuli, extracellular cytokine signals initiate the differentiation of naive cd4+ t cells into specialized effector t-helper (th) and regulatory t (treg) cell subsets. the lineage specification and commitment process occurs through the combinatorial action of multiple transcription factors (tfs) and epigenetic mechanisms that drive lineage-specific gene expression programs. in this article, we review recent studies on the transcriptional and epigenetic regulation of distinct th cell lineages. moreover, we review current study linking immune disease-associated single-nucleotide polymorphisms with distal regulatory elements and their potential role in the disease etiology. © 2014 the authors. immunological reviews published by john wiley & sons ltd.”
Nemoda, Z., & Szyf, M.. (2017). Epigenetic Alterations and Prenatal Maternal Depression. Birth Defects Research
Plain numerical DOI: 10.1002/bdr2.1081
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“Major depressive disorder of the mother affects 6 to 17% of pregnancies worldwide and can lead to negative outcomes, such as preterm delivery and later mental health problems of the child. it has been proposed that developmental programming has long-lasting effects in the offspring that might be mediated by epigenetic mechanisms, such as dna methylation. altered stress regulation or impaired immunological function of the mother can potentially affect dna methylation processes of the fetus, changing gene expression levels in utero. these underlying biological processes can be tested in animal models, where pharmacological experiments using epigenetic drugs can prove causality. recent human studies show that dna methylation changes of hypothesis-driven candidate gene regions, such as the promoter of the glucocorticoid receptor and the serotonin transporter, were associated with maternal depression in peripheral tissue samples of newborns’ cord blood, infants’ saliva, or adults’ peripheral blood. in addition, epigenome-wide association studies using blood cells show modest but significant changes in a subset of genes involved in immune functions. these dna methylation changes were found mainly in enhancers, which point to regulatory effects in gene expression. limited number of studies using brain tissue showed a significant overlap of differentially methylated genes in the different studies. in conclusion, prenatal maternal depression can induce covalent modifications in the offspring’s dna, which are detectable at birth in leukocytes and could be potentially present in other tissues, consistent with the hypothesis that system-wide epigenetic changes are involved in life-long responses to the psychosocial environment in utero. birth defects research 109:888–897, 2017. © 2017 wiley periodicals, inc.”
Kondo, Y., Katsushima, K., Ohka, F., Natsume, A., & Shinjo, K.. (2014). Epigenetic dysregulation in glioma. Cancer Science
Plain numerical DOI: 10.1111/cas.12379
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“Given that treatment options for patients with glioblastoma are limited, much effort has been made to clarify the underlying mechanisms of gliomagenesis. recent genome-wide genomic and epigenomic analyses have revealed that mutations in epigenetic modifiers occur frequently in gliomas and that dysregulation of epigenetic mechanisms is closely associated with glioma formation. given that epigenetic changes are reversible, understanding the epigenetic abnormalities that arise in gliomagenesis might be key to developing more effective treatment strategies for glioma. in this review, we focus on the recent advancements in epigenetic research with respect to gliomas, consider how epigenetic mechanisms dynamically regulate tumor cells, including the cancer stem cell population, and discuss perspectives and challenges for glioma treatment in the near future. in this review, we focus on the recent advancements in epigenetic research with respect to gliomas, consider how epigenetic mechanisms dynamically regulate tumor cells, including the cancer stem cell population, and discuss perspectives and challenges for glioma treatment in the near future. © 2014 the authors. cancer science published by wiley publishing asia pty ltd on behalf of japanese cancer association.”
Chen, X., Pan, X., Zhang, W., Guo, H., Cheng, S., He, Q., … Ding, L.. (2020). Epigenetic strategies synergize with PD-L1/PD-1 targeted cancer immunotherapies to enhance antitumor responses. Acta Pharmaceutica Sinica B
Plain numerical DOI: 10.1016/j.apsb.2019.09.006
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“Immunotherapy strategies targeting the programmed cell death ligand 1 (pd-l1)/programmed cell death 1 (pd-1) pathway in clinical treatments have achieved remarkable success in treating multiple types of cancer. however, owing to the heterogeneity of tumors and individual immune systems, pd-l1/pd-1 blockade still shows slow response rates in controlling malignancies in many patients. accumulating evidence has shown that an effective response to anti-pd-l1/anti-pd-1 therapy requires establishing an integrated immune cycle. damage in any step of the immune cycle is one of the most important causes of immunotherapy failure. impairments in the immune cycle can be restored by epigenetic modification, including reprogramming the environment of tumor-associated immunity, eliciting an immune response by increasing the presentation of tumor antigens, and by regulating t cell trafficking and reactivation. thus, a rational combination of pd-l1/pd-1 blockade and epigenetic agents may offer great potential to retrain the immune system and to improve clinical outcomes of checkpoint blockade therapy.”
Zhu, B., & Reinberg, D.. (2011). Epigenetic inheritance: Uncontested?. Cell Research
Plain numerical DOI: 10.1038/cr.2011.26
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“Epigenetics is currently defined as the inheritance of variation (-genetics) above and beyond (epi-) changes in the dna sequence. despite the fact that histones are believed to carry important epigenetic information, little is known about the molecular mechanisms of the inheritance of histone-based epigenetic information, including histone modifications and histone variants. here we review recent progress and discuss potential models for the mitotic inheritance of histone modifications-based epigenetic information. © 2011 ibcb, sibs, cas all rights reserved.”
McCoy, R. M., Julian, R., Kumar, S. R. V., Ranjan, R., Varala, K., & Li, Y.. (2021). A systems biology approach to identify essential epigenetic regulators for specific biological processes in plants. Plants
Plain numerical DOI: 10.3390/plants10020364
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“Upon sensing developmental or environmental cues, epigenetic regulators transform the chromatin landscape of a network of genes to modulate their expression and dictate adequate cellular and organismal responses. knowledge of the specific biological processes and genomic loci controlled by each epigenetic regulator will greatly advance our understanding of epigenetic regulation in plants. to facilitate hypothesis generation and testing in this domain, we present epinet, an extensive gene regulatory network (grn) featuring epigenetic regulators. epinet was enabled by (i) curated knowledge of epigenetic regulators involved in dna methylation, histone modifica-tion, chromatin remodeling, and sirna pathways; and (ii) a machine-learning network inference approach powered by a wealth of public transcriptome datasets. we applied genie3, a machine-learning network inference approach, to mine public arabidopsis transcriptomes and construct tis-sue-specific grns with both epigenetic regulators and transcription factors as predictors. the re-sultant grns, named epinet, can now be intersected with individual transcriptomic studies on biological processes of interest to identify the most influential epigenetic regulators, as well as pre-dicted gene targets of the epigenetic regulators. we demonstrate the validity of this approach using case studies of shoot and root apical meristem development.”
Wang, Y., Qian, M., Ruan, P., Teschendorff, A. E., & Wang, S.. (2019). Detection of epigenetic field defects using a weighted epigenetic distance-based method. Nucleic Acids Research
Plain numerical DOI: 10.1093/nar/gky882
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“Identifying epigenetic field defects, notably early dna methylation alterations, is important for early cancer detection. research has suggested these early methylation alterations are infrequent across samples and identifiable as outlier samples. here we developed a weighted epigenetic distance-based method characterizing (dis)similarity in methylation measures at multiple cpgs in a gene or a genetic region between pairwise samples, with weights to up-weight signal cpgs and down-weight noise cpgs. using distance-based approaches, weak signals that might be filtered out in a cpg site-level analysis could be accumulated and therefore boost the overall study power. in constructing epigenetic distances, we considered both differential methylation (dm) and differential variability (dv) signals. we demonstrated the superior performance of the proposed weighted epigenetic distance-based method over non-weighted versions and site-level ewas (epigenome-wide association studies) methods in simulation studies. application to breast cancer methylation data from gene expression omnibus (geo) comparing normal-adjacent tissue to tumor of breast cancer patients and normal tissue of independent age-matched cancer-free women identified novel epigenetic field defects that were missed by ewas methods, when majority were previously reported to be associated with breast cancer and were confirmed the progression to breast cancer. we further replicated some of the identified epigenetic field defects.”
Chang, Z., Yadav, V., Lee, S. C., & Heitman, J.. (2019). Epigenetic mechanisms of drug resistance in fungi. Fungal Genetics and Biology
Plain numerical DOI: 10.1016/j.fgb.2019.103253
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“The emergence of drug-resistant fungi poses a continuously increasing threat to human health. despite advances in preventive care and diagnostics, resistant fungi continue to cause significant mortality, especially in immunocompromised patients. therapeutic resources are further limited by current usage of only four major classes of antifungal drugs. resistance against these drugs has already been observed in pathogenic fungi requiring the development of much needed newer antifungal drugs. epigenetic changes such as dna or chromatin modifications alter gene expression levels in response to certain stimuli, including interaction with the host in the case of fungal pathogens. these changes can confer resistance to drugs by altering the expression of target genes or genes encoding drug efflux pumps. multiple pathogens share many of these epigenetic pathways; thus, targeting epigenetic pathways might also identify drug target candidates for the development of broad-spectrum antifungal drugs. in this review, we discuss the importance of epigenetic pathways in mediating drug resistance in fungi as well as in the development of anti-fungal drugs.”
Colamatteo, A., Carbone, F., Bruzzaniti, S., Galgani, M., Fusco, C., Maniscalco, G. T., … De Rosa, V.. (2020). Molecular Mechanisms Controlling Foxp3 Expression in Health and Autoimmunity: From Epigenetic to Post-translational Regulation. Frontiers in Immunology
Plain numerical DOI: 10.3389/fimmu.2019.03136
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“The discovery of the transcription factor forkhead box-p3 (foxp3) has shed fundamental insights into the understanding of the molecular determinants leading to generation and maintenance of t regulatory (treg) cells, a cell population with a key immunoregulatory role. work over the past few years has shown that fine-tuned transcriptional and epigenetic events are required to ensure stable expression of foxp3 in treg cells. the equilibrium between phenotypic plasticity and stability of treg cells is controlled at the molecular level by networks of transcription factors that bind regulatory sequences, such as enhancers and promoters, to regulate foxp3 expression. recent reports have suggested that specific modifications of dna and histones are required for the establishment of the chromatin structure in conventional cd4+ t (tconv) cells for their future differentiation into the treg cell lineage. in this review, we discuss the molecular events that control foxp3 gene expression and address the associated alterations observed in human diseases. also, we explore how foxp3 influences the gene expression programs in treg cells and how unique properties of treg cell subsets are defined by other transcription factors.”
Guo, Y., Yu, S., Zhang, C., & Kong, A. N. T.. (2015). Epigenetic regulation of Keap1-Nrf2 signaling. Free Radical Biology and Medicine
Plain numerical DOI: 10.1016/j.freeradbiomed.2015.06.013
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“The kelch-like ech-associated protein 1 (keap1)-nuclear factor erythroid 2-related factor 2 (nrf2) signaling axis serves as a ‘master regulator’ in response to oxidative/electrophilic stresses and chemical insults through the coordinated induction of a wide array of cytoprotective genes. therefore, activation of nrf2 is considered to be an important approach for preventing chronic diseases triggered by stresses and toxins, including cancer. despite extensive studies suggested that the keap1-nrf2 signaling pathway is subject to multiple layers of regulation at the transcriptional, translational, and post-translational levels, the potential epigenetic regulation of nrf2 and keap1 has begun to be recognized only in recent years. epigenetic modifications, heritable alterations in gene expression that occur without changes in the primary dna sequence, have been reported to be profoundly involved in oxidative stress responses. in this review, we discuss the latest findings regarding the epigenetic regulation of keap1-nrf2 signaling by dna methylation, histone modification, and micrornas. the crosstalk among these epigenetic modifications in the regulation of keap1-nrf2 signaling pathways is also discussed. studies of the epigenetic modification of nrf2 and keap1 have not only enhanced our understanding of this complex cellular defense system but have also provided potential new therapeutic targets for the prevention of certain diseases.”
Mulero-Navarro, S., & Esteller, M.. (2008). Epigenetic biomarkers for human cancer: The time is now. Critical Reviews in Oncology/Hematology
Plain numerical DOI: 10.1016/j.critrevonc.2008.03.001
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“The importance of epigenetic processes in the development of cancer is clear. the study of epigenetics is therefore bound to contribute to the improvement of human health. aberrations in dna methylation, post-translational modifications of histones, chromatin remodeling and micrornas patterns are the main epigenetic alterations, and these are associated with tumorigenesis. epigenetic technologies in cancer studies are helping increase the number of cancer candidate genes and allow us to examine changes in 5-methylcytosine dna and histone modifications at a genome-wide level. in fact, all the various cellular pathways contributing to the neoplastic phenotype are affected by epigenetic genes in cancer. they are being explored as biomarkers in clinical use for early detection of disease, tumor classification and response to treatment with classical chemotherapy agents, target compounds and epigenetic drugs. encouraging results have been obtained with histone deacetylase and dna methyltransferase inhibitors, leading the us food and drug administration to approve several of them for the treatment of hematological malignancies and lymphoproliferative disorders, such as myelodysplastic syndrome and cutaneous lymphoma. however, many tasks remains to be done, such as the clinical validation of epigenetic biomarkers to allow the accurate prediction of the outcome of cancer patients and their potential chemosensitivity to current pharmacological treatments. © 2008 elsevier ireland ltd. all rights reserved.”
Huang, X. A., Yin, H., Sweeney, S., Raha, D., Snyder, M., & Lin, H.. (2013). A Major Epigenetic Programming Mechanism Guided by piRNAs. Developmental Cell
Plain numerical DOI: 10.1016/j.devcel.2013.01.023
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“A central enigma in epigenetics is how epigenetic factors are guided to specific genomic sites for their function. previously, we reported that a piwi-pirna complex associates with the pirna-complementary site in the drosophila genome and regulates its epigenetic state. here, we report that piwi-pirna complexes bind to numerous pirna-complementary sequences throughout the genome, implicating pirnas as a major mechanism that guides piwi and piwi-associated epigenetic factors to program the genome. to test this hypothesis, we demonstrate that inserting pirna-complementary sequences to an ectopic site leads to piwi, hp1a, and su(var)3-9 recruitment to the site as well as h3k9me2/3 enrichment and reduced rna polymerase ii association, indicating that pirna is both necessary and sufficient to recruit piwi and epigenetic factors to specific genomic sites. piwi deficiency drastically changed the epigenetic landscape and polymerase ii profile throughout the genome, revealing the piwi-pirna mechanism as a major epigenetic programming mechanism in drosophila.”
Wang, G., & Köhler, C.. (2017). Epigenetic processes in flowering plant reproduction. Journal of Experimental Botany
Plain numerical DOI: 10.1093/jxb/erw486
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“Seeds provide up to 70% of the energy intake of the human population, emphasizing the relevance of understanding the genetic and epigenetic mechanisms controlling seed formation. in flowering plants, seeds are the product of a double fertilization event, leading to the formation of the embryo and the endosperm surrounded by maternal tissues. analogous to mammals, plants undergo extensive epigenetic reprogramming during both gamete formation and early seed development, a process that is supposed to be required to enforce silencing of transposable elements and thus to maintain genome stability. global changes of dna methylation, histone modifications, and small rnas are closely associated with epigenome programming during plant reproduction. here, we review current knowledge on chromatin changes occurring during sporogenesis and gametogenesis, as well as early seed development in major flowering plant models.”
Lawson, J. T., Smith, J. P., Bekiranov, S., Garrett-Bakelman, F. E., & Sheffield, N. C.. (2020). COCOA: Coordinate covariation analysis of epigenetic heterogeneity. Genome Biology
Plain numerical DOI: 10.1186/s13059-020-02139-4
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“A key challenge in epigenetics is to determine the biological significance of epigenetic variation among individuals. we present coordinate covariation analysis (cocoa), a computational framework that uses covariation of epigenetic signals across individuals and a database of region sets to annotate epigenetic heterogeneity. cocoa is the first such tool for dna methylation data and can also analyze any epigenetic signal with genomic coordinates. we demonstrate cocoa’s utility by analyzing dna methylation, atac-seq, and multi-omic data in supervised and unsupervised analyses, showing that cocoa provides new understanding of inter-sample epigenetic variation. cocoa is available on bioconductor (http://bioconductor.org/packages/cocoa).”
Sermer, D., Pasqualucci, L., Wendel, H. G., Melnick, A., & Younes, A.. (2019). Emerging epigenetic-modulating therapies in lymphoma. Nature Reviews Clinical Oncology
Plain numerical DOI: 10.1038/s41571-019-0190-8
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“Despite considerable advances in the treatment of lymphoma, the prognosis of patients with relapsed and/or refractory disease continues to be poor; thus, a continued need exists for the development of novel approaches and therapies. epigenetic dysregulation might drive and/or promote tumorigenesis in various types of malignancies and is prevalent in both b cell and t cell lymphomas. over the past decade, a large number of epigenetic-modifying agents have been developed and introduced into the clinical management of patients with haematological malignancies. in this review, we provide a concise overview of the most promising epigenetic therapies for the treatment of lymphomas, including inhibitors of histone deacetylases (hdacs), dna methyltransferases (dnmts), enhancer of zeste homologue 2 (ezh2), bromodomain and extra-terminal domain proteins (bets), protein arginine n-methyltransferases (prmts) and isocitrate dehydrogenases (idhs), and highlight the most promising future directions of research in this area.”
Thaker, V. V. (
2017).
GENETIC AND EPIGENETIC CAUSES OF OBESITY..
Adolescent Medicine: State of the Art Reviews
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“Obesity is a complex, heritable trait influenced by the interplay of genetics, epigenetics, metagenomics and the environment. with the increasing access to high precision diagnostic tools for genetic investigations, numerous genes influencing the phenotype have been identified, especially in early onset severe obesity. this review summarizes the current knowledge on the known genetic causes of obesity and the available therapeutic options. furthermore, we discuss the role and potential mechanism of epigenetic changes that may be involved as mediators of the environmental influences and that may provide future opportunities for intervention.”
Gan, L., Yang, Y., Li, Q., Feng, Y., Liu, T., & Guo, W.. (2018). Epigenetic regulation of cancer progression by EZH2: From biological insights to therapeutic potential. Biomarker Research
Plain numerical DOI: 10.1186/s40364-018-0122-2
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“Enhancer of zeste homolog 2 (ezh2), a histone methyltransferase and a catalytic component of prc2, catalyzes tri-methylation of histone h3 at lys 27 (h3k27me3) to regulate gene expression through epigenetic machinery. ezh2 also functions both as a transcriptional suppressor and a transcriptional co-activator, depending on h3k27me3 or not and on the different cellular contexts. unsurprisingly, numerous studies have highlighted the role of ezh2 in cancer development and progression. through modulating critical gene expression, ezh2 promotes cell survival, proliferation, epithelial to mesenchymal, invasion, and drug resistance of cancer cells. the tumor suppressive effects of ezh2 are also identified. what is more, ezh2 has decisive roles in immune cells (for example, t cells, nk cells, dendritic cells and macrophages), which are essential components in tumor microenvironment. in this review, we aim to discuss the molecular functions of ezh2, highlight recent findings regarding the physiological functions and related regulation of ezh2 in cancer pathogenesis. furthermore, we summarized and updated the emerging roles of ezh2 in tumor immunity, and current pre-clinical and clinical trials of ezh2 inhibitors in cancer therapy.”
Saksena, N., Bonam, S. R., & Miranda-Saksena, M.. (2021). Epigenetic Lens to Visualize the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) Infection in COVID-19 Pandemic. Frontiers in Genetics
Plain numerical DOI: 10.3389/fgene.2021.581726
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“In <20 years, we have witnessed three different epidemics with coronaviruses, sars-cov, mers-cov, and sars-cov-2 in human populations, causing widespread mortality. sars-cov-2, through its rapid global spread, has led to the pandemic that we call covid-19. as of february 1, 2021, the global infections linked to sars-cov-2 stand at 103,503,340, with 2,236,960 deaths, and 75,108,099 recoveries. this review attempts to highlight host-pathogen interaction with particular emphasis on the role of epigenetic machinery in regulating the disease. although researchers, since the start of the pandemic, have been intensely engaged in diverse areas to understand the mechanisms involved in sars-cov-2 infection to find answers that can bring about innovative ways to swiftly treat and prevent disease progression, this review provides an overview on how the host epigenetics is modulated and subverted by sars-cov-2 to enter the host cells and drive immunopathogenesis. epigenetics is the study that combines genetic and non-genetic factors controlling phenotypic variation, which are primarily a consequence of external and environmental stimuli. these stimuli alter the activity of a gene without impinging on the dna code. in viral-host interactions, dna/rna methylation, non-coding rnas, chromatin remodeling, and histone modifications are known to regulate and modulate host gene expression patterns. viruses such as coronaviruses (an rna virus) show intrinsic association with these processes. they have evolved the ability to tamper with host epigenetic machinery to interfere with immune sensing pathways to evade host immune response, thereby enhancing its replication and pathogenesis post-entry. these epigenetic alterations allow the virus to weaken the host’s immune response to successfully spread infection. how this occurs, and what epigenetic mechanisms are altered is poorly understood both for coronaviruses and other respiratory rna viruses. the review highlights several cutting-edge aspects of epigenetic work primarily pertinent to sars-cov-2, which has been published between 2019 and 2020 to showcase the current knowledge both in terms of success and failures and take lessons that will assist us in understanding the disease to develop better treatments suited to kill sars-cov-2.”
Peixoto, P., Etcheverry, A., Aubry, M., Missey, A., Lachat, C., Perrard, J., … Hervouet, E.. (2019). EMT is associated with an epigenetic signature of ECM remodeling genes. Cell Death and Disease
Plain numerical DOI: 10.1038/s41419-019-1397-4
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“Type iii epithelial–mesenchymal transition (emt) has been previously associated with increased cell migration, invasion, metastasis, and therefore cancer aggressiveness. this reversible process is associated with an important gene expression reprogramming mainly due to epigenetic plasticity. nevertheless, most of the studies describing the central role of epigenetic modifications during emt were performed in a single-cell model and using only one mode of emt induction. in our study, we studied the overall modulations of gene expression and epigenetic modifications in four different emt-induced cell models issued from different tissues and using different inducers of emt. pangenomic analysis (transcriptome and chip–sequencing) validated our hypothesis that gene expression reprogramming during emt is largely regulated by epigenetic modifications of a wide range of genes. indeed, our results confirmed that each emt model is unique and can be associated with a specific transcriptome profile and epigenetic program. however, we could select some genes or pathways that are similarly regulated in the different models and that could therefore be used as a common signature of all emt models and become new biomarkers of the emt phenotype. as an example, we can cite the regulation of gene-coding proteins involved in the degradation of the extracellular matrix (ecm), which are highly induced in all emt models. based on our investigations and results, we identified adam19 as a new biomarker of in vitro and in vivo emt and we validated this biological new marker in a cohort of non-small lung carcinomas.”
Gallo-Franco, J. J., Sosa, C. C., Ghneim-Herrera, T., & Quimbaya, M.. (2020). Epigenetic Control of Plant Response to Heavy Metal Stress: A New View on Aluminum Tolerance. Frontiers in Plant Science
Plain numerical DOI: 10.3389/fpls.2020.602625
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“High concentrations of heavy metal (hm) ions impact agronomic staple crop production in acid soils (ph ≤ 5) due to their cytotoxic, genotoxic, and mutagenic effects. among cytotoxic ions, the trivalent aluminum cation (al3+) formed by solubilization of aluminum (al) into acid soils, is one of the most abundant and toxic elements under acidic conditions. in recent years, several studies have elucidated the different signal transduction pathways involved in hm responses, identifying complementary genetic mechanisms conferring tolerance to plants. although epigenetics has become more relevant in abiotic stress studies, epigenetic mechanisms underlying plant responses to hm stress remain poorly understood. this review describes the main epigenetic mechanisms related to crop responses during stress conditions, specifically, the molecular evidence showing how epigenetics is at the core of plant adaptation responses to hm ions. we highlight the epigenetic mechanisms that induce al tolerance. likewise, we analyze the pivotal relationship between epigenetic and genetic factors associated with hm tolerance. finally, using rice as a study case, we performed a general analysis over previously whole-genome bisulfite-seq published data. specific genes related to al tolerance, measured in contrasting tolerant and susceptible rice varieties, exhibited differences in dna methylation frequency. the differential methylation patterns could be associated with epigenetic regulation of rice responses to al stress, highlighting the major role of epigenetics over specific abiotic stress responses.”
Li, X., Joehanes, R., Hoeschele, I., Rich, S. S., Rotter, J. I., Levy, D., … Sofer, T.. (2019). Association between sleep disordered breathing and epigenetic age acceleration: Evidence from the Multi-Ethnic Study of Atherosclerosis. EBioMedicine
Plain numerical DOI: 10.1016/j.ebiom.2019.11.020
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“Background: sleep disordered breathing (sdb) is a common disorder that results in oxidative stress and inflammation and is associated with multiple age-related health outcomes. epigenetic age acceleration is a dna methylation (dnam)-based marker of fast biological aging. we examined the associations of sdb traits with epigenetic age acceleration. methods: a sample of 622 participants from the multi-ethnic study of atherosclerosis (mesa) had blood dnam measured and underwent type 2 in-home polysomnography that assessed apnea-hypopnea index (ahi), percentage of sleep time with oxygen saturation lower than 90% (per90), and arousal index. dnam data provided measures of dnam-age acceleration and dnam-phenoage acceleration. the association of each sdb trait with age acceleration was estimated using linear regression, controlling for covariates. in secondary analyses, we studied the associations of sdb traits with epigenetic age acceleration 2–10 years after sleep study in 530 individuals from the framingham heart study (fhs). findings: in mesa, ahi was associated with greater dnam-phenoage acceleration (β = 0.03; 95% ci [0.001, 0.06]). arousal index was associated with greater dnam-age acceleration (β = 0.04; 95% ci [0.01, 0.07]). both associations were stronger in women than men. in the secondary fhs analyses, per90 was associated with greater dnam-age acceleration and this association was stronger in men. interpretation: more severe sdb was associated with epigenetic age acceleration in both cohorts. future work should prospectively study short- and long-term effects of sdb, and whether treatment reduces epigenetic age acceleration among those individuals with sbd. funding: national institutes of health.”
Sluiter, F., Incollingo Rodriguez, A. C., Nephew, B. C., Cali, R., Murgatroyd, C., & Santos, H. P.. (2020). Pregnancy associated epigenetic markers of inflammation predict depression and anxiety symptoms in response to discrimination. Neurobiology of Stress
Plain numerical DOI: 10.1016/j.ynstr.2020.100273
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“Latina mothers, who have one of the highest fertility rates among ethnic groups in the united states (us), often experience discrimination. psychosocial influences during pregnancy, such as discrimination stress, promotes inflammation. however, the role of epigenetic markers of inflammation as a mediator between, and predictor of, maternal discrimination stress and neuropsychiatric outcomes has not been extensively studied. the current study investigates the role of dna methylation at foxp3 treg-cell-specific demethylated region (tsdr), as a marker of regulatory t (treg) cells that are important negative regulators of inflammation, and the promoter of tumour necrosis factor-alpha (tnf-α) gene, an important pro-inflammatory cytokine, in relation to discrimination stress during pregnancy and depression and anxiety symptomatology. a sample of 148 latina women residing in the us (mean age 27.6 years) were assessed prenatally at 24–32 weeks’ gestation and 4–6 weeks postnatally for perceived discrimination exposure (everyday discrimination scale, eds), emotional distress (depression, anxiety, perinatal-specific depression), acculturation, and acculturative stress. dna methylation levels at the foxp3 and tnfα promoter regions from blood samples collected at the prenatal stage were assessed by bisulphite pyrosequencing. regression analyses showed that prenatal eds associated with postnatal emotional distress, depression and anxiety symptoms only in those individuals with higher than mean levels of foxp3 tsdr and tnfα promoter methylation; no such significant associations were found in those with lower than mean levels of methylation for either. we further found that these relationships were mediated by tnfα only in those with high foxp3 tsdr methylation, implying that immunosuppression via tnfα promoter methylation buffers the impact of discrimination stress on postpartum symptomatology. these results indicate that epigenetic markers of immunosuppression and inflammation play an important role in resilience or sensitivity, respectively, to prenatal stress.”
Gu, H. F.. (2019). Genetic and epigenetic studies in diabetic kidney disease. Frontiers in Genetics
Plain numerical DOI: 10.3389/fgene.2019.00507
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“Chronic kidney disease is a worldwide health crisis, while diabetic kidney disease (dkd) has become the leading cause of end-stage renal disease (esrd). dkd is a microvascular complication and occurs in 30-40% of diabetes patients. epidemiological investigations and clinical observations on the familial clustering and heritability in dkd have highlighted an underlying genetic susceptibility. furthermore, dkd is a progressive and long-term diabetic complication, in which epigenetic effects and environmental factors interact with an individual’s genetic background. in recent years, researchers have undertaken genetic and epigenetic studies of dkd in order to better understand its molecular mechanisms. in this review, clinical material, research approaches and experimental designs that have been used for genetic and epigenetic studies of dkd are described. current information from genetic and epigenetic studies of dkd and esrd in patients with diabetes, including the approaches of genome-wide association study (gwas) or epigenome-wide association study (ewas) and candidate gene association analyses, are summarized. further investigation of molecular defects in dkd with new approaches such as next generation sequencing analysis and phenome-wide association study (phewas) is also discussed.”
Lavebratt, C., Almgren, M., & Ekström, T. J.. (2012). Epigenetic regulation in obesity. International Journal of Obesity
Plain numerical DOI: 10.1038/ijo.2011.178
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“The availability to the dna strand and the activity of the transcription machinery is crucial for the cell to use the information in the dna. the epigenetic mechanisms dna methylation, modification of histone tails, other chromatin-modifying processes and interference by small rnas regulate the cell-type-specific dna expression. epigenetic marks can be more or less plastic perpetuating responses to various molecular signals and environmental stimuli, but in addition apparently stochastic epigenetic marks have been found. there is substantial evidence from animal and man demonstrating that both transient and more long-term epigenetic mechanisms have a role in the regulation of the molecular events governing adipogenesis and glucose homeostasis. intrauterine exposure such as poor maternal nutrition has consistently been demonstrated to contribute to a particular epigenotype and thereby developmental metabolic priming of the exposed offspring in animal and man. epigenetic modifications can be passed not only from one cell generation to the next, but metabolic disease-related epigenotypes have been proposed to also be transmitted germ-line. future more comprehensive knowledge on epigenetic regulation will complement genome sequence data for the understanding of the complex etiology of obesity and related disorder. © 2012 macmillan publishers limited all rights reserved.”
Shorter, K. R., & Miller, B. H.. (2015). Epigenetic mechanisms in schizophrenia. Progress in Biophysics and Molecular Biology
Plain numerical DOI: 10.1016/j.pbiomolbio.2015.04.008
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“Epigenetic modifications, including dna methylation, histone modifications, and non-coding rnas, have been implicated in a number of complex diseases. schizophrenia and other major psychiatric and neurodevelopmental disorders are associated with abnormalities in multiple epigenetic mechanisms, resulting in altered gene expression during development and adulthood. polymorphisms and copy number variants in schizophrenia risk genes contribute to the high heritability of the disease, but environmental factors that lead to epigenetic modifications may either reduce or exacerbate the expression of molecular and behavioral phenotypes associated with schizophrenia and related disorders. in the present paper, we will review the current understanding of molecular dysregulation in schizophrenia, including disruption of the dopamine, nmda, and gaba signaling pathways, and discuss the role of epigenetic factors underlying disease pathology.”
Widmann, M., Nieß, A. M., & Munz, B.. (2019). Physical Exercise and Epigenetic Modifications in Skeletal Muscle. Sports Medicine
Plain numerical DOI: 10.1007/s40279-019-01070-4
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“Physical activity and sports play major roles in the overall health status of humans. it is well known that regular exercise helps to lower the risk for a broad variety of health problems, such as cardiovascular disease, type 2 diabetes, and cancer. being physically active induces a wide variety of molecular adaptations, for example fiber type switches or other metabolic alterations, in skeletal muscle tissue. these adaptations are based on exercise-induced changes to the skeletal muscle transcriptome. understanding their nature is crucial to improve the development of exercise-based therapeutic strategies. recent research indicates that specifically epigenetic mechanisms, i.e., pathways that induce changes in gene expression patterns without altering the dna base sequence, might play a major role in controlling skeletal muscle transcriptional patterns. epigenetic mechanisms include dna and histone modifications, as well as expression of specific micrornas. they can be modulated by environmental factors or external stimuli, such as exercise, and eventually induce specific and fine-tuned changes to the transcriptional response. in this review, we highlight current knowledge on epigenetic changes induced in exercising skeletal muscle, their target genes, and resulting phenotypic changes. in addition, we raise the question of whether epigenetic modifications might serve as markers for the design and management of optimized and individualized training protocols, as prognostic tools to predict training adaptation, or even as targets for the design of ‘exercise mimics’.”
Lind, M. I., & Spagopoulou, F.. (2018). Evolutionary consequences of epigenetic inheritance. Heredity
Plain numerical DOI: 10.1038/s41437-018-0113-y
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Chang, Z., Yadav, V., Lee, S. C., & Heitman, J.. (2019). Epigenetic mechanisms of drug resistance in fungi. Fungal Genetics and Biology
Plain numerical DOI: 10.1016/j.fgb.2019.103253
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“The emergence of drug-resistant fungi poses a continuously increasing threat to human health. despite advances in preventive care and diagnostics, resistant fungi continue to cause significant mortality, especially in immunocompromised patients. therapeutic resources are further limited by current usage of only four major classes of antifungal drugs. resistance against these drugs has already been observed in pathogenic fungi requiring the development of much needed newer antifungal drugs. epigenetic changes such as dna or chromatin modifications alter gene expression levels in response to certain stimuli, including interaction with the host in the case of fungal pathogens. these changes can confer resistance to drugs by altering the expression of target genes or genes encoding drug efflux pumps. multiple pathogens share many of these epigenetic pathways; thus, targeting epigenetic pathways might also identify drug target candidates for the development of broad-spectrum antifungal drugs. in this review, we discuss the importance of epigenetic pathways in mediating drug resistance in fungi as well as in the development of anti-fungal drugs.”
Kondo, Y., Katsushima, K., Ohka, F., Natsume, A., & Shinjo, K.. (2014). Epigenetic dysregulation in glioma. Cancer Science
Plain numerical DOI: 10.1111/cas.12379
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“Given that treatment options for patients with glioblastoma are limited, much effort has been made to clarify the underlying mechanisms of gliomagenesis. recent genome-wide genomic and epigenomic analyses have revealed that mutations in epigenetic modifiers occur frequently in gliomas and that dysregulation of epigenetic mechanisms is closely associated with glioma formation. given that epigenetic changes are reversible, understanding the epigenetic abnormalities that arise in gliomagenesis might be key to developing more effective treatment strategies for glioma. in this review, we focus on the recent advancements in epigenetic research with respect to gliomas, consider how epigenetic mechanisms dynamically regulate tumor cells, including the cancer stem cell population, and discuss perspectives and challenges for glioma treatment in the near future. in this review, we focus on the recent advancements in epigenetic research with respect to gliomas, consider how epigenetic mechanisms dynamically regulate tumor cells, including the cancer stem cell population, and discuss perspectives and challenges for glioma treatment in the near future. © 2014 the authors. cancer science published by wiley publishing asia pty ltd on behalf of japanese cancer association.”
Burggren, W. W.. (2015). Dynamics of epigenetic phenomena: Intergenerational and intragenerational phenotype “washout”. Journal of Experimental Biology
Plain numerical DOI: 10.1242/jeb.107318
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“Epigenetic studies of both intragenerational and transgenerational epigenetic phenotypic modifications have proliferated in the last few decades. however, the strong reductionist focus on mechanism that prevails in many epigenetic studies to date has diverted attention away what might be called the ‘dynamics’ of epigenetics and its role in comparative biology. epigenetic dynamics describes how both transgenerational and intragenerational epigenetic phenotypic modifications change in non-linear patterns over time. importantly, a dynamic perspective suggests that epigenetic phenomena should not be regarded as ‘digital’ (on-off), in which a modified trait necessarily suddenly disappears between one generation and the next. rather, dynamic epigenetic phenomena may be better depicted by graded, time-related changes that can potentially involve the ‘washout’ of modified phenotype both within and across generations. conceivably, an epigenetic effect might also ‘wash-in’ over multiple generations, and there may be unexplored additive effects resulting from the pressures of environmental stressors that wax, wane and then wax again across multiple generations. recognition of epigenetic dynamics is also highly dependent on the threshold for detection of the phenotypic modification of interest, especially when phenotypes wash out or wash in. thus, studies of transgenerational epigenetic effects (and intragenerational effects, for that matter) that search for persistence of the phenomenon are best conducted with highly sensitive, precise quantitative methods. all of the scenarios in this review representing epigenetic dynamics are possible and some even likely. focused investigations that concentrate on the time course will reveal much about both the impact and mechanisms of epigenetic phenomena.”
Latzel, V., Zhang, Y., Karlsson Moritz, K., Fischer, M., & Bossdorf, O.. (2012). Epigenetic variation in plant responses to defence hormones. Annals of Botany
Plain numerical DOI: 10.1093/aob/mcs088
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“Background and aimsthere is currently much speculation about the role of epigenetic variation as a determinant of heritable variation in ecologically important plant traits. however, we still know very little about the phenotypic consequences of epigenetic variation, in particular with regard to more complex traits related to biotic interactions.methodshere, a test was carried out to determine whether variation in dna methylation alone can cause heritable variation in plant growth responses to jasmonic acid and salicylic acid, two key hormones involved in induction of plant defences against herbivores and pathogens. in order to be able to ascribe phenotypic differences to epigenetic variation, the hormone responses were studied of epigenetic recombinant inbred lines (epirils) of arabidopsis thaliana – lines that are highly variable at the level of dna methylation but nearly identical at the level of dna sequence.key resultssignificant heritable variation was found among epirils both in the means of phenotypic traits, including growth rate, and in the degree to which these responded to treatment with jasmonic acid and salicylic acid. moreover, there was a positive epigenetic correlation between the responses of different epirils to the two hormones, suggesting that plant responses to herbivore and pathogen attack may have a similar molecular epigenetic basis.conclusionsthis study demonstrates that epigenetic variation alone can cause heritable variation in, and thus potentially microevolution of, plant responses to defence hormones. this suggests that part of the variation of plant defences observed in natural populations may be due to underlying epigenetic, rather than entirely genetic, variation. © 2012 the author. published by oxford university press on behalf of the annals of botany company. all rights reserved.”
McCoy, R. M., Julian, R., Kumar, S. R. V., Ranjan, R., Varala, K., & Li, Y.. (2021). A systems biology approach to identify essential epigenetic regulators for specific biological processes in plants. Plants
Plain numerical DOI: 10.3390/plants10020364
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“Upon sensing developmental or environmental cues, epigenetic regulators transform the chromatin landscape of a network of genes to modulate their expression and dictate adequate cellular and organismal responses. knowledge of the specific biological processes and genomic loci controlled by each epigenetic regulator will greatly advance our understanding of epigenetic regulation in plants. to facilitate hypothesis generation and testing in this domain, we present epinet, an extensive gene regulatory network (grn) featuring epigenetic regulators. epinet was enabled by (i) curated knowledge of epigenetic regulators involved in dna methylation, histone modifica-tion, chromatin remodeling, and sirna pathways; and (ii) a machine-learning network inference approach powered by a wealth of public transcriptome datasets. we applied genie3, a machine-learning network inference approach, to mine public arabidopsis transcriptomes and construct tis-sue-specific grns with both epigenetic regulators and transcription factors as predictors. the re-sultant grns, named epinet, can now be intersected with individual transcriptomic studies on biological processes of interest to identify the most influential epigenetic regulators, as well as pre-dicted gene targets of the epigenetic regulators. we demonstrate the validity of this approach using case studies of shoot and root apical meristem development.”
Fang, M., Hutchinson, L., Deng, A., & Green, M. R.. (2016). Common BRAF(V600E)-directed pathway mediates widespread epigenetic silencing in colorectal cancer and melanoma. Proceedings of the National Academy of Sciences of the United States of America
Plain numerical DOI: 10.1073/pnas.1525619113
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“During cancer development, it is well established that many genes, including tumor suppressor genes, are hypermethylated and transcriptionally repressed, a phenomenon referred to as epigenetic silencing. in general, the factors involved in, and the mechanistic basis of, epigenetic silencing during cancer development are not well understood. we have recently described an epigenetic silencing pathway, directed by the oncogenic b-raf proto-oncogene (braf) variant braf(v600e), that mediates widespread epigenetic silencing in colorectal cancer (crc). notably, the braf(v600e) mutation is also present in 50-70% of melanomas. here, we show that the same pathway we identified in crc also directs epigenetic silencing of a similar set of genes in braf-positive melanoma. in both crc and melanoma, braf(v600e) promotes epigenetic silencing through up-regulation of v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog g (mafg), a transcriptional repressor with sequencespecific dna-binding activity. the elevated concentration of mafg drives dna binding on the promoter. promoter-bound mafg recruits a set of corepressors that includes its heterodimeric partner btb and cnc homology 1, basic leucine zipper transcription factor 1(bach1), the chromatin remodeling factor chromodomain helicase dna-binding protein 8(chd8), and the dna methyltransferase dnmt3b, resulting in hypermethylation and transcriptional silencing. our results reveal a common braf(v600e)-directed transcriptional regulatory pathway that mediates epigenetic silencing in unrelated solid tumors and provide strong support for an instructive model of oncoprotein-directed epigenetic silencing.”
Tirosh, A., & Kebebew, E.. (2020). Genetic and epigenetic alterations in pancreatic neuroendocrine tumors. Journal of Gastrointestinal Oncology
Plain numerical DOI: 10.21037/jgo.2020.03.11
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“Neuroendocrine tumors (nets) are a heterogenous group of tumors that originate from neuroendocrine cells, mainly in the pancreas and the gastrointestinal and bronchopulmonary tracts. there has been considerable progress in our understanding of the genetic and epigenetic changes associated with pancreatic nets (pnets). the main genetic alterations that drive pnets include genetic alterations in men1, vhl and genes involved in the mtor pathway, daxx and/or atrx mutations and their association with alternative telomere lengthening, and genes involved in dna damage repair and chromatin modification. the epigenetic alterations in pnets are also common based on genome-wide dna methylation profiling studies, with a high rate of cpg hypermethylation in men1-associated pnets compared to sporadic and vhl-associated pnets. moreover, the dysregulated dna methylation status is associated with distinct gene expression profiles. this article reviews the commonly and recently discovered genetic and epigenetic changes that are associated with pnets, inherited pnets, and genotype–phenotype associations, and it discusses their clinical relevance.”
Ye, F., Huang, J., Wang, H., Luo, C., & Zhao, K.. (2019). Targeting epigenetic machinery: Emerging novel allosteric inhibitors. Pharmacology and Therapeutics
Plain numerical DOI: 10.1016/j.pharmthera.2019.107406
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“Epigenetics has emerged as an extremely exciting fast-growing area of biomedical research in post genome era. epigenetic dysfunction is tightly related with various diseases such as cancer and aging related degeneration, potentiating epigenetics modulators as important therapeutics targets. indeed, inhibitors of histone deacetylase and dna methyltransferase have been approved for treating blood tumor malignancies, whereas inhibitors of histone methyltransferase and histone acetyl-lysine recognizer bromodomain are in clinical stage. however, it remains a great challenge to discover potent and selective inhibitors by targeting catalytic site, as the same subfamily of epigenetic enzymes often share high sequence identity and very conserved catalytic core pocket. it is well known that epigenetic modifications are usually carried out by multi-protein complexes, and activation of catalytic subunit is often tightly regulated by other interactive protein component, especially in disease conditions. therefore, it is not unusual that epigenetic complex machinery may exhibit allosteric regulation site induced by protein-protein interactions. targeting allosteric site emerges as a compelling alternative strategy to develop epigenetic drugs with enhanced druggability and pharmacological profiles. in this review, we highlight recent progress in the development of allosteric inhibitors for epigenetic complexes through targeting protein–protein interactions. we also summarized the status of clinical applications of those inhibitors. finally, we provide perspectives of future novel allosteric epigenetic machinery modulators emerging from otherwise undruggable single protein target.”
Furuya, K., Ikura, M., & Ikura, T.. (2019). Epigenetic interplays between DNA demethylation and histone methylation for protecting oncogenesis. Journal of Biochemistry
Plain numerical DOI: 10.1093/jb/mvy124
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“Epigenetic systems are organized by different types of modifications on histones and dna. to determine how epigenetic systems can produce variable, yet stable cellular outcomes, understanding the collaboration between these modifications is the key. a recent study by yamagata and kobayashi revealed the direct interplay between the regulation of two epigenetic modifications: dna de-methylation by tet2 and histone h3-k36 methylation. mechanistically, this finding could explain how cells are protected from oncogenesis by maintaining the integrity of active transcription. the recent identification of epigenetic modifier mutations in leukaemia suggested that it is not just the turning â € on’ and â € off’ of particular transcriptional events that causes disease occurrence, but rather it is the aberration in epigenetic regulation, i.e. the timing and duration of the activation/inactivation of these transcripts. thus, a comprehensive understanding of how epigenetic interplays tune transcription will be the new perspective for disease research.”
Puri, D., Dhawan, J., & Mishra, R. K.. (2010). The paternal hidden agenda: Epigenetic inheritance through sperm chromatin. Epigenetics
Plain numerical DOI: 10.4161/epi.5.5.12005
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“Epigenetic modifications play a crucial role in developmental gene regulation. these modifications, being reversible, provide a layer of information over and above the dna sequence, that has plasticity and leads to the generation of cell type-specific epigenomes during cellular differentiation. in almost all higher eukaryotes, the oocyte provides not only its cytoplasm, mitochondria, maternally deposited rna and proteins but also an epigenetic component in the form of dna and histone-modifications. during spermeiogenesis however, most of the histones are replaced by protamines, leading to a loss of the epigenetic component. the sperm is, therefore, viewed as a passive carrier of the paternal genome with a disproportionate, lower epigenetic contribution except for dna methylation, to the next generation. a recent study overturns this view by demonstrating a locus-specific retention of histones, with specific modifications in the sperm chromatin at the promoters of developmentally important genes. this programmed retention of epigenetic marks with a role in embryonic development is suggested to offset, in some measure, the dominant maternal effect. this new finding helps in addressing the question of epigenetic transmission of environmental and ‘lifestyle’ experiences across generations and raises the question of ‘parental conflict’ at the loci that may be differentially marked. © 2010 landes bioscience.”
Maleszewska, M., & Kaminska, B.. (2013). Is glioblastoma an epigenetic malignancy?. Cancers
Plain numerical DOI: 10.3390/cancers5031120
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“Epigenetic modifications control gene expression by regulating the access of nuclear proteins to their target dna and have been implicated in both normal cell differentiation and oncogenic transformation. epigenetic abnormalities can occur both as a cause and as a consequence of cancer. oncogenic transformation can deeply alter the epigenetic information enclosed in the pattern of dna methylation or histone modifications. in addition, in some cancers epigenetic dysfunctions can drive oncogenic transformation. growing evidence emphasizes the interplay between metabolic disturbances, epigenomic changes and cancer, i.e., mutations in the metabolic enzymes sdh, fh, and idh may contribute to cancer development. epigenetic-based mechanisms are reversible and the possibility of -resetting{norm of matrix} the abnormal cancer epigenome by applying pharmacological or genetic strategies is an attractive, novel approach. gliomas are incurable with all current therapeutic approaches and new strategies are urgently needed. increasing evidence suggests the role of epigenetic events in development and/or progression of gliomas. in this review, we summarize current data on the occurrence and significance of mutations in the epigenetic and metabolic enzymes in pathobiology of gliomas. we discuss emerging therapies targeting specific epigenetic modifications or chromatin modifying enzymes either alone or in combination with other treatment regimens. © 2013 by the authors; licensee mdpi, basel, switzerland.”
Guo, Y., Yu, S., Zhang, C., & Kong, A. N. T.. (2015). Epigenetic regulation of Keap1-Nrf2 signaling. Free Radical Biology and Medicine
Plain numerical DOI: 10.1016/j.freeradbiomed.2015.06.013
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“The kelch-like ech-associated protein 1 (keap1)-nuclear factor erythroid 2-related factor 2 (nrf2) signaling axis serves as a ‘master regulator’ in response to oxidative/electrophilic stresses and chemical insults through the coordinated induction of a wide array of cytoprotective genes. therefore, activation of nrf2 is considered to be an important approach for preventing chronic diseases triggered by stresses and toxins, including cancer. despite extensive studies suggested that the keap1-nrf2 signaling pathway is subject to multiple layers of regulation at the transcriptional, translational, and post-translational levels, the potential epigenetic regulation of nrf2 and keap1 has begun to be recognized only in recent years. epigenetic modifications, heritable alterations in gene expression that occur without changes in the primary dna sequence, have been reported to be profoundly involved in oxidative stress responses. in this review, we discuss the latest findings regarding the epigenetic regulation of keap1-nrf2 signaling by dna methylation, histone modification, and micrornas. the crosstalk among these epigenetic modifications in the regulation of keap1-nrf2 signaling pathways is also discussed. studies of the epigenetic modification of nrf2 and keap1 have not only enhanced our understanding of this complex cellular defense system but have also provided potential new therapeutic targets for the prevention of certain diseases.”
Li, K., Wei, Q., Liu, F. F., Hu, F., Xie, A. ji, Zhu, L. Q., & Liu, D.. (2018). Synaptic Dysfunction in Alzheimer’s Disease: Aβ, Tau, and Epigenetic Alterations. Molecular Neurobiology
Plain numerical DOI: 10.1007/s12035-017-0533-3
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“Alzheimer’s disease (ad) is a complex neurodegenerative disorder characterized in the early stages by loss of learning and memory. however, the mechanism underlying these symptoms remains unclear. the best correlation between cognitive decline and pathological changes is in synaptic dysfunction. histopathological hallmarks of ad are the abnormal aggregation of aβ and tau. evidence suggests that aβ and tau oligomers contribute to synaptic loss in ad. recently, direct links between epigenetic alterations, such as dysfunction in non-coding rnas (ncrnas), and synaptic pathologies have emerged, raising interest in exploring the potential roles of ncrnas in the synaptic deficits in ad. in this paper, we summarize the potential roles of aβ, tau, and epigenetic alterations (especially by ncrnas) in the synaptic dysfunction of ad and discuss the novel findings in this area.”
Loison, L.. (2018). Lamarckism and epigenetic inheritance: a clarification. Biology and Philosophy
Plain numerical DOI: 10.1007/s10539-018-9642-2
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“Since the 1990s, the terms ‘lamarckism’ and ‘lamarckian’ have seen a significant resurgence in biological publications. the discovery of new molecular mechanisms (dna methylation, histone modifications, rna interference, etc.) have been interpreted as evidence supporting the reality and efficiency of the inheritance of acquired characters, and thus the revival of lamarckism. the present paper aims at giving a critical evaluation of such interpretations. i argue that two types of arguments allow to draw a clear distinction between the genuine lamarckian concept of inheritance of acquired characters and transgenerational epigenetic inheritance. the first concerns the explanandum of the processes under consideration: molecular mechanisms of transgenerational epigenetic inheritance are understood as evolved products of natural selection. this means that the kind of inheritance of acquired characters they might be responsible for is an obligatory emergent feature of evolution, whereas traditional lamarckisms conceived the inheritance of acquired characters as a property inherent in living matter itself. the second argument concerns the explanans of the inheritance of acquired characters: in light of current knowledge, epigenetic mechanisms are not able to drive adaptive evolution by themselves. emergent lamarckian phenomena would be possible if and only if individual epigenetic variation allowed the inheritance of acquired characters to be a factor of unlimited change. this implies specific requirements for epigenetic variation, which i explicitly define and expand upon. i then show that given current knowledge, these requirements are not empirically grounded.”
Borrelli, E., Nestler, E. J., Allis, C. D., & Sassone-Corsi, P.. (2008). Decoding the Epigenetic Language of Neuronal Plasticity. Neuron
Plain numerical DOI: 10.1016/j.neuron.2008.10.012
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“Neurons are submitted to an exceptional variety of stimuli and are able to convert these into high-order functions, such as storing memories, controlling behavior, and governing consciousness. these unique properties are based on the highly flexible nature of neurons, a characteristic that can be regulated by the complex molecular machinery that controls gene expression. epigenetic control, which largely involves events of chromatin remodeling, appears to be one way in which transcriptional regulation of gene expression can be modified in neurons. this review will focus on how epigenetic control in the mature nervous system may guide dynamic plasticity processes and long-lasting cellular neuronal responses. we outline the molecular pathways underlying chromatin transitions, propose the presence of an ‘epigenetic indexing code,’ and discuss how central findings accumulating at an exponential pace in the field of epigenetics are conceptually changing our perspective of adult brain function. © 2008 elsevier inc. all rights reserved.”
Hong, Y. K., Li, Y., Pandit, H., Li, S. P., Pulliam, Z., Zheng, Q., … Martin, R. C. G.. (2019). Epigenetic modulation enhances immunotherapy for hepatocellular carcinoma. Cellular Immunology
Plain numerical DOI: 10.1016/j.cellimm.2018.12.010
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“Background: anti-pdl-1 immunotherapy for hepatocellular carcinoma (hcc) demonstrated a mixed response. polycomb repressor complex 2(prc2) contributes to the initiation and progression of hcc by suppressing tumor antigens and inhibiting an immune response. two components of epigenetic modulation are enhancer of zeste homolog 2 (ezh2, the catalytic component of prc2) and dna methyltransferase 1 (dnmt1). we aim to investigate the potential role of epigenetic therapy targeting ezh2 and dnmt1 as a novel strategy to modulate immunotherapy response in hcc. methods: hepg2, hep3b, and hepa1-6 hcc cell lines were treated with ezh2 inhibitor (dznep) and dnmt1 inhibitor (5-azacytidine) with and without anti-pdl-1. quantitative rt-pcr and immunohistochemistry were performed to evaluate the expression of tumor suppressors, tumor antigens, and th1 chemokines. in-vivo c57/lj immunocompetent mice model with subcutaneous tumor inoculation was performed with intraperitoneal drug injections. results: there was a significant upregulation of th1 chemokines in hepg2 (cxcl9 5.5 ± 0.2 relative fold change; cxcl10 1.44 × 103 ± 37 relative fold change) and hep3b (cxcl 9 6.85 × 103 ± 1.3 × 103 relative fold change; cxcl 10 2.15 × 103 ± 3.1 × 102 relative fold change). additionally, there was a significant induction of cancer testis antigens ny-eso-1 (3.6–3.7 ± 0.3 relative fold change) and lage (8.3–11.7 ± 1.9 relative fold change). in vivo model demonstrated statistically significant tumor regression in the combination treatment group (0.02 g ± 0.02) compared to epigenetic therapy (0.63 g ± 0.61) or immunotherapy alone (0.15 g ± 0.21) with untreated control (2.4 g ± 0.71). there was significantly increased trafficking of cytotoxic t- lymphocytes and associated apoptosis for the combination treatment group compared to epigenetic or immunotherapy alone. conclusions: this study demonstrates that epigenetic modulation could be a novel potential strategy to augment immunotherapy for hcc by stimulating t cell trafficking into tumor microenvironment via activation of transcriptionally repressed chemokine genes responsible for t-cell trafficking, inducing previously silent neoantigens for immune targets, and allowing tumor regression as a result. a clinical trial of this feasible combination therapy of these clinically available agents is warranted.”
Creighton, S. D., Stefanelli, G., Reda, A., & Zovkic, I. B.. (2020). Epigenetic mechanisms of learning and memory: Implications for aging. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms21186918
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“The neuronal epigenome is highly sensitive to external events and its function is vital for producing stable behavioral outcomes, such as the formation of long-lasting memories. the importance of epigenetic regulation in memory is now well established and growing evidence points to altered epigenome function in the aging brain as a contributing factor to age-related memory decline. in this review, we first summarize the typical role of epigenetic factors in memory processing in a healthy young brain, then discuss the aspects of this system that are altered with aging. there is general agreement that many epigenetic marks are modified with aging, but there are still substantial inconsistencies in the precise nature of these changes and their link with memory decline. here, we discuss the potential source of age-related changes in the epigenome and their implications for therapeutic intervention in age-related cognitive decline.”
Morrison, F. G., Logue, M. W., Guetta, R., Maniates, H., Stone, A., Schichman, S. A., … Wolf, E. J.. (2019). Investigation of bidirectional longitudinal associations between advanced epigenetic age and peripheral biomarkers of inflammation and metabolic syndrome. Aging
Plain numerical DOI: 10.18632/aging.101992
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“Epigenetic age estimations based on dna methylation (dnam) can predict human chronological age with a high level of accuracy. these dnam age algorithms can also be used to index advanced cellular age, when estimated dnam age exceeds chronological age. advanced dnam age has been associated with several diseases and metabolic and inflammatory pathology, but the causal direction of this association is unclear. the goal of this study was to examine potential bidirectional associations between advanced epigenetic age and metabolic and inflammatory markers over time in a longitudinal cohort of 179 veterans with a high prevalence of posttraumatic stress disorder (ptsd) who were assessed over the course of two years. analyses focused on two commonly investigated metrics of advanced dnam age derived from the horvath (developed across multiple tissue types) and hannum (developed in whole blood) dnam age algorithms. results of cross-lagged panel models revealed that advanced hannum dnam age at time 1 (t1) was associated with increased (i.e., accounting for t1 levels) metabolic syndrome (mets) severity at time 2 (t2; p = < 0.001). this association was specific to worsening lipid panels and indicators of abdominal obesity (p = 0.001). in contrast, no baseline measures of inflammation or metabolic pathology were associated with changes in advanced epigenetic age over time. no associations emerged between advanced horvath dnam age and any of the examined biological parameters. results suggest that advanced epigenetic age, when measured using an algorithm developed in whole blood, may be a prognostic marker of pathological metabolic processes. this carries implications for understanding pathways linking advanced epigenetic age to morbidity and mortality.”
Chen, X., Pan, X., Zhang, W., Guo, H., Cheng, S., He, Q., … Ding, L.. (2020). Epigenetic strategies synergize with PD-L1/PD-1 targeted cancer immunotherapies to enhance antitumor responses. Acta Pharmaceutica Sinica B
Plain numerical DOI: 10.1016/j.apsb.2019.09.006
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“Immunotherapy strategies targeting the programmed cell death ligand 1 (pd-l1)/programmed cell death 1 (pd-1) pathway in clinical treatments have achieved remarkable success in treating multiple types of cancer. however, owing to the heterogeneity of tumors and individual immune systems, pd-l1/pd-1 blockade still shows slow response rates in controlling malignancies in many patients. accumulating evidence has shown that an effective response to anti-pd-l1/anti-pd-1 therapy requires establishing an integrated immune cycle. damage in any step of the immune cycle is one of the most important causes of immunotherapy failure. impairments in the immune cycle can be restored by epigenetic modification, including reprogramming the environment of tumor-associated immunity, eliciting an immune response by increasing the presentation of tumor antigens, and by regulating t cell trafficking and reactivation. thus, a rational combination of pd-l1/pd-1 blockade and epigenetic agents may offer great potential to retrain the immune system and to improve clinical outcomes of checkpoint blockade therapy.”
Jeong, H. M., Kwon, M. J., & Shin, Y. K.. (2014). Overexpression of cancer-associated genes via epigenetic derepression mechanisms in gynecologic cancer. Frontiers in Oncology
Plain numerical DOI: 10.3389/fonc.2014.00012
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“Like other cancers, most gynecologic cancers are caused by aberrant expression of cancer-related genes. epigenetics is one of the most important gene expression mechanisms, which contribute to cancer development and progression by regulating cancer-related genes. since the discovery of differential gene expression patterns in cancer cells when compared with normal cells, extensive efforts have been made to explore the origins of abnormal gene expression in cancer. epigenetics, the study of inheritable changes in gene expression that do not alter dna sequence is a key area of this research. dna methylation and histone modification are well-known epigenetic mechanisms, while micrornas and alternative splicing have recently been identified as important regulators of epigenetic mechanisms. these mechanisms not only affect specific target gene expression but also regulate the functioning of other epigenetic mechanisms. moreover, these diverse epigenetic regulations occur simultaneously. epigenetic regulation of gene expression is extraordinarily complicated and all epigenetic mechanisms to be studied at once to determine the exact gene regulation mechanisms. traditionally, the contribution of epigenetics to cancer is thought to be mediated through the inactivation of tumor suppressor genes expression. but recently, it is arising that some oncogenes or cancer-promoting genes (cpgs) are overexpressed in diverse type of cancers through epigenetic derepression mechanism, such as dna and histone demethylation. epigenetic derepression arises from diverse epigenetic changes, and all of these mechanisms actively interact with each other to increase oncogenes or cpgs expression in cancer cell. oncogenes or cpgs overexpressed through epigenetic derepression can initiate cancer development, and accumulation of these abnormal epigenetic changes makes cancer more aggressive and treatment resistance. this review discusses epigenetic mechanisms involved in the overexpression of oncogenes or cpgs via epigenetic derepression in gynecologic cancers. therefore, improved understanding of these epigenetic mechanisms will provide new targets for gynecologic cancer treatment. © 2014 jeong, kwon and shin.”
Yao, B., & Jin, P.. (2014). Unlocking epigenetic codes in neurogenesis. Genes and Development
Plain numerical DOI: 10.1101/gad.241547.114
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“During embryonic and adult neurogenesis, neuronal stem cells follow a highly conserved path of differentiation to give rise to functional neurons at various developmental stages. epigenetic regulation-including dna modifications, histone modifications, and noncoding regulatory rnas, such as microrna (mirna) and long noncoding rna (lncrna)-plays a pivotal role in embryonic and adult neurogenesis. here we review the latest in our understanding of the epigenetic regulation in neurogenesis, with a particular focus on newly identified cytosine modifications and their dynamics, along with our perspective for future studies. © 2014 yao and jin.”
Yu, J., Loh, X. J., Luo, Y., Ge, S., Fan, X., & Ruan, J.. (2020). Insights into the epigenetic effects of nanomaterials on cells. Biomaterials Science
Plain numerical DOI: 10.1039/c9bm01526d
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“With the development of nanotechnology, nanomaterials are increasingly being applied in health fields, such as biomedicine, pharmaceuticals, and cosmetics. concerns have therefore been raised over their toxicity and numerous studies have been carried out to assess their safety. most studies on the toxicity and therapeutic mechanisms of nanomaterials have revealed the effects of nanomaterials on cells at the transcriptome and proteome levels. however, epigenetic modifications, for example dna methylation, histone modification, and noncoding rna expression induced by nanomaterials, which play an important role in the regulation of gene expression, have not received sufficient attention. in this review, we therefore state the importance of studying epigenetic effects induced by nanomaterials; then we review the progress of nanomaterial epigenetic research in the assessment of toxicity, therapeutic, and other mechanisms. we also clarify the possible study directions for future nanomaterial epigenetic research. finally, we discuss the future development and challenges of nanomaterial epigenetics that must still be addressed. we hope to understand the potential toxicity of nanomaterials and clearly understand the therapeutic mechanism through a thorough investigation of nanomaterial epigenetics.”
Chen, L., Ge, B., Casale, F. P., Vasquez, L., Kwan, T., Garrido-Martín, D., … Soranzo, N.. (2016). Genetic Drivers of Epigenetic and Transcriptional Variation in Human Immune Cells. Cell
Plain numerical DOI: 10.1016/j.cell.2016.10.026
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“Characterizing the multifaceted contribution of genetic and epigenetic factors to disease phenotypes is a major challenge in human genetics and medicine. we carried out high-resolution genetic, epigenetic, and transcriptomic profiling in three major human immune cell types (cd14+ monocytes, cd16+ neutrophils, and naive cd4+ t cells) from up to 197 individuals. we assess, quantitatively, the relative contribution of cis-genetic and epigenetic factors to transcription and evaluate their impact as potential sources of confounding in epigenome-wide association studies. further, we characterize highly coordinated genetic effects on gene expression, methylation, and histone variation through quantitative trait locus (qtl) mapping and allele-specific (as) analyses. finally, we demonstrate colocalization of molecular trait qtls at 345 unique immune disease loci. this expansive, high-resolution atlas of multi-omics changes yields insights into cell-type-specific correlation between diverse genomic inputs, more generalizable correlations between these inputs, and defines molecular events that may underpin complex disease risk.”
Tripathi, S. K., & Lahesmaa, R.. (2014). Transcriptional and epigenetic regulation of T-helper lineage specification. Immunological Reviews
Plain numerical DOI: 10.1111/imr.12204
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“Summary: combined with tcr stimuli, extracellular cytokine signals initiate the differentiation of naive cd4+ t cells into specialized effector t-helper (th) and regulatory t (treg) cell subsets. the lineage specification and commitment process occurs through the combinatorial action of multiple transcription factors (tfs) and epigenetic mechanisms that drive lineage-specific gene expression programs. in this article, we review recent studies on the transcriptional and epigenetic regulation of distinct th cell lineages. moreover, we review current study linking immune disease-associated single-nucleotide polymorphisms with distal regulatory elements and their potential role in the disease etiology. © 2014 the authors. immunological reviews published by john wiley & sons ltd.”
Yehuda, R., Lehrner, A., & Bierer, L. M.. (2018). The public reception of putative epigenetic mechanisms in the transgenerational effects of trauma. Environmental Epigenetics
Plain numerical DOI: 10.1093/eep/dvy018
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“There has been great interest in the possibility that effects of trauma might be passed from parent to offspring through epigenetic mechanisms. this topic has stimulated discussion and controversy in the scientific literature, the popular press, and culture at large. this article describes the initial observations that have led to recent examinations of epigenetic mechanisms in association with effects of parental trauma exposure on offspring. epigenetic research in animals has provided models for how such effects might be transmitted. however, the attribution of any specific epigenetic mechanisms in human studies of offspring of trauma survivors is premature at this time. the article describes some of the ways in which initial epigenetic findings in the offspring of trauma survivors have been represented in the popular media. reports have ranged from overly simplistic and sensationalistic claims to global dismissals. the authors discuss the importance of clarity in language when describing epigenetic findings for lay audiences, the need to emphasize the limitations as well as the promise of research on intergenerational transmission of trauma effects, and the importance of countering popular interpretations that imply a reductionist biological determinism. scientists have an obligation to assist in translating important research findings and nascent avenues of research to the public. it is important to recognize the ways in which this research may unintentionally be received as supporting a narrative of permanent and significant damage in offspring, rather than contributing to discussions of potential resilience, adaptability, and mutability in biological systems affected by stress.”
Manukyan, M., & Singh, P. B.. (2012). Epigenetic rejuvenation. Genes to Cells
Plain numerical DOI: 10.1111/j.1365-2443.2012.01595.x
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“Induced pluripotent stem (ips) cells have provided a rational means of obtaining histo-compatible tissues for ‘patient-specific’ regenerative therapies (hanna 2010; yamanaka & blau 2010). despite the obvious potential of ips cell-based therapies, there are certain problems that must be overcome before these therapies can become safe and routine (ohi 2011; pera 2011). as an alternative, we have recently explored the possibility of using ‘epigenetic rejuvenation’, where the specialized functions of an old cell are rejuvenated in the absence of any change in its differentiated state (singh & zacouto 2010). the mechanism(s) that underpin ‘epigenetic rejuvenation’ are unknown and here we discuss model systems, using key epigenetic modifiers, which might shed light on the processes involved. epigenetic rejuvenation has advantages over ips cell techniques that are currently being pursued. first, the genetic and epigenetic abnormalities that arise through the cycle of dedifferentiation of somatic cells to ips cells followed by redifferentiation of ips cells into the desired cell type are avoided (gore 2011; hussein 2011; pera 2011): epigenetic rejuvenation does not require passage through the de-/redifferentiation cycle. second, because the aim of epigenetic rejuvenation is to ensure that the differentiated cell type retains its specialized function it makes redundant the question of transcriptional memory that is inimical to ips cell-based therapies (ohi 2011). third, to produce unrelated cell types using the ips technology takes a long time, around three weeks, whereas epigenetic rejuvenation of old cells will take only a matter of days. epigenetic rejuvenation provides the most safe, rapid and cheap route to successful regenerative medicine. © 2012 the authors. journal compilation © 2012 by the molecular biology society of japan/blackwell publishing ltd.”
Kaspar, D., Hastreiter, S., Irmler, M., Hrabé de Angelis, M., & Beckers, J.. (2020). Nutrition and its role in epigenetic inheritance of obesity and diabetes across generations. Mammalian Genome
Plain numerical DOI: 10.1007/s00335-020-09839-z
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“Nutritional constraints including not only caloric restriction or protein deficiency, but also energy-dense diets affect metabolic health and frequently lead to obesity and insulin resistance, as well as glucose intolerance and type 2 diabetes. the effects of these environmental factors are often mediated via epigenetic modifiers that target the expression of metabolic genes. more recently, it was discovered that such parentally acquired metabolic changes can alter the metabolic health of the filial and grand-filial generations. in mammals, this epigenetic inheritance can either follow an intergenerational or transgenerational mode of inheritance. in the case of intergenerational inheritance, epimutations established in gametes persist through the first round of epigenetic reprogramming occurring during preimplantation development. for transgenerational inheritance, epimutations persist additionally throughout the reprogramming that occurs during germ cell development later in embryogenesis. differentially expressed transcripts, genomic cytosine methylations, and several chemical modifications of histones are prime candidates for tangible marks which may serve as epimutations in inter- and transgenerational inheritance and which are currently being investigated experimentally. we review, here, the current literature in support of epigenetic inheritance of metabolic traits caused by nutritional constraints and potential mechanisms in man and in rodent model systems.”
Montecino, M., Carrasco, M. E., & Nardocci, G.. (2021). Epigenetic Control of Osteogenic Lineage Commitment. Frontiers in Cell and Developmental Biology
Plain numerical DOI: 10.3389/fcell.2020.611197
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“Within the eukaryotic nucleus the genomic dna is organized into chromatin by stably interacting with the histone proteins as well as with several other nuclear components including non-histone proteins and non-coding rnas. together these interactions distribute the genetic material into chromatin subdomains which can exhibit higher and lower compaction levels. this organization contributes to differentially control the access to genomic sequences encoding key regulatory genetic information. in this context, epigenetic mechanisms play a critical role in the regulation of gene expression as they modify the degree of chromatin compaction to facilitate both activation and repression of transcription. among the most studied epigenetic mechanisms we find the methylation of dna, atp-dependent chromatin remodeling, and enzyme-mediated deposition and elimination of post-translational modifications at histone and non-histone proteins. in this mini review, we discuss evidence that supports the role of these epigenetic mechanisms during transcriptional control of osteoblast-related genes. special attention is dedicated to mechanisms of epigenetic control operating at the runx2 and sp7 genes coding for the two principal master regulators of the osteogenic lineage during mesenchymal stem cell commitment.”
Li, A., Hu, B., & Chu, C.. (2021). Epigenetic regulation of nitrogen and phosphorus responses in plants. Journal of Plant Physiology
Plain numerical DOI: 10.1016/j.jplph.2021.153363
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“Nitrogen (n) and phosphorus (p) are two of the most important nutrients for plant growth and crop yields. in the last decade, plenty of studies have revealed the genetic factors and their regulatory networks which are involved in n and/or p uptake and utilization in different model plant species, especially in arabidopsis and rice. however, increasing evidences have shown that epigenetic regulation also plays a vital role in modulating plant responses to nutrient availability. in this review, we make a brief summary of epigenetic regulation including histone modifications, dna methylation, and other chromatin structure alterations in tuning n and p responses. we also give an outlook for future research directions to comprehensively dissect the involvement of epigenetic regulation in modulating nutrient response in plants.”
Carlini, V., Policarpi, C., & Hackett, J. A.. (
2021).
Epigenetic Inheritance is Gated by Naïve Pluripotency and Dppa2.
BioRxiv
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“Environmental factors can trigger cellular responses that propagate across mitosis or even generations. perturbations to the epigenome could underpin such acquired changes, however, the extent and contexts in which modified chromatin states confer heritable memory in mammals is unclear. here we exploit a modular epigenetic editing strategy to establish de novo heterochromatin domains (epialleles) at endogenous loci and track their inheritance in a developmental model. we find that naïve pluripotent phases systematically erase ectopic domains of heterochromatin via active mechanisms, which acts as an intergenerational safeguard against transmission of epialleles. upon lineage specification however, acquired chromatin states can be probabilistically inherited under selectively favourable conditions, including propagation of p53 silencing through in vivo development. using genome-wide crispr screening, we identify the mechanisms that block heritable silencing memory in pluripotent cells, and demonstrate removal of dppa2 unlocks the potential for epigenetic inheritance uncoupled from dna sequence. our study outlines a mechanistic basis for how epigenetic inheritance is restricted in mammals, and reveals genomic- and developmental-contexts in which heritable memory is feasible. ### competing interest statement the authors have declared no competing interest.”
Lyu, J., Li, J. J., Su, J., Peng, F., Chen, Y. E., Ge, X., & Li, W.. (2020). DORGE: Discovery of Oncogenes and tumoR suppressor genes using Genetic and Epigenetic features. Science Advances
Plain numerical DOI: 10.1126/sciadv.aba6784
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“Data-driven discovery of cancer driver genes, including tumor suppressor genes (tsgs) and oncogenes (ogs), is imperative for cancer prevention, diagnosis, and treatment. although epigenetic alterations are important for tumor initiation and progression, most known driver genes were identified based on genetic alterations alone. here, we developed an algorithm, dorge (discovery of oncogenes and tumor suppressor genes using genetic and epigenetic features), to identify tsgs and ogs by integrating comprehensive genetic and epigenetic data. dorge identified histone modifications as strong predictors for tsgs, and it found missense mutations, super enhancers, and methylation differences as strong predictors for ogs. we extensively validated dorge-predicted cancer driver genes using independent functional genomics data. we also found that dorge-predicted dual-functional genes (both tsgs and ogs) are enriched at hubs in protein-protein interaction and drug-gene networks. overall, our study has deepened the understanding of epigenetic mechanisms in tumorigenesis and revealed previously undetected cancer driver genes.”
Tollenaar, M. S., Beijers, R., Garg, E., Nguyen, T. T. T., Lin, D. T. S., MacIsaac, J. L., … de Weerth, C.. (2021). Internalizing symptoms associate with the pace of epigenetic aging in childhood. Biological Psychology
Plain numerical DOI: 10.1016/j.biopsycho.2021.108021
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“Childhood psychiatric symptoms may be associated with advanced biological aging. this study examined whether epigenetic age acceleration (eaa) associates with internalizing and externalizing symptoms that were prospectively collected across childhood in a longitudinal cohort study. at age 6 buccal epithelial cells from 148 children (69 girls) were collected to survey genome-wide dna methylation. eaa was estimated using the horvath clock. internalizing symptoms at ages 2.5 and 4 years significantly predicted higher eaa at age 6, which in turn was significantly associated with internalizing symptoms at ages 6–10 years. similar trends for externalizing symptoms did not reach statistical significance. these findings indicate advanced biological aging in relation to child mental health and may help better identify those at risk for lasting impairments associated with internalizing disorders.”
Kubota, T., & Mochizuki, K.. (2016). Epigenetic effect of environmental factors on autism spectrum disorders. International Journal of Environmental Research and Public Health
Plain numerical DOI: 10.3390/ijerph13050504
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“Both environmental factors and genetic factors are involved in the pathogenesis of autism spectrum disorders (asds). epigenetics, an essential mechanism for gene regulation based on chemical modifications of dna and histone proteins, is also involved in congenital asds. it was recently demonstrated that environmental factors, such as endocrine disrupting chemicals and mental stress in early life, can change epigenetic status and gene expression, and can cause asds. moreover, environmentally induced epigenetic changes are not erased during gametogenesis and are transmitted to subsequent generations, leading to changes in behavior phenotypes. however, epigenetics has a reversible nature since it is based on the addition or removal of chemical residues, and thus the original epigenetic status may be restored. indeed, several antidepressants and anticonvulsants used for mental disorders including asds restore the epigenetic state and gene expression. therefore, further epigenetic understanding of asds is important for the development of new drugs that take advantages of epigenetic reversibility.”
Crevillén, P., Yang, H., Cui, X., Greeff, C., Trick, M., Qiu, Q., … Dean, C.. (2014). Epigenetic reprogramming that prevents transgenerational inheritance of the vernalized state. Nature
Plain numerical DOI: 10.1038/nature13722
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“The reprogramming of epigenetic states in gametes and embryos is essential for correct development in plants and mammals. in plants, the germ line arises from somatic tissues of the flower, necessitating the erasure of chromatin modifications that have accumulated at specific loci during development or in response to external stimuli. if this process occurs inefficiently, it can lead to epigenetic states being inherited from one generation to the next. however, in most cases, accumulated epigenetic modifications are efficiently erased before the next generation. an important example of epigenetic reprogramming in plants is the resetting of the expression of the floral repressor locus flc in arabidopsis thaliana. flc is epigenetically silenced by prolonged cold in a process called vernalization. however, the locus is reactivated before the completion of seed development, ensuring the requirement for vernalization in every generation. in contrast to our detailed understanding of the polycomb-mediated epigenetic silencing induced by vernalization, little is known about the mechanism involved in the reactivation of flc. here we show that a hypomorphic mutation in the jumonji-domain-containing protein elf6 impaired the reactivation of flc in reproductive tissues, leading to the inheritance of a partially vernalized state. elf6 has h3k27me3 demethylase activity, and the mutation reduced this enzymatic activity in planta. consistent with this, in the next generation of mutant plants, h3k27me3 levels at the flc locus stayed higher, and flc expression remained lower, than in the wild type. our data reveal an ancient role for h3k27 demethylation in the reprogramming of epigenetic states in plant and mammalian embryos.”
Raj, K., Szladovits, B., Haghani, A., Zoller, J. A., Li, C. Z., & Horvath, S.. (
2020).
Epigenetic clock and methylation studies in cats.
BioRxiv
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“Human dna methylation profiles have been used successfully to develop highly accurate biomarkers of aging (‘epigenetic clocks’). although these human epigenetic clocks are not immediately applicable to all species of the animal kingdom, the principles underpinning them appear to be conserved even in animals that are evolutionarily far removed from humans. this is exemplified by recent development of epigenetic clocks for mice and other mammalian species. here, we describe epigenetic clocks for the domestic cat (felis catus), based on methylation profiles of cpgs with flanking dna sequences that are highly conserved between multiple mammalian species. methylation levels of these cpgs are measured using a custom-designed infinium array (horvathmammalmethylchip40). from these, we present 3 epigenetic clocks for cats; of which, one applies only to blood samples from cats, while the remaining two dual-species human-cat clocks apply both to cats and humans. as the rate of human epigenetic ageing is associated with a host of health conditions and pathologies, it is expected that these epigenetic clocks for cats would do likewise and possess the potential to be further developed for monitoring feline health as well as being used for identifying and validating anti-aging interventions.”
Jobe, E. M., McQuate, A. L., & Zhao, X.. (2012). Crosstalk among epigenetic pathways regulates neurogenesis. Frontiers in Neuroscience
Plain numerical DOI: 10.3389/fnins.2012.00059
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“The process of neurogenesis includes neural stem cell proliferation, fate specification, young neuron migration, neuronal maturation, and functional integration into existing circuits. although neurogenesis occurs largely during embryonic development, low levels but functionally important neurogenesis persists in restricted regions of the postnatal brain, including the subgranular zone of the dentate gyrus in the hippocampus and the subventricular zone of the lateral ventricles. this review will cover both embryonic and adult neurogenesis with an emphasis on the latter. of the many endogenous mediators of postnatal neurogenesis, epigenetic pathways, such as mediators of dna methylation, chromatin remodeling systems, and non-coding rna modulators, appear to play an integral role. mounting evidence shows that such epigenetic factors form regulatory networks, which govern each step of postnatal neurogenesis. in this review, we explore the emerging roles of epigenetic mechanisms particularly micrornas, element-1 silencing transcription factor/neuron-restrictive silencing factor (rest/nrsf), polycomb proteins, and methyl-cpg bindings proteins, in regulating the entire process of postnatal and adult neurogenesis. we further summarize recent data regarding how the crosstalk among these different epigenetic proteins forms the critical regulatory network that regulates neuronal development. we finally discuss how crosstalk between these pathways may serve to translate environmental cues into control of the neurogenic process. © 2012 jobe, mcquateand zhao.”
Ma, X., Liu, Z., Zhang, Z., Huang, X., & Tang, W.. (2017). Multiple network algorithm for epigenetic modules via the integration of genome-wide DNA methylation and gene expression data. BMC Bioinformatics
Plain numerical DOI: 10.1186/s12859-017-1490-6
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“Background: with the increase in the amount of dna methylation and gene expression data, the epigenetic mechanisms of cancers can be extensively investigate. available methods integrate the dna methylation and gene expression data into a network by specifying the anti-correlation between them. however, the correlation between methylation and expression is usually unknown and difficult to determine. results: to address this issue, we present a novel multiple network framework for epigenetic modules, namely, epigenetic module based on differential networks (emdn) algorithm, by simultaneously analyzing dna methylation and gene expression data. the emdn algorithm prevents the specification of the correlation between methylation and expression. the accuracy of emdn algorithm is more efficient than that of modern approaches. on the basis of the cancer genome atlas (tcga) breast cancer data, we observe that the emdn algorithm can recognize positively and negatively correlated modules and these modules are significantly more enriched in the known pathways than those obtained by other algorithms. these modules can serve as bio-markers to predict breast cancer subtypes by using methylation profiles, where positively and negatively correlated modules are of equal importance in the classification of cancer subtypes. epigenetic modules also estimate the survival time of patients, and this factor is critical for cancer therapy. conclusions: the proposed model and algorithm provide an effective method for the integrative analysis of dna methylation and gene expression. the algorithm is freely available as an r-package at https://github.com/william0701/emdn.”
Rius, M., & Lyko, F.. (2012). Epigenetic cancer therapy: Rationales, targets and drugs. Oncogene
Plain numerical DOI: 10.1038/onc.2011.601
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“The fundamental role of altered epigenetic modification patterns in tumorigenesis establishes epigenetic regulatory enzymes as important targets for cancer therapy. over the past few years, several drugs with an epigenetic activity have received approval for the treatment of cancer patients, which has led to a detailed characterization of their modes of action. the results showed that both established drug classes, the histone deacetylase (hdac) inhibitors and the dna methyltransferase inhibitors, show substantial limitations in their epigenetic specificity. hdac inhibitors are highly specific drugs, but the enzymes have a broad substrate specificity and deacetylate numerous proteins that are not associated with epigenetic regulation. similarly, the induction of global dna demethylation by non-specific inhibition of dna methyltransferases shows pleiotropic effects on epigenetic regulation with no apparent tumor-specificity. second-generation azanucleoside drugs have integrated the knowledge about the cellular uptake and metabolization pathways, but do not show any increased specificity for cancer epigenotypes. as such, the traditional rationale of epigenetic cancer therapy appears to be in need of refinement, as we move from the global inhibition of epigenetic modifications toward the identification and targeting of tumor-specific epigenetic programs. recent studies have identified epigenetic mechanisms that promote self-renewal and developmental plasticity in cancer cells. druggable somatic mutations in the corresponding epigenetic regulators are beginning to be identified and should facilitate the development of epigenetic therapy approaches with improved tumor specificity. © 2012 macmillan publishers limited all rights reserved.”
Martos, S. N., Tang, W. yee, & Wang, Z.. (2015). Elusive inheritance: Transgenerational effects and epigenetic inheritance in human environmental disease. Progress in Biophysics and Molecular Biology
Plain numerical DOI: 10.1016/j.pbiomolbio.2015.02.011
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“Epigenetic mechanisms involving dna methylation, histone modification, histone variants and nucleosome positioning, and noncoding rnas regulate cell-, tissue-, and developmental stage-specific gene expression by influencing chromatin structure and modulating interactions between proteins and dna. epigenetic marks are mitotically inherited in somatic cells and may be altered in response to internal and external stimuli. the idea that environment-induced epigenetic changes in mammals could be inherited through the germline, independent of genetic mechanisms, has stimulated much debate. many experimental models have been designed to interrogate the possibility of transgenerational epigenetic inheritance and provide insight into how environmental exposures influence phenotypes over multiple generations in the absence of any apparent genetic mutation. unexpected molecular evidence has forced us to reevaluate not only our understanding of the plasticity and heritability of epigenetic factors, but of the stability of the genome as well. recent reviews have described the difference between transgenerational and intergenerational effects; the two major epigenetic reprogramming events in the mammalian lifecycle; these two events making transgenerational epigenetic inheritance of environment-induced perturbations rare, if at all possible, in mammals; and mechanisms of transgenerational epigenetic inheritance in non-mammalian eukaryotic organisms. this paper briefly introduces these topics and mainly focuses on (1) transgenerational phenotypes and epigenetic effects in mammals, (2) environment-induced intergenerational epigenetic effects, and (3) the inherent difficulties in establishing a role for epigenetic inheritance in human environmental disease.”
Springer, N. M., & Schmitz, R. J.. (2017). Exploiting induced and natural epigenetic variation for crop improvement. Nature Reviews Genetics
Plain numerical DOI: 10.1038/nrg.2017.45
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“Plant breeding has traditionally relied on combining the genetic diversity present within a species to develop combinations of alleles that provide desired traits. epigenetic diversity may provide additional sources of variation within a species that could be captured or created for crop improvement. it will be important to understand the sources of epigenetic variation and the stability of newly formed epigenetic variants over generations to fully use the potential of epigenetic variation to improve crops. the development and application of methods for widespread epigenome profiling and engineering may generate new avenues for using the full potential of epigenetics in crop improvement.”
Brzeziańska, E., Dutkowska, A., & Antczak, A.. (2013). The significance of epigenetic alterations in lung carcinogenesis. Molecular Biology Reports
Plain numerical DOI: 10.1007/s11033-012-2063-4
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“Lung cancer is recognized as a leading cause of cancer-related death worldwide and its frequency is still increasing. the prognosis in lung cancer is poor and limited by the difficulties of diagnosis at early stage of disease, when it is amenable to surgery treatment. therefore, the advance in identification of lung cancer genetic and epigenetic markers with diagnostic and/or prognostic values becomes an important tool for future molecular oncology and personalized therapy. as in case of other tumors, aberrant epigenetic landscape has been documented also in lung cancer, both at early and late stage of carcinogenesis. hypermethylation of specific genes, mainly tumor suppressor genes, as well as hypomethylation of oncogenes and retrotransposons, associated with histopathological subtypes of lung cancer, has been found. epigenetic aberrations of histone proteins and, especially, the lower global levels of histone modifications have been associated with poorer clinical outcome in lung cancer. the recently discovered role of epigenetic modifications of microrna expression in tumors has been also proven in lung carcinogenesis. the identified epigenetic events in lung cancer contribute to its specific epigenotype and correlated phenotypic features. so far, some of them have been suggested to be cancer biomarkers for early detection, disease monitoring, prognosis, and risk assessment. as epigenetic aberrations are reversible, their correction has emerged as a promising therapeutic target. © 2012 the author(s).”
Villagra, C., & Frías-Lasserre, D.. (2020). Epigenetic Molecular Mechanisms in Insects. Neotropical Entomology
Plain numerical DOI: 10.1007/s13744-020-00777-8
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“Insects are the largest animal group on earth both in biomass and diversity. their outstanding success has inspired genetics and developmental research, allowing the discovery of dynamic process explaining extreme phenotypic plasticity and canalization. epigenetic molecular mechanisms (emms) are vital for several housekeeping functions in multicellular organisms, regulating developmental, ontogenetic trajectories and environmental adaptations. in insecta, emms are involved in the development of extreme phenotypic divergences such as polyphenisms and eusocial castes. here, we review the history of this research field and how the main emms found in insects help to understand their biological processes and diversity. emms in insects confer them rapid response capacity allowing insect either to change with plastic divergence or to keep constant when facing different stressors or stimuli. emms function both at intra as well as transgenerational scales, playing important roles in insect ecology and evolution. we discuss on how emms pervasive influences in insecta require not only the control of gene expression but also the dynamic interplay of emms with further regulatory levels, including genetic, physiological, behavioral, and environmental among others, as was earlier proposed by the probabilistic epigenesis model and developmental system theory.”
Bhat, M. I., & Kapila, R.. (2017). Dietary metabolites derived from gut microbiota: Critical modulators of epigenetic changes in mammals. Nutrition Reviews
Plain numerical DOI: 10.1093/nutrit/nux001
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“The mammalian gastrointestinal tract harbors trillions of commensal microorganisms, collectively known as the microbiota. the microbiota is a critical source of environmental stimuli and, thus, has a tremendous impact on the health of the host. the microbes within the microbiota regulate homeostasis within the gut, and any alteration in their composition can lead to disorders that include inflammatory bowel disease, allergy, autoimmune disease, diabetes, mental disorders, and cancer. hence, restoration of the gut flora following changes or imbalance is imperative for the host. the low-molecular-weight compounds and nutrients such as short-chain fatty acids, polyamines, polyphenols, and vitamins produced by microbial metabolism of nondigestible food components in the gut actively participate in various epigenomic mechanisms that reprogram the genome by altering the transcriptional machinery of a cell in response to environmental stimuli. these epigenetic modifications are caused by a set of highly dynamic enzymes, notably histone acetylases, deacetylases, dna methylases, and demethylases, that are influenced by microbial metabolites and other environmental cues. recent studies have shown that host expression of histone acetylases and histone deacetylases is important for regulating communication between the intestinal microbiota and the host cells. histone acetylases and deacetylases influence the molecular expression of genes that affect not only physiological functions but also behavioral shifts that occur via neuroepigenetic modifications of genes. the underlying molecular mechanisms, however, have yet to be fully elucidated and thus provide a new area of research. the present review provides insights into the current understanding of the microbiota and its association with mammalian epigenomics as well as the interaction of pathogens and probiotics with host epigenetic machinery.”
Herrera, C. M., & Bazaga, P.. (2016). Genetic and epigenetic divergence between disturbed and undisturbed subpopulations of a Mediterranean shrub: A 20-year field experiment. Ecology and Evolution
Plain numerical DOI: 10.1002/ece3.2161
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“Little is known on the potential of ecological disturbance to cause genetic and epigenetic changes in plant populations. we take advantage of a long-term field experiment initiated in 1986 to study the demography of the shrub lavandula latifolia, and compare genetic and epigenetic characteristics of plants in two adjacent subplots, one experimentally disturbed and one left undisturbed, 20 years after disturbance. experimental setup was comparable to an unreplicated ‘Before-after-control-impact’ (baci) design where a single pair of perturbed and control areas were compared. when sampled in 2005, plants in the two subplots had roughly similar ages, but they had established in contrasting environments: dense conspecific population (‘undisturbed’ subpopulation) versus open area with all conspecifics removed (‘disturbed’ subpopulation). plants were characterized genetically and epigenetically using amplified fragment length polymorphism (aflp) and two classes of methylation-sensitive aflp (msap) markers. subpopulations were similar in genetic diversity but differed in epigenetic diversity and multilocus genetic and epigenetic characteristics. epigenetic divergence between subpopulations was statistically unrelated to genetic divergence. bayesian clustering revealed an abrupt linear boundary between subpopulations closely coincident with the arbitrary demarcation line between subplots drawn 20 years back, which supports that genetic and epigenetic divergence between subpopulations was caused by artificial disturbance. there was significant fine-scale spatial structuring of msap markers in both subpopulations, which in the undisturbed one was indistinguishable from that of aflp markers. genetic differences between subpopulations could be explained by divergent selection alone, while the concerted action of divergent selection and disturbance-driven appearance of new methylation variants in the disturbed subpopulation is proposed to explain epigenetic differences. this study provides the first empirical evidence to date suggesting that relatively mild disturbances could leave genetic and epigenetic signatures on the next adult generation of long-lived plants.”
Rahman, M. M., Brane, A. C., & Tollefsbol, T. O.. (2019). MicroRNAs and Epigenetics Strategies to Reverse Breast Cancer. Cells
Plain numerical DOI: 10.3390/cells8101214
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“Breast cancer is a sporadic disease with genetic and epigenetic components. genomic instability in breast cancer leads to mutations, copy number variations, and genetic rearrangements, while epigenetic remodeling involves alteration by dna methylation, histone modification and micrornas (mirnas) of gene expression profiles. the accrued scientific findings strongly suggest epigenetic dysregulation in breast cancer pathogenesis though genomic instability is central to breast cancer hallmarks. being reversible and plastic, epigenetic processes appear more amenable toward therapeutic intervention than the more unidirectional genetic alterations. in this review, we discuss the epigenetic reprogramming associated with breast cancer such as shuffling of dna methylation, histone acetylation, histone methylation, and mirnas expression profiles. as part of this, we illustrate how epigenetic instability orchestrates the attainment of cancer hallmarks which stimulate the neoplastic transformation-tumorigenesis-malignancy cascades. as reversibility of epigenetic controls is a promising feature to optimize for devising novel therapeutic approaches, we also focus on the strategies for restoring the epistate that favor improved disease outcome and therapeutic intervention.”
Vasantharajan, S. S., Eccles, M. R., Rodger, E. J., Pattison, S., McCall, J. L., Gray, E. S., … Chatterjee, A.. (2021). The Epigenetic landscape of Circulating tumour cells. Biochimica et Biophysica Acta – Reviews on Cancer
Plain numerical DOI: 10.1016/j.bbcan.2021.188514
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“Cancer metastasis is the main reason for the high mortality in patients, contributing to 90% of cancer-related deaths. biomarkers for early detection and therapeutic monitoring are essential to improve cancer outcomes. circulating tumour cells (ctcs) arise from solid tumours and are capable of metastatic dissemination via the bloodstream or lymphatic system. thus, ctcs can potentially be developed as a minimally invasive biomarker for early detection and therapeutic monitoring. despite its clinical potential, research on ctcs remains limited, and this is likely due to their low numbers, short half-life, and the lack of robust methods for their isolation. there is also a need for molecular characterisation of ctcs to identify tumour-specific features, such as epigenetic signatures of metastasis. this review provides an overview of the epigenetic landscape of ctcs. we discuss the role of epigenetic modifications in ctc dissemination,metastatic tumour formation and progression and highlight its clinical implications”
Klomp, M. J., Dalm, S. U., de Jong, M., Feelders, R. A., Hofland, J., & Hofland, L. J.. (2020). Epigenetic regulation of somatostatin and somatostatin receptors in neuroendocrine tumors and other types of cancer. Reviews in Endocrine and Metabolic Disorders
Plain numerical DOI: 10.1007/s11154-020-09607-z
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“Both somatostatin (sst) and somatostatin receptors (sstrs) are proteins with important functions in both physiological tissue and in tumors, particularly in neuroendocrine tumors (nets). nets are frequently characterized by high sstrs expression levels. sst analogues (ssas) that bind and activate sstr have anti-proliferative and anti-secretory activity, thereby reducing both the growth as well as the hormonal symptoms of nets. moreover, the high expression levels of sstr type-2 (sstr2) in nets is a powerful target for therapy with radiolabeled ssas. due to the important role of both sst and sstrs, it is of great importance to elucidate the mechanisms involved in regulating their expression in nets, as well as in other types of tumors. the field of epigenetics recently gained interest in net research, highlighting the importance of this process in regulating the expression of gene and protein expression. in this review we will discuss the role of the epigenetic machinery in controlling the expression of both sstrs and the neuropeptide sst. particular attention will be given to the epigenetic regulation of these proteins in nets, whereas the involvement of the epigenetic machinery in other types of cancer will be discussed as well. in addition, we will discuss the possibility to target enzymes involved in the epigenetic machinery to modify the expression of the sst-system, thereby possibly improving therapeutic options.”
Liu, H., & Zhao, H.. (2019). Prognosis related miRNAs, DNA methylation, and epigenetic interactions in lung adenocarcinoma. Neoplasma
Plain numerical DOI: 10.4149/neo_2018_181029N805
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“Our study aimed to identify prognosis related epigenetic interactions of dna methylation-mirna-gene in lung adenocarcinoma. the rna-seq, dna methylation and mirna-seq data of squamous cell cancer samples were downloaded from tcga. the dna methylation-mirna-gene interactions were collected via illumina methylation platform and mirtar-base database. linear regression model was utilized for the identification of epigenetic interactions. the epigenetic interactions related to prognosis were selected via kaplan-meier analysis. genes in the interactions were used for pathway enrichment. differentially expressed genes (degs) between high methylation level/high mirna expression level (h/h) and low methylation level/low mirna expression level (l/l) samples were screened. the correlations of epigenetic interactions with clinical features were also explored. total of 454 lung adenocarcinoma patient samples were collected. the 1063 interactions were comprised of 1083 dna methylation probes, 271 mirnas and 528 genes, including cg14146378-hsa-mir-205-arid1b, cg15375596-has-mir-1275-igf1r, cg26691953-hsa-mir-195-ccnt1, etc. a total of 95 epigenetic interactions were significantly associated with prognosis. among all the identified degs, low-expressed rassf4, znf704, tfdp1, plxnb2, tmc04, znf878, aridib and high-expressed znf704, znf451, thop1, igf1r were related with poor prognosis, while low-expressed ldhb, arid2, prkcsh, hdac4, nipa1, rabac1, trim28 and high-expressed fam160b1, dnaaf3, ccnt1, adap1, zfpm1, ccl11 were related with good prognosis. fifteen epigenetic interactions were significantly related with clinical features. gene expression and n-glycan trimming in the er and calnexin/calre-ticulin cycle were two significant enriched pathways. interactions of cg14146378-hsa-mir-205-arid1b and cg15375596-has-mir-1275-igf1r may be used as prognosis indicators in lung adenocarcinoma.”
Lee, H. S., & Park, T.. (2020). The influences of DNA methylation and epigenetic clocks, on metabolic disease, in middle-aged Koreans. Clinical Epigenetics
Plain numerical DOI: 10.1186/s13148-020-00936-z
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“Background: considering that dna methylation (dnam) profiles are, in large part, modifiable by lifestyle and environmental influences, it has been proposed that epigenetic clocks provide a better estimate of biological age than chronological age, as associated with current health status. even though metabolic diseases induce precocious aging, little is known about associations between metabolic syndrome (mets) and dna methylation clocks, and stochastic epigenetic mutations (sems), in a korean population. therefore, we assessed four different epigenetic clocks (pan-tissue, hannum, phenoage, and grimage), and their accelerations, on mets and mets-related lifestyle factors, in koreans. we measured genome-wide dna methylation (485,512 cpgs), using an illumina 450 methylation beadchip array, with data from 349 blood samples. results: dnam grimage strongly correlated with chronological age (r = 0.77, p < 0.001) compared to the other three epigenetic clocks and sems. dnam-based surrogate markers, with regard to mets, including the gene encoding plasminogen activator inhibitor-1 (pai1), also correlated with chronological age. within cohorts stratified by age group, sex, regional area, smoking, and alcohol drinking, a positive correlation was observed between dnam grimage and chronological age (0.43 ≤ r ≤ 0.78). in particular, we identified mets to associate with accelerated grimage, and age-adjusted pai1, in the middle-age group. accerelated grimage also associated with risk of mets in the middle-age group (odds ratio = 1.16, p = 0.046), which appears to mediate their associations with fasting glucose. multiple linear regression showed that dnam grimage, and its acceleration, associate with mets scores, in the middle-age group (r = 0.26, p = 0.006). age-adjusted pai1 was also significantly different between the mets and control groups, and further associated with mets scores (r = 0.31, p < 0.001), in the middle age group. conclusion: dnam grimage is a surrogate marker for mets, and its component score, in koreans. this association can be observed only in middle age. therefore, appropriate dna methylation clocks may aid in the prediction of korean metabolic diseases.”
Eslaminejad, M. B., Fani, N., & Shahhoseini, M.. (
2013).
Epigenetic regulation of osteogenic and chondrogenic differentiation of mesenchymal stem cells in culture.
Cell Journal
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“Management of mesenchymal stem cells (mscs) capabilities to differentiate in to osteogenic and chondrogenic lineages would be of utmost importance for their future use in difficult to treat cases of destroyed bone and cartilage. thus, an understanding of the epigenetic mechanisms as important modulators of stem cell differentiation might be useful. epigenetic mechanism refers to a process that regulates heritable and long-lasting alterations in gene expression without changing the dna sequence. such stable changes would be mediated by several mechanisms including dna methylation and histone modifications. the involvement of epigenetic mechanisms during msc bone and cartilage differentiation has been investigated during the past decade. the purpose of this review is to cover outstanding research works that have attempted to ascertain the underlying epigenetic changes of the nuclear genome during in vitro differentiation of mscs into bone and cartilage cell lineages. understanding such genomic alterations may assist scientists to develop and recognize reagents that are able to efficiently promote this cellular differentiation. before summarizing the progress on epigenetic regulation of msc bone and cartilage differentiation, a brief description will be given regarding in vitro conditions that favor msc osteocytic and chondrocytic differentiation and the main mechanisms responsible for epigenetic regulation of differentiation.”
Stener-Victorin, E.. (2020). Epigenetic and transgenerational transmission of polycystic ovary syndrome. Current Opinion in Endocrine and Metabolic Research
Plain numerical DOI: 10.1016/j.coemr.2020.03.005
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“Polycystic ovary syndrome (pcos) is the leading cause of reproductive and metabolic disorders among women worldwide. although pcos is also linked to several comorbidities including insulin resistance, type 2 diabetes, and psychiatric disease, the etiology remains unclear. evidence suggests the impact of genetic, intrauterine and environmental factors, as well as epigenetic mechanisms. although the inheritance of pcos is unclear, studies indicate that it runs in families. this narrative review gives an overview of the inheritance and epigenetic mechanisms in pcos, as well as discussion as to whether a pcos phenotype can be transmitted to subsequent generations and possible mechanisms of such transmission.”
Sundaram, M. K., Unni, S., Somvanshi, P., Bhardwaj, T., Mandal, R. K., Hussain, A., & Haque, S.. (2019). Genistein modulates signaling pathways and targets several epigenetic markers in hela cells. Genes
Plain numerical DOI: 10.3390/genes10120955
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“Background: several epigenetic changes are responsible for transcriptional alterations of signaling pathways and tumour suppressor genes (tsgs) contributing to carcinogenesis. this study was aimed to examine the effect of the phytochemical, genistein on various molecular targets in hela cells. methods: quantitative pcr was used to analyze the expression of various molecular targets. biochemical assays were employed to study the epigenetic enzymes. to correlate the transcriptional status of the selected tsgs and epigenetic modulation, their promoter 5’Cpg methylation levels were evaluated by quantitative methylation array followed by methylation specific restriction digestion. results: the expression of several genes involved in the cell cycle regulation, migration, inflammation, phosphatidylinositol 3-kinase (pi3k) and mitogen activated kinase-like protein (mapk) pathway were found to be modulated including ccnb1, twist1, mmp14, tert, akt1, ptprr, fos and il1a. genistein modulated the expression of dna methyltransferases (dnmts), histone deacetylases (hdacs), histone methyltransferases (hmts), demethylases, and histone phosphorylases. furthermore, genistein decreased the activity of dnmts, hdacs, and hmts and reduced global dna methylation levels. promoter methylation of several tsgs, including fhit, runx3, cdh1, pten, and soc51, was lowered with corresponding transcriptional increase. network analysis indicated similar effect of genistein. conclusion: this study presents a comprehensive mechanism of action of genistein showcasing effective epigenetic modulation and widespread transcriptional changes resulting in restoration of tumour suppressor gene expression. this study corroborates the development of genistein as a candidate for anti-cancer therapy.”
Wu, X., Ye, J., Wang, Z., & Zhao, C.. (2021). Epigenetic Age Acceleration Was Delayed in Schizophrenia. Schizophrenia Bulletin
Plain numerical DOI: 10.1093/schbul/sbaa164
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“Schizophrenia is a serious neuropsychiatric disorder with abnormal age-related neurodevelopmental (or neurodegenerative) trajectories. although an accelerated aging hypothesis of schizophrenia has been proposed, the quantitative study of the disruption of the physiological trajectory caused by schizophrenia is inconclusive. in this study, we employed 3 ‘epigenetic clock’methods to quantify the epigenetic age of a large sample size of whole blood (1069 samples from patients with schizophrenia vs 1264 samples from unaffected controls) and brain tissues (500 samples from patients with schizophrenia vs 711 samples from unaffected controls). we observed significant positive correlations between epigenetic age and chronological age in both blood and brain tissues from unaffected controls and patients with schizophrenia, as estimated by 3 methods. furthermore, we observed that epigenetic age acceleration was significantly delayed in schizophrenia from the whole blood samples (aged 20-90 years) and brain frontal cortex tissues (aged 20-39 years). intriguingly, the genes regulated by the epigenetic clock also contained schizophrenia-associated genes, displaying differential expression and methylation in patients with schizophrenia and involving in the regulation of cell activation and development. these findings were further supported by the dysregulated leukocyte composition in patients with schizophrenia. our study presents quantitative evidence for a neurodevelopmental model of schizophrenia from the perspective of a skewed ‘epigenetic clock.’moreover, landmark changes in an easily accessible biological sample, blood, reveal the value of these epigenetic clock genes as peripheral biomarkers for schizophrenia.”
Pham, T. X., & Lee, J. Y.. (2017). Epigenetic regulation of adipokines. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms18081740
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“Adipose tissue expansion in obesity leads to changes in the expression of adipokines, adipocyte-specific hormones that can regulate whole body energy metabolism. epigenetic regulation of gene expression is a mechanism by which cells can alter gene expression through the modifications of dna and histones. epigenetic mechanisms, such as dna methylation and histone modifications, are intimately tied to energy metabolism due to their dependence on metabolic intermediates such as s-adenosylmethionine and acetyl-coa. altered expression of adipokines in obesity may be due to epigenetic changes. the goal of this review is to highlight current knowledge of epigenetic regulation of adipokines.”
Rando, O. J., & Verstrepen, K. J.. (2007). Timescales of Genetic and Epigenetic Inheritance. Cell
Plain numerical DOI: 10.1016/j.cell.2007.01.023
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“According to classical evolutionary theory, phenotypic variation originates from random mutations that are independent of selective pressure. however, recent findings suggest that organisms have evolved mechanisms to influence the timing or genomic location of heritable variability. hypervariable contingency loci and epigenetic switches increase the variability of specific phenotypes; error-prone dna replicases produce bursts of variability in times of stress. interestingly, these mechanisms seem to tune the variability of a given phenotype to match the variability of the acting selective pressure. although these observations do not undermine darwin’s theory, they suggest that selection and variability are less independent than once thought. © 2007 elsevier inc. all rights reserved.”
Faam, B., Ali Ghaffari, M., Ghadiri, A., & Azizi, F.. (2015). Epigenetic modifications in human thyroid cancer (review). Biomedical Reports
Plain numerical DOI: 10.3892/br.2014.375
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“Thyroid carcinoma is the most common endocrine malignancy of the endocrine organs, and its incidence rate has steadily increased over the last decade. over 95% of thyroid carcinoma is derived from follicular cells that have a spectrum of differentiation to the most invasive malignancy. the molecular pathogenesis of thyroid cancer remains to be clarified, although activating the ret, ras and braf oncogenes have been well characterized. increasing evidence from previous studies demonstrates that acquired epigenetic abnormalities participating with genetic alteration results in altered patterns of gene expression/function. aberrant dna methylation has been established in the cpg regions and micrornas (mirnas) expression profile recognized in cancer development. in the present review, a literature review was performed using medline and pubmed with the terms ‘epigenetic patterns in thyroid cancer [or papillary thyroid carcinoma (ptc), follicular thyroid carcinoma (ftc), medullary thyroid cancer (mtc), anaplastic thyroid cancer (atc)]’, ‘dna methylation in thyroid cancer (or ptc, ftc, mtc, atc)’, ‘mirna expression in thyroid cancer (or ptc, ftc, mtc, atc)’, ‘epigenetic patterns in cancer’ and the current understanding of epigenetic patterns in thyroid cancer was discussed.”
Henderson, I. R., & Jacobsen, S. E.. (2007). Epigenetic inheritance in plants. Nature
Plain numerical DOI: 10.1038/nature05917
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“The function of plant genomes depends on chromatin marks such as the methylation of dna and the post-translational modification of histones. techniques for studying model plants such as arabidopsis thaliana have enabled researchers to begin to uncover the pathways that establish and maintain chromatin modifications, and genomic studies are allowing the mapping of modifications such as dna methylation on a genome-wide scale. small rnas seem to be important in determining the distribution of chromatin modifications, and rna might also underlie the complex epigenetic interactions that occur between homologous sequences. plants use these epigenetic silencing mechanisms extensively to control development and parent-of-origin imprinted gene expression. ©2007 nature publishing group.”
Rusk, N.. (2019). Creating epigenetic memory. Nature Methods
Plain numerical DOI: 10.1038/s41592-019-0312-3
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“A three-component system of epigenetic writers and readers preserves memory over many generations of cells.”
Gu, H. F.. (2019). Genetic and epigenetic studies in diabetic kidney disease. Frontiers in Genetics
Plain numerical DOI: 10.3389/fgene.2019.00507
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“Chronic kidney disease is a worldwide health crisis, while diabetic kidney disease (dkd) has become the leading cause of end-stage renal disease (esrd). dkd is a microvascular complication and occurs in 30-40% of diabetes patients. epidemiological investigations and clinical observations on the familial clustering and heritability in dkd have highlighted an underlying genetic susceptibility. furthermore, dkd is a progressive and long-term diabetic complication, in which epigenetic effects and environmental factors interact with an individual’s genetic background. in recent years, researchers have undertaken genetic and epigenetic studies of dkd in order to better understand its molecular mechanisms. in this review, clinical material, research approaches and experimental designs that have been used for genetic and epigenetic studies of dkd are described. current information from genetic and epigenetic studies of dkd and esrd in patients with diabetes, including the approaches of genome-wide association study (gwas) or epigenome-wide association study (ewas) and candidate gene association analyses, are summarized. further investigation of molecular defects in dkd with new approaches such as next generation sequencing analysis and phenome-wide association study (phewas) is also discussed.”
Nojadeh, J. N., & Daghghagh, H.. (2016). Change of epigenetic modification and human reproduction. Asian Pacific Journal of Reproduction
Plain numerical DOI: 10.1016/j.apjr.2015.12.002
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“In recent years, it has become consumedly clear that changing of epigenetic modification is essential during both early and late oogenesis and spermatogenesis. also epigenetic modifications are involved in some cases such as embryo development and growth, diseases and responsible for x-chromosome inactivation and genomic imprinting. epigenetic reprogramming can be explained as any mitotic or meiotic changing which does not result any alteration in dna sequence but will have important effect on the normal embryonic development. germline epigenetic reprogramming in addition to requiring epigenetic modification to compose the germline, the primordial germ cells uniquely undergo striking wave of epigenetic reprogramming that most other lineage do not undergo. epigenetic modification is affected by both internal factors and environmental factors during pre- and post-natal development. because all of the epigenetic modification steps are not clear, by means of understanding epigenetic modification, misreprogramming of these steps can be modified with the aid of drugs and nutrients. moreover, epigenetic regulation is essential to obtain the biological intricacy of multicellular organisms, cloning and producing of offspring by assisted reproductive technology (art).the objective of this review is to provide comprehensive summary of the current knowledge in the field of epigenetic modification in relation to male and female germline development and reproduction.”
Maleszewska, M., & Kaminska, B.. (2013). Is glioblastoma an epigenetic malignancy?. Cancers
Plain numerical DOI: 10.3390/cancers5031120
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“Epigenetic modifications control gene expression by regulating the access of nuclear proteins to their target dna and have been implicated in both normal cell differentiation and oncogenic transformation. epigenetic abnormalities can occur both as a cause and as a consequence of cancer. oncogenic transformation can deeply alter the epigenetic information enclosed in the pattern of dna methylation or histone modifications. in addition, in some cancers epigenetic dysfunctions can drive oncogenic transformation. growing evidence emphasizes the interplay between metabolic disturbances, epigenomic changes and cancer, i.e., mutations in the metabolic enzymes sdh, fh, and idh may contribute to cancer development. epigenetic-based mechanisms are reversible and the possibility of -resetting{norm of matrix} the abnormal cancer epigenome by applying pharmacological or genetic strategies is an attractive, novel approach. gliomas are incurable with all current therapeutic approaches and new strategies are urgently needed. increasing evidence suggests the role of epigenetic events in development and/or progression of gliomas. in this review, we summarize current data on the occurrence and significance of mutations in the epigenetic and metabolic enzymes in pathobiology of gliomas. we discuss emerging therapies targeting specific epigenetic modifications or chromatin modifying enzymes either alone or in combination with other treatment regimens. © 2013 by the authors; licensee mdpi, basel, switzerland.”
Creighton, S. D., Stefanelli, G., Reda, A., & Zovkic, I. B.. (2020). Epigenetic mechanisms of learning and memory: Implications for aging. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms21186918
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“The neuronal epigenome is highly sensitive to external events and its function is vital for producing stable behavioral outcomes, such as the formation of long-lasting memories. the importance of epigenetic regulation in memory is now well established and growing evidence points to altered epigenome function in the aging brain as a contributing factor to age-related memory decline. in this review, we first summarize the typical role of epigenetic factors in memory processing in a healthy young brain, then discuss the aspects of this system that are altered with aging. there is general agreement that many epigenetic marks are modified with aging, but there are still substantial inconsistencies in the precise nature of these changes and their link with memory decline. here, we discuss the potential source of age-related changes in the epigenome and their implications for therapeutic intervention in age-related cognitive decline.”
Furuya, K., Ikura, M., & Ikura, T.. (2019). Epigenetic interplays between DNA demethylation and histone methylation for protecting oncogenesis. Journal of Biochemistry
Plain numerical DOI: 10.1093/jb/mvy124
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“Epigenetic systems are organized by different types of modifications on histones and dna. to determine how epigenetic systems can produce variable, yet stable cellular outcomes, understanding the collaboration between these modifications is the key. a recent study by yamagata and kobayashi revealed the direct interplay between the regulation of two epigenetic modifications: dna de-methylation by tet2 and histone h3-k36 methylation. mechanistically, this finding could explain how cells are protected from oncogenesis by maintaining the integrity of active transcription. the recent identification of epigenetic modifier mutations in leukaemia suggested that it is not just the turning â € on’ and â € off’ of particular transcriptional events that causes disease occurrence, but rather it is the aberration in epigenetic regulation, i.e. the timing and duration of the activation/inactivation of these transcripts. thus, a comprehensive understanding of how epigenetic interplays tune transcription will be the new perspective for disease research.”
Descalzi, G., Ikegami, D., Ushijima, T., Nestler, E. J., Zachariou, V., & Narita, M.. (2015). Epigenetic mechanisms of chronic pain. Trends in Neurosciences
Plain numerical DOI: 10.1016/j.tins.2015.02.001
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“Neuropathic and inflammatory pain promote a large number of persisting adaptations at the cellular and molecular level, allowing even transient tissue or nerve damage to elicit changes in cells that contribute to the development of chronic pain and associated symptoms. there is evidence that injury-induced changes in chromatin structure drive stable changes in gene expression and neural function, which may cause several symptoms, including allodynia, hyperalgesia, anxiety, and depression. recent findings on epigenetic changes in the spinal cord and brain during chronic pain may guide fundamental advances in new treatments. here, we provide a brief overview of epigenetic regulation in the nervous system and then discuss the still-limited literature that directly implicates epigenetic modifications in chronic pain syndromes.”
Loison, L.. (2018). Lamarckism and epigenetic inheritance: a clarification. Biology and Philosophy
Plain numerical DOI: 10.1007/s10539-018-9642-2
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“Since the 1990s, the terms ‘lamarckism’ and ‘lamarckian’ have seen a significant resurgence in biological publications. the discovery of new molecular mechanisms (dna methylation, histone modifications, rna interference, etc.) have been interpreted as evidence supporting the reality and efficiency of the inheritance of acquired characters, and thus the revival of lamarckism. the present paper aims at giving a critical evaluation of such interpretations. i argue that two types of arguments allow to draw a clear distinction between the genuine lamarckian concept of inheritance of acquired characters and transgenerational epigenetic inheritance. the first concerns the explanandum of the processes under consideration: molecular mechanisms of transgenerational epigenetic inheritance are understood as evolved products of natural selection. this means that the kind of inheritance of acquired characters they might be responsible for is an obligatory emergent feature of evolution, whereas traditional lamarckisms conceived the inheritance of acquired characters as a property inherent in living matter itself. the second argument concerns the explanans of the inheritance of acquired characters: in light of current knowledge, epigenetic mechanisms are not able to drive adaptive evolution by themselves. emergent lamarckian phenomena would be possible if and only if individual epigenetic variation allowed the inheritance of acquired characters to be a factor of unlimited change. this implies specific requirements for epigenetic variation, which i explicitly define and expand upon. i then show that given current knowledge, these requirements are not empirically grounded.”
Wilson, C. L., Mann, D. A., & Borthwick, L. A.. (2017). Epigenetic reprogramming in liver fibrosis and cancer. Advanced Drug Delivery Reviews
Plain numerical DOI: 10.1016/j.addr.2017.10.011
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“Novel insights into the epigenetic control of chronic liver diseases are now emerging. recent advances in our understanding of the critical roles of dna methylation, histone modifications and ncrna may now be exploited to improve management of fibrosis/cirrhosis and cancer. furthermore, improved technologies for the detection of epigenetic markers from patients’ blood and tissues will vastly improve diagnosis, treatment options and prognostic tracking. the aim of this review is to present recent findings from the field of liver epigenetics and to explore their potential for translation into therapeutics to prevent disease promoting epigenome reprogramming and reverse epigenetic changes.”
Lavebratt, C., Almgren, M., & Ekström, T. J.. (2012). Epigenetic regulation in obesity. International Journal of Obesity
Plain numerical DOI: 10.1038/ijo.2011.178
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“The availability to the dna strand and the activity of the transcription machinery is crucial for the cell to use the information in the dna. the epigenetic mechanisms dna methylation, modification of histone tails, other chromatin-modifying processes and interference by small rnas regulate the cell-type-specific dna expression. epigenetic marks can be more or less plastic perpetuating responses to various molecular signals and environmental stimuli, but in addition apparently stochastic epigenetic marks have been found. there is substantial evidence from animal and man demonstrating that both transient and more long-term epigenetic mechanisms have a role in the regulation of the molecular events governing adipogenesis and glucose homeostasis. intrauterine exposure such as poor maternal nutrition has consistently been demonstrated to contribute to a particular epigenotype and thereby developmental metabolic priming of the exposed offspring in animal and man. epigenetic modifications can be passed not only from one cell generation to the next, but metabolic disease-related epigenotypes have been proposed to also be transmitted germ-line. future more comprehensive knowledge on epigenetic regulation will complement genome sequence data for the understanding of the complex etiology of obesity and related disorder. © 2012 macmillan publishers limited all rights reserved.”
Sharavanan, V. J., Sivaramakrishnan, M., Sivarajasekar, N., Senthilrani, N., Kothandan, R., Dhakal, N., … Naushad, M.. (2020). Pollutants inducing epigenetic changes and diseases. Environmental Chemistry Letters
Plain numerical DOI: 10.1007/s10311-019-00944-3
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“Pollution is a major issue impacting the health of life and ecosystems. in particular, some pollutants may alter gene expression by epigenetic mechanisms such as deoxyribonucleic acid (dna) methylation, histone modifications, and microrna (mirna) expression. epigenetics is the study of heritable changes without alteration in the dna sequence. in the healthy state, the coordinated actions of interconnected epigenetic factors are responsible for proper cell development and cell regulation. epigenetic mechanisms are tissue-specific; hence, a pollutant may or may not cause an alteration depending on the type of tissue. here we review mechanisms by which pollutants disrupt epigenetic factors. we focus on the impact of arsenic, cadmium, nickel, mercury, benzene, bisphenol a, dioxin, hexahydro-1,3,5-trinitro-1,3,5-triazine and diethylstilbestrol. a list of diseases related to epigenetic factors and heavy metals exposure is provided.”
Jeong, H. M., Kwon, M. J., & Shin, Y. K.. (2014). Overexpression of cancer-associated genes via epigenetic derepression mechanisms in gynecologic cancer. Frontiers in Oncology
Plain numerical DOI: 10.3389/fonc.2014.00012
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“Like other cancers, most gynecologic cancers are caused by aberrant expression of cancer-related genes. epigenetics is one of the most important gene expression mechanisms, which contribute to cancer development and progression by regulating cancer-related genes. since the discovery of differential gene expression patterns in cancer cells when compared with normal cells, extensive efforts have been made to explore the origins of abnormal gene expression in cancer. epigenetics, the study of inheritable changes in gene expression that do not alter dna sequence is a key area of this research. dna methylation and histone modification are well-known epigenetic mechanisms, while micrornas and alternative splicing have recently been identified as important regulators of epigenetic mechanisms. these mechanisms not only affect specific target gene expression but also regulate the functioning of other epigenetic mechanisms. moreover, these diverse epigenetic regulations occur simultaneously. epigenetic regulation of gene expression is extraordinarily complicated and all epigenetic mechanisms to be studied at once to determine the exact gene regulation mechanisms. traditionally, the contribution of epigenetics to cancer is thought to be mediated through the inactivation of tumor suppressor genes expression. but recently, it is arising that some oncogenes or cancer-promoting genes (cpgs) are overexpressed in diverse type of cancers through epigenetic derepression mechanism, such as dna and histone demethylation. epigenetic derepression arises from diverse epigenetic changes, and all of these mechanisms actively interact with each other to increase oncogenes or cpgs expression in cancer cell. oncogenes or cpgs overexpressed through epigenetic derepression can initiate cancer development, and accumulation of these abnormal epigenetic changes makes cancer more aggressive and treatment resistance. this review discusses epigenetic mechanisms involved in the overexpression of oncogenes or cpgs via epigenetic derepression in gynecologic cancers. therefore, improved understanding of these epigenetic mechanisms will provide new targets for gynecologic cancer treatment. © 2014 jeong, kwon and shin.”
Le Luyer, J., Laporte, M., Beacham, T. D., Kaukinen, K. H., Withler, R. E., Leong, J. S., … Bernatchez, L.. (2017). Parallel epigenetic modifications induced by hatchery rearing in a Pacific salmon. Proceedings of the National Academy of Sciences of the United States of America
Plain numerical DOI: 10.1073/pnas.1711229114
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“Wild stocks of pacific salmonids have experienced sharp declines in abundance over the past century. consequently, billions of fish are released each year for enhancing abundance and sustaining fisheries. however, the beneficial role of this widely used management practice is highly debated since fitness decrease of hatchery-origin fish in the wild has been documented. artificial selection in hatcheries has often been invoked as the most likely explanation for reduced fitness, and most studies to date have focused on finding signatures of hatchery-induced selection at the dna level. we tested an alternative hypothesis, that captive rearing induces epigenetic reprogramming, by comparing genome-wide patterns of methylation and variation at the dna level in hatchery-reared coho salmon (oncorhynchus kisutch) with those of their wild counterparts in two geographically distant rivers. we found a highly significant proportion of epigenetic variation explained by the rearing environment that was as high as the one explained by the river of origin. the differentially methylated regions show enrichment for biological functions that may affect the capacity of hatchery-born smolts to migrate successfully in the ocean. shared epigenetic variation between hatchery-reared salmon provides evidence for parallel epigenetic modifications induced by hatchery rearing in the absence of genetic differentiation between hatchery and natural-origin fish for each river. this study highlights epigenetic modifications induced by captive rearing as a potential explanatory mechanism for reduced fitness in hatchery-reared salmon.”
Tollenaar, M. S., Beijers, R., Garg, E., Nguyen, T. T. T., Lin, D. T. S., MacIsaac, J. L., … de Weerth, C.. (2021). Internalizing symptoms associate with the pace of epigenetic aging in childhood. Biological Psychology
Plain numerical DOI: 10.1016/j.biopsycho.2021.108021
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“Childhood psychiatric symptoms may be associated with advanced biological aging. this study examined whether epigenetic age acceleration (eaa) associates with internalizing and externalizing symptoms that were prospectively collected across childhood in a longitudinal cohort study. at age 6 buccal epithelial cells from 148 children (69 girls) were collected to survey genome-wide dna methylation. eaa was estimated using the horvath clock. internalizing symptoms at ages 2.5 and 4 years significantly predicted higher eaa at age 6, which in turn was significantly associated with internalizing symptoms at ages 6–10 years. similar trends for externalizing symptoms did not reach statistical significance. these findings indicate advanced biological aging in relation to child mental health and may help better identify those at risk for lasting impairments associated with internalizing disorders.”
Radford, E. J.. (2018). Exploring the extent and scope of epigenetic inheritance. Nature Reviews Endocrinology
Plain numerical DOI: 10.1038/s41574-018-0005-5
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“Environmental factors, particularly during early life, are important for the later metabolic health of the individual. in our obesogenic environment, it is of major socio-economic importance to investigate the mechanisms that contribute to the risk of metabolic ill health. increasing evidence from a variety of model organisms suggests that non-genetically determined phenotypes, including metabolic effects such as glucose intolerance and obesity, can be passed between generations, which encourages us to revisit heredity. inheritance of altered epigenetic information through the germ line has been proposed as one plausible mechanism. whether the germline epigenome can be altered by environmental conditions such as diet and the extent to which this occurs in humans are the subject of intense current interest and debate, especially given that extensive germline epigenetic reprogramming is known to occur. as epigenetic mechanisms are often highly conserved between organisms, studying epigenetic inheritance in plants and lower metazoans has the potential to inform our investigation in mammals. this review explores the extent to which epigenetic inheritance contributes to heredity in these different organisms, whether the environment can affect epigenetic inheritance and whether there is any evidence for the inheritance of acquired phenotypes.”
Latzel, V., Zhang, Y., Karlsson Moritz, K., Fischer, M., & Bossdorf, O.. (2012). Epigenetic variation in plant responses to defence hormones. Annals of Botany
Plain numerical DOI: 10.1093/aob/mcs088
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“Background and aimsthere is currently much speculation about the role of epigenetic variation as a determinant of heritable variation in ecologically important plant traits. however, we still know very little about the phenotypic consequences of epigenetic variation, in particular with regard to more complex traits related to biotic interactions.methodshere, a test was carried out to determine whether variation in dna methylation alone can cause heritable variation in plant growth responses to jasmonic acid and salicylic acid, two key hormones involved in induction of plant defences against herbivores and pathogens. in order to be able to ascribe phenotypic differences to epigenetic variation, the hormone responses were studied of epigenetic recombinant inbred lines (epirils) of arabidopsis thaliana – lines that are highly variable at the level of dna methylation but nearly identical at the level of dna sequence.key resultssignificant heritable variation was found among epirils both in the means of phenotypic traits, including growth rate, and in the degree to which these responded to treatment with jasmonic acid and salicylic acid. moreover, there was a positive epigenetic correlation between the responses of different epirils to the two hormones, suggesting that plant responses to herbivore and pathogen attack may have a similar molecular epigenetic basis.conclusionsthis study demonstrates that epigenetic variation alone can cause heritable variation in, and thus potentially microevolution of, plant responses to defence hormones. this suggests that part of the variation of plant defences observed in natural populations may be due to underlying epigenetic, rather than entirely genetic, variation. © 2012 the author. published by oxford university press on behalf of the annals of botany company. all rights reserved.”
Issa, M. E., Takhsha, F. S., Chirumamilla, C. S., Perez-Novo, C., Vanden Berghe, W., & Cuendet, M.. (2017). Epigenetic strategies to reverse drug resistance in heterogeneous multiple myeloma. Clinical Epigenetics
Plain numerical DOI: 10.1186/s13148-017-0319-5
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“Multiple myeloma (mm) is a hematological malignancy, which remains incurable because most patients eventually relapse or become refractory to current treatments. due to heterogeneity within the cancer cell microenvironment, cancer cell populations employ a dynamic survival strategy to chemotherapeutic treatments, which frequently results in a rapid acquisition of therapy resistance. besides resistance-conferring genetic alterations within a tumor cell population selected during drug treatment, recent findings also reveal non-mutational mechanisms of drug resistance, involving a small population of ‘cancer stem cells’ (cscs) which are intrinsically more refractory to the effects of a variety of anticancer drugs. other studies have implicated epigenetic mechanisms in reversible drug tolerance to protect the population from eradication by potentially lethal exposures, suggesting that acquired drug resistance does not necessarily require a stable heritable genetic alteration. clonal evolution of mm cells and the bone marrow microenvironment changes contribute to drug resistance. mm-cscs may not be a static population and survive as phenotypically and functionally different cell types via the transition between stem-like and non-stem-like states in local microenvironments, as observed in other types of cancers. targeting mm-cscs is clinically relevant, and different approaches have been suggested to target molecular, metabolic and epigenetic signatures, and the self-renewal signaling characteristic of mm csc-like cells. here, we summarize epigenetic strategies to reverse drug resistance in heterogeneous multiple myeloma.”
Caprio, C., Sacco, A., Giustini, V., & Roccaro, A. M.. (2020). Epigenetic aberrations in multiple myeloma. Cancers
Plain numerical DOI: 10.3390/cancers12102996
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“Multiple myeloma (mm) is a plasma cell dyscrasia characterized by proliferation of clonal plasma cells within the bone marrow. several advances in defining key processes responsible for mm pathogenesis and disease progression have been made; and dysregulation of epigenetics, including dna methylation and histone modification, has emerged as a crucial regulator of mm pathogenesis. in the present review article, we will focus on the role of epigenetic modifications within the specific context of mm.”
Khaliq, M., & Fallahi-Sichani, M.. (2019). Epigenetic mechanisms of escape from BRAF oncogene dependency. Cancers
Plain numerical DOI: 10.3390/cancers11101480
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“About eight percent of all human tumors (including 50% of melanomas) carry gain-offunction mutations in the braf oncogene. mutated braf and subsequent hyperactivation of the mapk signaling pathway has motivated the use of mapk-targeted therapies for these tumors. despite great promise, however, mapk-targeted therapies in braf-mutant tumors are limited by the emergence of drug resistance. mechanisms of resistance include genetic, non-genetic and epigenetic alterations. epigenetic plasticity, often modulated by histone-modifying enzymes and gene regulation, can influence a tumor cell’s braf dependency and therefore, response to therapy. in this review, focusing primarily on class 1 braf-mutant cells, we will highlight recent work on the contribution of epigenetic mechanisms to inter- and intratumor cell heterogeneity in mapktargeted therapy response.”
Carlini, V., Policarpi, C., & Hackett, J. A.. (
2021).
Epigenetic Inheritance is Gated by Naïve Pluripotency and Dppa2.
BioRxiv
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“Environmental factors can trigger cellular responses that propagate across mitosis or even generations. perturbations to the epigenome could underpin such acquired changes, however, the extent and contexts in which modified chromatin states confer heritable memory in mammals is unclear. here we exploit a modular epigenetic editing strategy to establish de novo heterochromatin domains (epialleles) at endogenous loci and track their inheritance in a developmental model. we find that naïve pluripotent phases systematically erase ectopic domains of heterochromatin via active mechanisms, which acts as an intergenerational safeguard against transmission of epialleles. upon lineage specification however, acquired chromatin states can be probabilistically inherited under selectively favourable conditions, including propagation of p53 silencing through in vivo development. using genome-wide crispr screening, we identify the mechanisms that block heritable silencing memory in pluripotent cells, and demonstrate removal of dppa2 unlocks the potential for epigenetic inheritance uncoupled from dna sequence. our study outlines a mechanistic basis for how epigenetic inheritance is restricted in mammals, and reveals genomic- and developmental-contexts in which heritable memory is feasible. ### competing interest statement the authors have declared no competing interest.”
Wardhana, W., & Soeatmadji, D. W.. (
2019).
The Role of Epigenetic Changes in The Development of Diabetes Mellitus.
Acta Medica Indonesiana
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“Diabetes mellitus (dm) is one of the most abundant diseases in the 21st century and believed as result of interaction between genes and environment exposure. there is a hypotesis of epigenetic mechanisms, using molecular basis to explain about the mechanism of dm. because of the enviromental exposure including nutrition status and hyperglycemia state, the risk of dm has started since pre-conception, last until adulthood and will be inhireted trans-generational . mainly, there are 3 epigenetic mechanisms that have role in dm. epigenetic mechanisms are also have role in the metabolic memory that the dm complications may still developed although the blood glucose level is already normal. the restriction of calory intake may help delaying the development and onset of degerative diseases including dm by stabilizing genome through epigenetic mechanisms.”
Cai, F. F., Kohler, C., Zhang, B., Wang, M. H., Chen, W. J., & Zhong, X. Y.. (2011). Epigenetic therapy for breast cancer. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms12074465
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“Both genetic and epigenetic alterations can control the progression of cancer. genetic alterations are impossible to reverse, while epigenetic alterations are reversible. this advantage suggests that epigenetic modifications should be preferred in therapy applications. dna methyltransferases and histone deacetylases have become the primary targets for studies in epigenetic therapy. some dna methylation inhibitors and histone deacetylation inhibitors are approved by the us food and drug administration as anti-cancer drugs. therefore, the uses of epigenetic targets are believed to have great potential as a lasting favorable approach in treating breast cancer. © 2011 by the authors.”
Pham, T. X., & Lee, J. Y.. (2017). Epigenetic regulation of adipokines. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms18081740
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“Adipose tissue expansion in obesity leads to changes in the expression of adipokines, adipocyte-specific hormones that can regulate whole body energy metabolism. epigenetic regulation of gene expression is a mechanism by which cells can alter gene expression through the modifications of dna and histones. epigenetic mechanisms, such as dna methylation and histone modifications, are intimately tied to energy metabolism due to their dependence on metabolic intermediates such as s-adenosylmethionine and acetyl-coa. altered expression of adipokines in obesity may be due to epigenetic changes. the goal of this review is to highlight current knowledge of epigenetic regulation of adipokines.”
Hu, J., & Yu, Y.. (2019). Epigenetic response profiles into environmental epigenotoxicant screening and health risk assessment: A critical review. Chemosphere
Plain numerical DOI: 10.1016/j.chemosphere.2019.03.096
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“The epigenome may be an important interface between exposure to environmental contaminants and adverse outcome on human health. many environmental pollutants deregulate gene expression and promote diseases by modulating the epigenome. adverse epigenetic responses have been widely used for risk assessment of chemical substances. various pollutants, including trace elements and persistent organic pollutants, have been detected frequently in the environment. epigenetic toxicity of environmental matrices including water, air, soil, and food cannot be ignored. this review provides a comprehensive overview of epigenetic effects of pollutants and environmental matrices. we start with an overview of the mechanisms of epigenetic regulation and the effects of several types of environmental pollutants (trace elements, persistent organic pollutants, endocrine disrupting chemicals, and volatile organic pollutants) on epigenetic modulation. we then discuss the epigenetic responses to environmental water, air, and soil based on in vivo and in vitro assays. finally, we discuss recommendations to promote the incorporation of epigenotoxicity into contamination screening and health risk assessment.”
Pierce, R. C., Fant, B., Swinford-Jackson, S. E., Heller, E. A., Berrettini, W. H., & Wimmer, M. E.. (2018). Environmental, genetic and epigenetic contributions to cocaine addiction. Neuropsychopharmacology
Plain numerical DOI: 10.1038/s41386-018-0008-x
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“Decades of research on cocaine has produced volumes of data that have answered many important questions about the nature of this highly addictive drug. sadly, none of this information has translated into the development of effective therapies for the treatment of cocaine addiction. this review endeavors to assess the current state of cocaine research in an attempt to identify novel pathways for therapeutic development. for example, risk of cocaine addiction is highly heritable but genome-wide analyses comparing cocaine-dependent individuals to controls have not resulted in promising targets for drug development. is this because the genetics of addiction is too complex or because the existing research methodologies are inadequate? likewise, animal studies have revealed dozens of enduring changes in gene expression following prolonged exposure to cocaine, none of which have translated into therapeutics either because the resulting compounds were ineffective or produced intolerable side-effects. recently, attention has focused on epigenetic modifications resulting from repeated cocaine intake, some of which appear to be heritable through changes in the germline. while epigenetic changes represent new vistas for therapeutic development, selective manipulation of epigenetic marks is currently challenging even in animals such that translational potential is a distant prospect. this review will reveal that despite the enormous progress made in understanding the molecular and physiological bases of cocaine addiction, there is much that remains a mystery. continued advances in genetics and molecular biology hold potential for revealing multiple pathways toward the development of treatments for the continuing scourge of cocaine addiction.”
Damal Villivalam, S., You, D., Kim, J., Lim, H. W., Xiao, H., Zushin, P. J. H., … Kang, S.. (2020). TET1 is a beige adipocyte-selective epigenetic suppressor of thermogenesis. Nature Communications
Plain numerical DOI: 10.1038/s41467-020-18054-y
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“It has been suggested that beige fat thermogenesis is tightly controlled by epigenetic regulators that sense environmental cues such as temperature. here, we report that subcutaneous adipose expression of the dna demethylase tet1 is suppressed by cold and other stimulators of beige adipocyte thermogenesis. tet1 acts as an autonomous repressor of key thermogenic genes, including ucp1 and ppargc1a, in beige adipocytes. adipose-selective tet1 knockout mice generated by using fabp4-cre improves cold tolerance and increases energy expenditure and protects against diet-induced obesity and insulin resistance. moreover, the suppressive role of tet1 in the thermogenic gene regulation of beige adipocytes is largely dna demethylase-independent. rather, tet1 coordinates with hdac1 to mediate the epigenetic changes to suppress thermogenic gene transcription. taken together, tet1 is a potent beige-selective epigenetic breaker of the thermogenic gene program. our findings may lead to a therapeutic strategy to increase energy expenditure in obesity and related metabolic disorders.”
Kinoshita, T., & Seki, M.. (2014). Epigenetic memory for stress response and adaptation in plants. Plant and Cell Physiology
Plain numerical DOI: 10.1093/pcp/pcu125
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“In contrast to the majority of animal species, plants are sessile organisms and are, therefore, constantly challenged by environmental perturbations. over the past few decades, our knowledge of how plants perceive environmental stimuli has increased considerably, e.g. the mechanisms for transducing environmental stress stimuli into cellular signaling cascades and gene transcription networks. in addition, it has recently been shown that plants can remember past environmental events and can use these memories to aid responses when these events recur. in this mini review, we focus on recent progress in determination of the epigenetic mechanisms used by plants under various environmental stresses. epigenetic mechanisms are now known to play a vital role in the control of gene expression through small rnas, histone modifications and dna methylation. these are inherited through mitotic cell divisions and, in some cases, can be transmitted to the next generation. they therefore offer a possible mechanism for stress memories in plants. recent studies have yielded evidence indicating that epigenetic mechanisms are indeed essential for stress memories and adaptation in plants.”
Caprio, C., Sacco, A., Giustini, V., & Roccaro, A. M.. (2020). Epigenetic aberrations in multiple myeloma. Cancers
Plain numerical DOI: 10.3390/cancers12102996
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“Multiple myeloma (mm) is a plasma cell dyscrasia characterized by proliferation of clonal plasma cells within the bone marrow. several advances in defining key processes responsible for mm pathogenesis and disease progression have been made; and dysregulation of epigenetics, including dna methylation and histone modification, has emerged as a crucial regulator of mm pathogenesis. in the present review article, we will focus on the role of epigenetic modifications within the specific context of mm.”
Srivastava, R., Srivastava, R., & Ahn, S. H.. (2016). The Epigenetic Pathways to Ribosomal DNA Silencing. Microbiology and Molecular Biology Reviews
Plain numerical DOI: 10.1128/mmbr.00005-16
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“ Heterochromatin is the transcriptionally repressed portion of eukaryotic chromatin that maintains a condensed appearance throughout the cell cycle. at sites of ribosomal dna (rdna) heterochromatin, epigenetic states contribute to gene silencing and genome stability, which are required for proper chromosome segregation and a normal life span. here, we focus on recent advances in the epigenetic regulation of rdna silencing in saccharomyces cerevisiae and in mammals, including regulation by several histone modifications and several protein components associated with the inner nuclear membrane within the nucleolus. finally, we discuss the perturbations of rdna epigenetic pathways in regulating cellular aging and in causing various types of diseases. ”
Sharavanan, V. J., Sivaramakrishnan, M., Sivarajasekar, N., Senthilrani, N., Kothandan, R., Dhakal, N., … Naushad, M.. (2020). Pollutants inducing epigenetic changes and diseases. Environmental Chemistry Letters
Plain numerical DOI: 10.1007/s10311-019-00944-3
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“Pollution is a major issue impacting the health of life and ecosystems. in particular, some pollutants may alter gene expression by epigenetic mechanisms such as deoxyribonucleic acid (dna) methylation, histone modifications, and microrna (mirna) expression. epigenetics is the study of heritable changes without alteration in the dna sequence. in the healthy state, the coordinated actions of interconnected epigenetic factors are responsible for proper cell development and cell regulation. epigenetic mechanisms are tissue-specific; hence, a pollutant may or may not cause an alteration depending on the type of tissue. here we review mechanisms by which pollutants disrupt epigenetic factors. we focus on the impact of arsenic, cadmium, nickel, mercury, benzene, bisphenol a, dioxin, hexahydro-1,3,5-trinitro-1,3,5-triazine and diethylstilbestrol. a list of diseases related to epigenetic factors and heavy metals exposure is provided.”
Issa, M. E., Takhsha, F. S., Chirumamilla, C. S., Perez-Novo, C., Vanden Berghe, W., & Cuendet, M.. (2017). Epigenetic strategies to reverse drug resistance in heterogeneous multiple myeloma. Clinical Epigenetics
Plain numerical DOI: 10.1186/s13148-017-0319-5
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“Multiple myeloma (mm) is a hematological malignancy, which remains incurable because most patients eventually relapse or become refractory to current treatments. due to heterogeneity within the cancer cell microenvironment, cancer cell populations employ a dynamic survival strategy to chemotherapeutic treatments, which frequently results in a rapid acquisition of therapy resistance. besides resistance-conferring genetic alterations within a tumor cell population selected during drug treatment, recent findings also reveal non-mutational mechanisms of drug resistance, involving a small population of ‘cancer stem cells’ (cscs) which are intrinsically more refractory to the effects of a variety of anticancer drugs. other studies have implicated epigenetic mechanisms in reversible drug tolerance to protect the population from eradication by potentially lethal exposures, suggesting that acquired drug resistance does not necessarily require a stable heritable genetic alteration. clonal evolution of mm cells and the bone marrow microenvironment changes contribute to drug resistance. mm-cscs may not be a static population and survive as phenotypically and functionally different cell types via the transition between stem-like and non-stem-like states in local microenvironments, as observed in other types of cancers. targeting mm-cscs is clinically relevant, and different approaches have been suggested to target molecular, metabolic and epigenetic signatures, and the self-renewal signaling characteristic of mm csc-like cells. here, we summarize epigenetic strategies to reverse drug resistance in heterogeneous multiple myeloma.”
Khaliq, M., & Fallahi-Sichani, M.. (2019). Epigenetic mechanisms of escape from BRAF oncogene dependency. Cancers
Plain numerical DOI: 10.3390/cancers11101480
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“About eight percent of all human tumors (including 50% of melanomas) carry gain-offunction mutations in the braf oncogene. mutated braf and subsequent hyperactivation of the mapk signaling pathway has motivated the use of mapk-targeted therapies for these tumors. despite great promise, however, mapk-targeted therapies in braf-mutant tumors are limited by the emergence of drug resistance. mechanisms of resistance include genetic, non-genetic and epigenetic alterations. epigenetic plasticity, often modulated by histone-modifying enzymes and gene regulation, can influence a tumor cell’s braf dependency and therefore, response to therapy. in this review, focusing primarily on class 1 braf-mutant cells, we will highlight recent work on the contribution of epigenetic mechanisms to inter- and intratumor cell heterogeneity in mapktargeted therapy response.”
Nestler, E. J.. (2014). Epigenetic mechanisms of drug addiction. Neuropharmacology
Plain numerical DOI: 10.1016/j.neuropharm.2013.04.004
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“Drug addiction involves potentially life-long behavioral abnormalities that are caused in vulnerable individuals by repeated exposure to a drug of abuse. the persistence of these behavioral changes suggests that long-lasting changes in gene expression, within particular regions of the brain, may contribute importantly to the addiction phenotype. work over the past decade has demonstrated a crucial role for epigenetic mechanisms in driving lasting changes in gene expression in diverse tissues, including brain. this has prompted recent research aimed at characterizing the influence of epigenetic regulatory events in mediating the lasting effects of drugs of abuse on the brain in animal models of drug addiction. this review provides a progress report of this still early work in the field. as will be seen, there is robust evidence that repeated exposure to drugs of abuse induces changes within the brain’s reward regions in three major modes of epigenetic regulation – histone modifications such as acetylation and methylation, dna methylation, and non-coding rnas. in several instances, it has been possible to demonstrate directly the contribution of such epigenetic changes to addiction-related behavioral abnormalities. studies of epigenetic mechanisms of addiction are also providing an unprecedented view of the range of genes and non-genic regions that are affected by repeated drug exposure and the precise molecular basis of that regulation. work is now needed to validate key aspects of this work in human addiction and evaluate the possibility of mining this information to develop new diagnostic tests and more effective treatments for addiction syndromes. this article is part of a special issue entitled ‘nida 40th anniversary issue’. © 2013 elsevier ltd. all rights reserved.”
Halley-Stott, R. P., & Gurdon, J. B.. (2013). Epigenetic memory in the context of nuclear reprogramming and cancer. Briefings in Functional Genomics
Plain numerical DOI: 10.1093/bfgp/elt011
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“Epigenetic memory represents a natural mechanism whereby the identity of a cell is maintained through successive cell cycles, allowing the specification and maintenance of differentiation during development and in adult cells. cancer is a loss or reversal of the stable differentiated state of adult cells and may be mediated in part by epigenetic changes.the identity of somatic cells can also be reversed experimentally by nuclear reprogramming.nuclear reprogramming experiments reveal the mechanisms required to activate embryonic gene expression in adult cells and thus provide insight into the reversal of epigenetic memory. in this article, we will introduce epigenetic memory and the mechanisms by which it may operate.we limit our discussion primarily to the context of nuclear reprogramming and briefly discuss the relevance of memory and reprogramming to cancer biology.©the author 2013. published by oxford university press.”
Descalzi, G., Ikegami, D., Ushijima, T., Nestler, E. J., Zachariou, V., & Narita, M.. (2015). Epigenetic mechanisms of chronic pain. Trends in Neurosciences
Plain numerical DOI: 10.1016/j.tins.2015.02.001
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“Neuropathic and inflammatory pain promote a large number of persisting adaptations at the cellular and molecular level, allowing even transient tissue or nerve damage to elicit changes in cells that contribute to the development of chronic pain and associated symptoms. there is evidence that injury-induced changes in chromatin structure drive stable changes in gene expression and neural function, which may cause several symptoms, including allodynia, hyperalgesia, anxiety, and depression. recent findings on epigenetic changes in the spinal cord and brain during chronic pain may guide fundamental advances in new treatments. here, we provide a brief overview of epigenetic regulation in the nervous system and then discuss the still-limited literature that directly implicates epigenetic modifications in chronic pain syndromes.”
de Nigris, F., Ruosi, C., Colella, G., & Napoli, C.. (2021). Epigenetic therapies of osteoporosis. Bone
Plain numerical DOI: 10.1016/j.bone.2020.115680
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“The study of epigenetics reaches its 50th anniversary, however, its clinical application is gradually coming into the clinical setting. osteoporosis is one of the major and widely diffused bone diseases. pathogenic mechanisms at the epigenetic level may interfere with bone remodeling occurring during osteoporosis. preclinical models were used to understand whether such events may interfere with the disease. besides, observational clinical trials investigated epigenetic-related biomarkers. this effort leads to some epigenetic-related therapies in clinical trials for the treatment of osteoporosis. bisphosphonates (bps), target therapy blocking rank/rankl pathway, and anti-sclerostin antibody (sost) are the main therapeutic approaches. however, future large trials will reveal whether epigenetic therapies of osteoporosis will remain a work in progress or data will become more robust in the real-world management of these frailty patients.”
Vanheer, L. N., Zhang, H., Lin, G., & Kafsack, B. F. C.. (2020). Activity of epigenetic inhibitors against plasmodium falciparum asexual and sexual blood stages. Antimicrobial Agents and Chemotherapy
Plain numerical DOI: 10.1128/AAC.02523-19
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“Earlier genetic and inhibitor studies showed that epigenetic regulation of gene expression is critical for malaria parasite survival in multiple life stages and a promising target for new antimalarials. we therefore evaluated the activity of 350 diverse epigenetic inhibitors against multiple stages of plasmodium falciparum. we observed ≥90% inhibition at 10 μm for 28% of compounds against asexual blood stages and early gametocytes, of which a third retained ≥90% inhibition at 1 μm.”
Karpathakis, A., Dibra, H., & Thirlwell, C.. (2013). Neuroendocrine tumours: Cracking the epigenetic code. Endocrine-Related Cancer
Plain numerical DOI: 10.1530/ERC-12-0338
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“The field of epigenetics has evolved rapidly over recent years providing insight into the tumorigenesis of many solid and haematological malignancies. determination of epigenetic modifications in neuroendocrine tumour (net) development is imperative if we are to improve our understanding of the biology of this heterogenous group of tumours. epigenetic marks such as dna methylation at rassf1a are frequent findings in nets of all origins and may be associated with worse prognosis. microrna signatures and histone modifications have been identified which can differentiate subtypes of net and distinguish net from adenocarcinoma in cases of diagnostic uncertainty. historically, candidate genedriven approaches have yielded limited insight into the epigenetics of net. recent progress has been facilitated by development of high-throughput tools including second-generation sequencing and arrays for analysis of the ‘epigenome’ of tumour and normal tissue, permitting unbiased approaches such as exome sequencing that identified mutations of chromatin-remodelling genes atrx/daxx in 44% of pancreatic nets. epigenetic changes are reversible and therefore represent an attractive therapeutic target; to date, clinical outcomes of epigenetic therapies in solid tumours have been disappointing; however, in vitro studies on nets are promising and further clinical trials are required to determine utility of this class of novel agents. in this review, we perform a comprehensive evaluation of epigenetic changes found in nets to date, including rare nets such as phaeochromocytoma and adrenocortical tumours. we suggest priorities for future research and discuss potential clinical applications and novel therapies. copyright © 2013 society for endocrinology.”
Damal Villivalam, S., You, D., Kim, J., Lim, H. W., Xiao, H., Zushin, P. J. H., … Kang, S.. (2020). TET1 is a beige adipocyte-selective epigenetic suppressor of thermogenesis. Nature Communications
Plain numerical DOI: 10.1038/s41467-020-18054-y
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“It has been suggested that beige fat thermogenesis is tightly controlled by epigenetic regulators that sense environmental cues such as temperature. here, we report that subcutaneous adipose expression of the dna demethylase tet1 is suppressed by cold and other stimulators of beige adipocyte thermogenesis. tet1 acts as an autonomous repressor of key thermogenic genes, including ucp1 and ppargc1a, in beige adipocytes. adipose-selective tet1 knockout mice generated by using fabp4-cre improves cold tolerance and increases energy expenditure and protects against diet-induced obesity and insulin resistance. moreover, the suppressive role of tet1 in the thermogenic gene regulation of beige adipocytes is largely dna demethylase-independent. rather, tet1 coordinates with hdac1 to mediate the epigenetic changes to suppress thermogenic gene transcription. taken together, tet1 is a potent beige-selective epigenetic breaker of the thermogenic gene program. our findings may lead to a therapeutic strategy to increase energy expenditure in obesity and related metabolic disorders.”
Schiele, M. A., Gottschalk, M. G., & Domschke, K.. (2020). The applied implications of epigenetics in anxiety, affective and stress-related disorders – A review and synthesis on psychosocial stress, psychotherapy and prevention. Clinical Psychology Review
Plain numerical DOI: 10.1016/j.cpr.2020.101830
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“Mental disorders are highly complex and multifactorial in origin, comprising an elaborate interplay of genetic and environmental factors. epigenetic mechanisms such as dna modifications (e.g. cpg methylation), histone modifications (e.g. acetylation) and micrornas function as a translator between genes and the environment. indeed, environmental influences such as exposure to stress shape epigenetic patterns, and lifetime experiences continue to alter the function of the genome throughout the lifespan. here, we summarize the recently burgeoning body of research regarding the involvement of aberrant epigenetic signatures in mediating an increased vulnerability to a wide range of mental disorders. we review the current knowledge of epigenetic changes to constitute useful markers predicting the clinical response to psychotherapeutic interventions, and of psychotherapy to alter – and potentially reverse – epigenetic risk patterns. given first evidence pointing to a transgenerational transmission of epigenetic information, epigenetic alterations arising from successful psychotherapy might be transferred to future generations and thus contribute to the prevention of mental disorders. findings are integrated into a multi-level framework highlighting challenges pertaining to the mechanisms of action and clinical implications of epigenetic research. promising future directions regarding the prediction, prevention, and personalized treatment of mental disorders in line with a ‘precision medicine’ approach are discussed.”
Jia, Z. H., Wang, X. G., & Zhang, H.. (2019). Overcome cancer drug resistance by targeting epigenetic modifications of centrosome. Cancer Drug Resistance
Plain numerical DOI: 10.20517/cdr.2018.010
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“The centrosome is an organelle that serves as the microtubule- and actin-organizing center of human cells. although the centrosome is small of size, it is great important on cellular function that regulates cytoskeletal organization and governs precise spindle orientation/positioning ensuring equal distribution of cellular components in cell division. epigenetic modifications to centrosome proteins can lead to centrosome aberrations, such as disorganized spindles and centrosome amplification causing aneuploidy and genomic instability. epigenetic disturbances are associated not only with carcinogenesis and cancer progression, but also with drug resistance to chemotherapy. in this review, we discuss mechanisms of epigenetic alteration during the centrosome biogenesis in cancer. we provide an update on the current status of clinical trials that aim to target epigenetic modifications in centrosome aberrations and to thwart drug resistance.”
Wilson, C. L., Mann, D. A., & Borthwick, L. A.. (2017). Epigenetic reprogramming in liver fibrosis and cancer. Advanced Drug Delivery Reviews
Plain numerical DOI: 10.1016/j.addr.2017.10.011
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“Novel insights into the epigenetic control of chronic liver diseases are now emerging. recent advances in our understanding of the critical roles of dna methylation, histone modifications and ncrna may now be exploited to improve management of fibrosis/cirrhosis and cancer. furthermore, improved technologies for the detection of epigenetic markers from patients’ blood and tissues will vastly improve diagnosis, treatment options and prognostic tracking. the aim of this review is to present recent findings from the field of liver epigenetics and to explore their potential for translation into therapeutics to prevent disease promoting epigenome reprogramming and reverse epigenetic changes.”
Yu, J., Xu, F., Wei, Z., Zhang, X., Chen, T., & Pu, L.. (2020). Epigenomic landscape and epigenetic regulation in maize. Theoretical and Applied Genetics
Plain numerical DOI: 10.1007/s00122-020-03549-5
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“Key message: epigenetic regulation has been implicated in the control of multiple agronomic traits in maize. here, we review current advances in our understanding of epigenetic regulation, which has great potential for improving agronomic traits and the environmental adaptability of crops. abstract: epigenetic regulation plays vital role in the control of complex agronomic traits. epigenetic variation could contribute to phenotypic diversity and can be used to improve the quality and productivity of crops. maize (zea mays l.), one of the most widely cultivated crops for human food, animal feed, and ethanol biofuel, is a model plant for genetic studies. recent advances in high-throughput sequencing technology have made possible the study of epigenetic regulation in maize on a genome-wide scale. in this review, we discuss recent epigenetic studies in maize many achieved by chinese research groups. these studies have explored the roles of dna methylation, posttranslational modifications of histones, chromatin remodeling, and noncoding rnas in the regulation of gene expression in plant development and environment response. we also provide our future prospects for manipulating epigenetic regulation to improve crops.”
Wang, S. E., & Jiang, Y. hui. (2019). Potential of Epigenetic Therapy for Prader-Willi Syndrome. Trends in Pharmacological Sciences
Plain numerical DOI: 10.1016/j.tips.2019.07.002
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“Prader-willi syndrome (pws) is a neurobehavioral and epigenetic disorder caused by the deficiency of paternally expressed genes in the chromosome 15q11-q13. this unique molecular defect renders pws an exciting opportunity to explore epigenetic therapy. here, we briefly highlight recent findings from small molecule screening and crispr/cas9-mediated epigenome editing that offer promising therapeutic options along with the challenges that remain in developing a successful epigenetic therapy for pws in humans.”
Le Luyer, J., Laporte, M., Beacham, T. D., Kaukinen, K. H., Withler, R. E., Leong, J. S., … Bernatchez, L.. (2017). Parallel epigenetic modifications induced by hatchery rearing in a Pacific salmon. Proceedings of the National Academy of Sciences of the United States of America
Plain numerical DOI: 10.1073/pnas.1711229114
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“Wild stocks of pacific salmonids have experienced sharp declines in abundance over the past century. consequently, billions of fish are released each year for enhancing abundance and sustaining fisheries. however, the beneficial role of this widely used management practice is highly debated since fitness decrease of hatchery-origin fish in the wild has been documented. artificial selection in hatcheries has often been invoked as the most likely explanation for reduced fitness, and most studies to date have focused on finding signatures of hatchery-induced selection at the dna level. we tested an alternative hypothesis, that captive rearing induces epigenetic reprogramming, by comparing genome-wide patterns of methylation and variation at the dna level in hatchery-reared coho salmon (oncorhynchus kisutch) with those of their wild counterparts in two geographically distant rivers. we found a highly significant proportion of epigenetic variation explained by the rearing environment that was as high as the one explained by the river of origin. the differentially methylated regions show enrichment for biological functions that may affect the capacity of hatchery-born smolts to migrate successfully in the ocean. shared epigenetic variation between hatchery-reared salmon provides evidence for parallel epigenetic modifications induced by hatchery rearing in the absence of genetic differentiation between hatchery and natural-origin fish for each river. this study highlights epigenetic modifications induced by captive rearing as a potential explanatory mechanism for reduced fitness in hatchery-reared salmon.”
Schenk, A., Bloch, W., & Zimmer, P.. (2016). Natural killer cells—An epigenetic perspective of development and regulation. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms17030326
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“Based on their ability to recognize and eliminate various endo- and exogenous pathogens as well as pathological alterations, natural killer (nk) cells represent an important part of the cellular innate immune system. although the knowledge about their function is growing, little is known about their development and regulation on the molecular level. research of the past decade suggests that modifications of the chromatin, which do not affect the base sequence of the dna, also known as epigenetic alterations, are strongly involved in these processes. here, the impact of epigenetic modifications on the development as well as the expression of important activating and inhibiting nk-cell receptors and their effector function is reviewed. furthermore, external stimuli such as physical activity and their influence on the epigenetic level are discussed.”
Brunet, A., & Berger, S. L.. (2014). Epigenetics of aging and aging-related disease. Journals of Gerontology – Series A Biological Sciences and Medical Sciences
Plain numerical DOI: 10.1093/gerona/glu042
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“Aging is associated with a wide range of human disorders, including cancer, diabetes, cardiovascular, and neurodegenerative diseases. long thought to be an inexorable road toward decline and diseases, aging is in fact remarkably plastic. such plasticity could be harnessed to approach age-related diseases from a novel perspective. although many studies have focused on the genes that impact aging, the nongenetic regulation of aging is gaining increasing attention. specifically, aging is associated with profound epigenetic changes, resulting in alterations of gene expression and disturbances in broad genome architecture and the epigenomic landscape. the potential reversibility of these epigenetic changes that occur as a hallmark of aging offers exciting opportunities to alter the trajectory of age-related diseases. this short review highlights key epigenetic players in the regulation of aging, as well as both future goals and challenges to the utilization of epigenetic strategies to delay and reverse the main diseases of aging. © 2014 the author.”
Qureshi, I. A., & Mehler, M. F.. (2014). Epigenetic Mechanisms Underlying the Pathogenesis of Neurogenetic Diseases. Neurotherapeutics
Plain numerical DOI: 10.1007/s13311-014-0302-1
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“There have been considerable advances in uncovering the complex genetic mechanisms that underlie nervous system disease pathogenesis, particularly with the advent of exome and whole genome sequencing techniques. the emerging field of epigenetics is also providing further insights into these mechanisms. here, we discuss our understanding of the interplay that exists between genetic and epigenetic mechanisms in these disorders, highlighting the nascent field of epigenetic epidemiology—which focuses on analyzing relationships between the epigenome and environmental exposures, development and aging, other health-related phenotypes, and disease states—and next-generation research tools (i.e., those leveraging synthetic and chemical biology and optogenetics) for examining precisely how epigenetic modifications at specific genomic sites affect disease processes.”
Tecalco-Cruz, A. C., Ramírez-Jarquín, J. O., Alvarez-Sánchez, M. E., & Zepeda-Cervantes, J.. (2020). Epigenetic basis of Alzheimer disease. World Journal of Biological Chemistry
Plain numerical DOI: 10.4331/wjbc.v11.i2.62
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“Alzheimer disease (ad) is the primary form of dementia that occurs spontaneously in older adults. interestingly, the epigenetic profile of the cells forming the central nervous system changes during aging and may contribute to the progression of some neurodegenerative diseases such as ad. in this review, we present general insights into relevant epigenetic mechanisms and their relationship with aging and ad. the data suggest that some epigenetic changes during aging could be utilized as biomarkers and target molecules for the prevention and control of ad.”
Zimmermann, C. A., Hoffmann, A., Raabe, F., & Spengler, D.. (2015). Role of Mecp2 in experience-dependent epigenetic programming. Genes
Plain numerical DOI: 10.3390/genes6010060
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“Mutations in the x-linked gene mecp2, the founding member of a family of proteins recognizing and binding to methylated dna, are the genetic cause of a devastating neurodevelopmental disorder in humans, called rett syndrome. available evidence suggests that mecp2 protein has a critical role in activity-dependent neuronal plasticity and transcription during brain development. moreover, recent studies in mice show that various posttranslational modifications, notably phosphorylation, regulate mecp2’s functions in learning and memory, drug addiction, depression-like behavior, and the response to antidepressant treatment. the hypothalamic-pituitary-adrenal (hpa) axis drives the stress response and its deregulation increases the risk for a variety of mental disorders. early-life stress (els) typically results in sustained hpa-axis deregulation and is a major risk factor for stress related diseases, in particular major depression. interestingly, mecp2 protein has been shown to contribute to els-dependent epigenetic programming of crh, avp, and pomc, all of these genes enhance hpa-axis activity. hereby els regulates mecp2 phosphorylation, dna binding, and transcriptional activities in a tissue-specific and temporospatial manner. overall, these findings suggest mecp2 proteins are so far underestimated and have a more dynamic role in the mediation of the gene-environment dialog and epigenetic programming of the neuroendocrine stress system in health and disease.”
Yakovlev, I. A., & Fossdal, C. G.. (2017). In silico analysis of small RNAs suggest roles for novel and conserved miRNAs in the formation of epigenetic memory in somatic embryos of Norway spruce. Frontiers in Physiology
Plain numerical DOI: 10.3389/fphys.2017.00674
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“Epigenetic memory in norway spruce affects the timing of bud burst and bud set, vitally important adaptive traits for this long-lived forest species. epigenetic memory is established in response to the temperature conditions during embryogenesis. somatic embryogenesis at different epitype inducing (epi) temperatures closely mimics the natural processes of epigenetic memory formation in seeds, giving rise to epigenetically different clonal plants in a reproducible and predictable manner, with respect to altered bud phenology. micrornas (mirnas) and other small non-coding rnas (srnas) play an essential role in the regulation of plant gene expression and may affect this epigenetic mechanism. we used ngs sequencing and computational in silico methods to identify and profile conserved and novel mirnas among small rnas in embryogenic tissues of norway spruce at three epi temperatures (18, 23 and 28°c). we detected three predominant classes of srnas related to a length of 24 nt, followed by a 21-22 nt class and a third 31 nt class of srnas. more than 2100 different mirnas within the prevailing length 21-22 nt were identified. profiling these putative mirnas allowed identification of 1053 highly expressed mirnas, including 523 conserved and 530 novels. 654 of these mirnas were found to be differentially expressed (dem) depending on epi temperature. for most dems, we defined their putative mrna targets. the targets represented mostly by transcripts of multiple-repeats proteins, like tir, nbs-lrr, ppr and tpr repeat, clathrin/vps proteins, myb-like, ap2, etc. notably, 124 de mirnas targeted 203 differentially expressed epigenetic regulators. developing norway spruce embryos possess a more complex srna structure than that reported for somatic tissues. a variety of the predicted mirnas showed distinct epi temperature dependent expression patterns. these putative epi mirnas target spruce genes with a wide range of functions, including genes known to be involved in epigenetic regulation, which in turn could provide a feedback process leading to the formation of epigenetic marks. we suggest that tir, nbs and lrr domain containing proteins could fulfill more general functions for signal transduction from external environmental stimuli and conversion them into molecular response. fine-tuning of the mirna production likely participates in both developmental regulation and epigenetic memory formation in norway spruce.”
Radford, E. J.. (2018). Exploring the extent and scope of epigenetic inheritance. Nature Reviews Endocrinology
Plain numerical DOI: 10.1038/s41574-018-0005-5
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“Environmental factors, particularly during early life, are important for the later metabolic health of the individual. in our obesogenic environment, it is of major socio-economic importance to investigate the mechanisms that contribute to the risk of metabolic ill health. increasing evidence from a variety of model organisms suggests that non-genetically determined phenotypes, including metabolic effects such as glucose intolerance and obesity, can be passed between generations, which encourages us to revisit heredity. inheritance of altered epigenetic information through the germ line has been proposed as one plausible mechanism. whether the germline epigenome can be altered by environmental conditions such as diet and the extent to which this occurs in humans are the subject of intense current interest and debate, especially given that extensive germline epigenetic reprogramming is known to occur. as epigenetic mechanisms are often highly conserved between organisms, studying epigenetic inheritance in plants and lower metazoans has the potential to inform our investigation in mammals. this review explores the extent to which epigenetic inheritance contributes to heredity in these different organisms, whether the environment can affect epigenetic inheritance and whether there is any evidence for the inheritance of acquired phenotypes.”
Denham, J.. (2018). Exercise and epigenetic inheritance of disease risk. Acta Physiologica
Plain numerical DOI: 10.1111/apha.12881
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“Epigenetics is the study of gene expression changes that occur in the absence of altered genotype. current evidence indicates a role for environmentally induced alterations to epigenetic modifications leading to health and disease changes across multiple generations. this phenomenon is called intergenerational or transgenerational epigenetic inheritance of health or disease. environmental insults, in the form of toxins, plastics and particular dietary interventions, perturb the epigenetic landscape and influence the health of f1 through to f4 generations in rodents. there is, however, the possibility that healthy lifestyles and environmental factors, such as exercise training, could lead to favourable, heritable epigenetic modifications that augment transcriptional programmes protective of disease, including metabolic dysfunction, heart disease and cancer. the health benefits conferred by regular physical exercise training are unquestionable, yet many of the molecular changes may have heritable health implications for future generations. similar to other environmental factors, exercise modulates the epigenome of somatic cells and researchers are beginning to study exercise epigenetics in germ cells. the germ cell epigenetic modifications affected by exercise offer a molecular mechanism for the inheritance of health and disease risk. the aims of this review are to: (i) provide an update on the expanding field of exercise epigenetics; (ii) offer an overview of data on intergenerational/transgenerational epigenetic inheritance of disease by environmental insults; (iii) to discuss the potential of exercise-induced intergenerational inheritance of health and disease risk; and finally, outline potential mechanisms and avenues for future work on epigenetic inheritance through exercise.”
Tsankova, N., Renthal, W., Kumar, A., & Nestler, E. J.. (2007). Epigenetic regulation in psychiatric disorders. Nature Reviews Neuroscience
Plain numerical DOI: 10.1038/nrn2132
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“Many neurological and most psychiatric disorders are not due to mutations in a single gene; rather, they involve molecular disturbances entailing multiple genes and signals that control their expression. recent research has demonstrated that complex ‘epigenetic’ mechanisms, which regulate gene activity without altering the dna code, have long-lasting effects within mature neurons. this review summarizes recent evidence for the existence of sustained epigenetic mechanisms of gene regulation in neurons that have been implicated in the regulation of complex behaviour, including abnormalities in several psychiatric disorders such as depression, drug addiction and schizophrenia. © 2007 nature publishing group.”
Papp, B., & Plath, K.. (2011). Reprogramming to pluripotency: Stepwise resetting of the epigenetic landscape. Cell Research
Plain numerical DOI: 10.1038/cr.2011.28
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“In 2006, the wall came down that limited the experimental conversion of differentiated cells into the pluripotent state. in a landmark report, shinya yamanaka’s group described that a handful of transcription factors (oct4, sox2, klf4 and c-myc) can convert a differentiated cell back to pluripotency over the course of a few weeks, thus reprograming them into induced pluripotent stem (ips) cells. the birth of ips cells started off a rush among researchers to increase the efficiency of the reprogramming process, to reveal the underlying mechanistic events, and allowed the generation of patient- and disease-specific human ips cells, which have the potential to be converted into relevant specialized cell types for replacement therapies and disease modeling. this review addresses the steps involved in resetting the epigenetic landscape during reprogramming. apparently, defined events occur during the course of the reprogramming process. immediately, upon expression of the reprogramming factors, some cells start to divide faster and quickly begin to lose their differentiated cell characteristics with robust downregulation of somatic genes. only a subset of cells continue to upregulate the embryonic expression program, and finally, pluripotency genes are upregulated establishing an embryonic stem cell-like transcriptome and epigenome with pluripotent capabilities. understanding reprogramming to pluripotency will inform mechanistic studies of lineage switching, in which differentiated cells from one lineage can be directly reprogrammed into another without going through a pluripotent intermediate. © 2011 ibcb, sibs, cas all rights reserved.”
Vicente-Dueñas, C., Hauer, J., Cobaleda, C., Borkhardt, A., & Sánchez-García, I.. (2018). Epigenetic Priming in Cancer Initiation. Trends in Cancer
Plain numerical DOI: 10.1016/j.trecan.2018.04.007
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“Recent evidence from hematopoietic and epithelial tumors revealed that the contribution of oncogenes to cancer development is mediated mainly through epigenetic priming of cancer-initiating cells, suggesting that genetic lesions that initiate the cancer process might be dispensable for the posterior tumor progression and maintenance. epigenetic priming may remain latent until it is later triggered by endogenous or environmental stimuli. this opinion article addresses the impact of epigenetic priming in cancer development and in the design of new therapeutic approaches.”
Kelly, T. K., De Carvalho, D. D., & Jones, P. A.. (2010). Epigenetic modifications as therapeutic targets. Nature Biotechnology
Plain numerical DOI: 10.1038/nbt.1678
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“Epigenetic modifications work in concert with genetic mechanisms to regulate transcriptional activity in normal tissues and are often dysregulated in disease. although they are somatically heritable, modifications of dna and histones are also reversible, making them good targets for therapeutic intervention. epigenetic changes often precede disease pathology, making them valuable diagnostic indicators for disease risk or prognostic indicators for disease progression. several inhibitors of histone deacetylation or dna methylation are approved for hematological malignancies by the us food and drug administration and have been in clinical use for several years. more recently, histone methylation and microrna expression have gained attention as potential therapeutic targets. the presence of multiple epigenetic aberrations within malignant tissue and the abilities of cells to develop resistance suggest that epigenetic therapies are most beneficial when combined with other anticancer strategies, such as signal transduction inhibitors or cytotoxic treatments. a key challenge for future epigenetic therapies will be to develop inhibitors with specificity to particular regions of chromosomes, thereby potentially reducing side effects. © 2010 nature america, inc. all rights reserved.”
Nemoda, Z., & Szyf, M.. (2017). Epigenetic Alterations and Prenatal Maternal Depression. Birth Defects Research
Plain numerical DOI: 10.1002/bdr2.1081
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“Major depressive disorder of the mother affects 6 to 17% of pregnancies worldwide and can lead to negative outcomes, such as preterm delivery and later mental health problems of the child. it has been proposed that developmental programming has long-lasting effects in the offspring that might be mediated by epigenetic mechanisms, such as dna methylation. altered stress regulation or impaired immunological function of the mother can potentially affect dna methylation processes of the fetus, changing gene expression levels in utero. these underlying biological processes can be tested in animal models, where pharmacological experiments using epigenetic drugs can prove causality. recent human studies show that dna methylation changes of hypothesis-driven candidate gene regions, such as the promoter of the glucocorticoid receptor and the serotonin transporter, were associated with maternal depression in peripheral tissue samples of newborns’ cord blood, infants’ saliva, or adults’ peripheral blood. in addition, epigenome-wide association studies using blood cells show modest but significant changes in a subset of genes involved in immune functions. these dna methylation changes were found mainly in enhancers, which point to regulatory effects in gene expression. limited number of studies using brain tissue showed a significant overlap of differentially methylated genes in the different studies. in conclusion, prenatal maternal depression can induce covalent modifications in the offspring’s dna, which are detectable at birth in leukocytes and could be potentially present in other tissues, consistent with the hypothesis that system-wide epigenetic changes are involved in life-long responses to the psychosocial environment in utero. birth defects research 109:888–897, 2017. © 2017 wiley periodicals, inc.”
Wardhana, W., & Soeatmadji, D. W.. (
2019).
The Role of Epigenetic Changes in The Development of Diabetes Mellitus.
Acta Medica Indonesiana
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“Diabetes mellitus (dm) is one of the most abundant diseases in the 21st century and believed as result of interaction between genes and environment exposure. there is a hypotesis of epigenetic mechanisms, using molecular basis to explain about the mechanism of dm. because of the enviromental exposure including nutrition status and hyperglycemia state, the risk of dm has started since pre-conception, last until adulthood and will be inhireted trans-generational . mainly, there are 3 epigenetic mechanisms that have role in dm. epigenetic mechanisms are also have role in the metabolic memory that the dm complications may still developed although the blood glucose level is already normal. the restriction of calory intake may help delaying the development and onset of degerative diseases including dm by stabilizing genome through epigenetic mechanisms.”
Daniel, S., Nylander, V., Ingerslev, L. R., Zhong, L., Fabre, O., Clifford, B., … Simar, D.. (2018). T cell epigenetic remodeling and accelerated epigenetic aging are linked to long-term immune alterations in childhood cancer survivors 11 Medical and Health Sciences 1107 Immunology. Clinical Epigenetics
Plain numerical DOI: 10.1186/s13148-018-0561-5
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“Background: cancer treatments have substantially improved childhood cancer survival but are accompanied by long-term complications, notably chronic inflammatory diseases. we hypothesize that cancer treatments could lead to long-term epigenetic changes in immune cells, resulting in increased prevalence of inflammatory diseases in cancer survivors. results: to test this hypothesis, we established the epigenetic and transcriptomic profiles of immune cells from 44 childhood cancer survivors (ccs, > 16 years old) on full remission (> 5 years) who had received chemotherapy alone or in combination with total body irradiation (tbi) and hematopoietic stem cell transplant (hsct). we found that more than 10 years post-treatment, ccs treated with tbi/hsct showed an altered dna methylation signature in t cell, particularly at genes controlling immune and inflammatory processes and oxidative stress. dna methylation remodeling in t cell was partially associated with chronic expression changes of nearby genes, increased frequency of type 1 cytokine-producing t cell, elevated systemic levels of these cytokines, and over-activation of related signaling pathways. survivors exposed to tbi/hsct were further characterized by an epigenetic-aging-signature of t cell consistent with accelerated epigenetic aging. to investigate the potential contribution of irradiation to these changes, we established two cell culture models. we identified that radiation partially recapitulated the immune changes observed in survivors through a bystander effect that could be mediated by circulating factors. conclusion: cancer treatments, in particular tbi/hsct, are associated with long-term immune disturbances. we propose that epigenetic remodeling of immune cells following cancer therapy augments inflammatory- and age-related diseases, including metabolic complications, in childhood cancer survivors.”
Hu, J., & Yu, Y.. (2019). Epigenetic response profiles into environmental epigenotoxicant screening and health risk assessment: A critical review. Chemosphere
Plain numerical DOI: 10.1016/j.chemosphere.2019.03.096
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“The epigenome may be an important interface between exposure to environmental contaminants and adverse outcome on human health. many environmental pollutants deregulate gene expression and promote diseases by modulating the epigenome. adverse epigenetic responses have been widely used for risk assessment of chemical substances. various pollutants, including trace elements and persistent organic pollutants, have been detected frequently in the environment. epigenetic toxicity of environmental matrices including water, air, soil, and food cannot be ignored. this review provides a comprehensive overview of epigenetic effects of pollutants and environmental matrices. we start with an overview of the mechanisms of epigenetic regulation and the effects of several types of environmental pollutants (trace elements, persistent organic pollutants, endocrine disrupting chemicals, and volatile organic pollutants) on epigenetic modulation. we then discuss the epigenetic responses to environmental water, air, and soil based on in vivo and in vitro assays. finally, we discuss recommendations to promote the incorporation of epigenotoxicity into contamination screening and health risk assessment.”
Fernández-Ponce, C., Navarro Quiroz, R., Díaz Perez, A., Aroca Martinez, G., Cadena Bonfanti, A., Acosta Hoyos, A., … Navarro Quiroz, E.. (2021). MicroRNAs overexpressed in Crohn’s disease and their interactions with mechanisms of epigenetic regulation explain novel aspects of Crohn’s disease pathogenesis. Clinical Epigenetics
Plain numerical DOI: 10.1186/s13148-021-01022-8
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“Background: in this review, we were interested to identify the wide universe of enzymes associated with epigenetic modifications, whose gene expression is regulated by mirnas with a high relative abundance in crohn’s disease (cd) affected tissues, with the aim to determine their impact in the pathogenesis and evolution of the disease. methods: we used hmdd and bibliometrix r-package in order to identify the mirnas overexpressed in cd. the identified enzymes associated with epigenetic mechanisms and post-translational modifications, regulated by mirnas upregulated in cd, were analyzed using string v11 database. results: we found 190 mirnas with great abundance in patients with cd, of which 26 mirnas regulate the gene expression of enzymes known to catalyze epigenetic modifications involved in essentials pathophysiological processes, such as chromatin architecture reorganization, immune response regulation including cd4+ t cells polarization, integrity of gut mucosa, gut microbiota composition and tumorigenesis. conclusion: the integrated analysis of mirnas with a high relative abundance in patients with cd showed a combined and superimposed gene expression regulation of enzymes associated with relevant epigenetic mechanisms and that could explain, in part, the pathogenesis of cd.”
Imgenberg-Kreuz, J., Sandling, J. K., & Nordmark, G.. (2018). Epigenetic alterations in primary Sjögren’s syndrome – an overview. Clinical Immunology
Plain numerical DOI: 10.1016/j.clim.2018.04.004
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“Primary sjögren’s syndrome (pss) is a chronic autoimmune rheumatic disease characterized by inflammation of exocrine glands, mainly salivary and lacrimal glands. in addition, pss may affect multiple other organs resulting in systemic manifestations. although the precise etiology of pss remains elusive, pss is considered to be a multi-factorial disease, where underlying genetic predisposition, environmental factors and epigenetic mechanisms contribute to disease development. epigenetic mechanisms, such as dna methylation, histone modifications and non-coding rnas, may constitute a dynamic link between genome, environment and phenotypic manifestation by their modulating effects on gene expression. a growing body of studies reporting altered epigenetic landscapes in pss suggests that epigenetic mechanisms play a role in the pathogenesis of pss, and the reversible nature of epigenetic modifications suggests therapeutic strategies targeting epigenetic dysregulation in pss. this article reviews our current understanding of epigenetic mechanisms in pss and discusses implications for novel diagnostic and therapeutic approaches.”
He, Y., Chen, T., & Zeng, X.. (2020). Genetic and Epigenetic Understanding of the Seasonal Timing of Flowering. Plant Communications
Plain numerical DOI: 10.1016/j.xplc.2019.100008
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“The developmental transition to flowering in many plants is timed by changing seasons, which enables plants to flower at a season that is favorable for seed production. many plants grown at high latitudes perceive the seasonal cues of changing day length and/or winter cold (prolonged cold exposure), to regulate the expression of flowering-regulatory genes through the photoperiod pathway and/or vernalization pathway, and thus align flowering with a particular season. recent studies in the model flowering plant arabidopsis thaliana have revealed that diverse transcription factors engage various chromatin modifiers to regulate several key flowering-regulatory genes including flowering locus c (flc) and flowering locus t (ft) in response to seasonal signals. here, we summarize the current understanding of molecular and chromatin-regulatory or epigenetic mechanisms underlying the vernalization response and photoperiodic control of flowering in arabidopsis. moreover, the conservation and divergence of regulatory mechanisms for seasonal flowering in crops and other plants are briefly discussed.”
Smith, A., Kaufman, F., Sandy, M. S., & Cardenas, A.. (2020). Cannabis Exposure During Critical Windows of Development: Epigenetic and Molecular Pathways Implicated in Neuropsychiatric Disease. Current Environmental Health Reports
Plain numerical DOI: 10.1007/s40572-020-00275-4
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“Purpose of review: cannabis exposure during critical windows of development may have intergenerational physiological consequences disrupting epigenetic programming and marks. this review examines the literature relating to pre-gestational and prenatal cannabinoid exposure and its effect on genes and molecular pathways related to the development of psychiatric disease. recent findings: developmental cannabis exposure alters epigenetic processes with functional gene consequences. these include potentially heritable alterations in genes and molecular pathways critical for brain development and associated with autism spectrum disorder (asd), attention deficit hyperactivity disorder (adhd), schizophrenia, addiction, and other psychiatric diseases. summary: cannabis consumption and mental health illness in adolescents and young adults are increasing in the united states (u.s.), and recent studies suggest that cannabis consumption during critical periods of brain development could contribute to mental health illness through epigenetic mechanisms. these findings warrant future studies and consideration by regulators and health communicators.”
Kresovich, J. K., Xu, Z., O’Brien, K. M., Weinberg, C. R., Sandler, D. P., & Taylor, J. A.. (2019). Epigenetic mortality predictors and incidence of breast cancer. Aging
Plain numerical DOI: 10.18632/aging.102523
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“Measures derived using blood dna methylation are increasingly under investigation as indicators of disease and mortality risk. three existing epigenetic age measures or ‘epigenetic clocks’ appear associated with breast cancer. two newly-developed epigenetic mortality predictors may be related to all-cancer incidence, but associations with specific cancers have not been examined in large studies. using humanmethylation450 beadchips to measure blood dna methylation in 2,773 cancer-free women enrolled in the sister study, we calculated two epigenetic mortality predictors: ‘Grimageaccel’ and the ‘mortality score’ (ms). using cox proportional hazard models, neither grimageaccel nor the ms were associated with overall breast cancer incidence (grimageaccel hazard ratio [hr]: 1.06, 95% confidence interval [ci]: 0.98-1.14, p=0.17; ms hr: 0.99, 95% ci: 0.92-1.07, p=0.85); however, a weak, positive association was observed for grimageaccel and invasive breast cancer (hr: 1.08, 95% ci: 0.99-1.17, p=0.08). stratification of invasive cancers by menopause status at diagnoses revealed the association was predominantly observed for postmenopausal breast cancer (hr: 1.10, 95% ci: 1.01, 1.20, p=0.04). although the ms was unrelated to breast cancer risk, we find evidence that grimageaccel may be weakly associated with invasive breast cancer, particularly for women diagnosed after menopause.”
Celiker, C., & Kalkan, R.. (2020). Genetic and epigenetic perspective of microbiota. Applied Microbiology and Biotechnology
Plain numerical DOI: 10.1007/s00253-020-10849-9
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“Abstract: the gut microbiota has an extremely important role within the body and it is necessary for the regulation of the metabolism of the host and also for the development of metabolic diseases such as obesity. here, we show several different factors leading to obesity such as epigenetic changes and how they result in differences to occur in the gut microbiota, along with gut dysbiosis which is caused by disturbances in the microbiota homeostasis. several studies have been explained in this paper, providing evidence in how these findings can actually decrease the susceptibility of obesity, whether it be by changing an individual’s diet pattern or observing the epigenetic changes which are taking place. key points: • the microbiota depends on an individual’s diet, lifestyle, environment, genetics and epigenetic profile. • changes of the gut microbiota can increase obesity susceptibility. • non-coding rna has an important role in the metabolic homeostasis in check so if a disturbance occurs it can lead to resistance to obesity.”
Qi, Y., Wang, D., Wang, D., Jin, T., Yang, L., Wu, H., … Wang, R.. (2016). HEDD: The human epigenetic drug database. Database
Plain numerical DOI: 10.1093/database/baw159
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“Epigenetic drugs are chemical compounds that target disordered post-translational modification of histone proteins and dna through enzymes, and the recognition of these changes by adaptor proteins. epigenetic drug-related experimental data such as gene expression probed by high-throughput sequencing, co-crystal structure probed by x-ray diffraction and binding constants probed by bio-assay have become widely available. the mining and integration of multiple kinds of data can be beneficial to drug discovery and drug repurposing. hemd and other epigenetic databases store comprehensively epigenetic data where users can acquire segmental information of epigenetic drugs. however, some data types such as high-throughput datasets are not provide by these databases and they do not support flexible queries for epigenetic drug-related experimental data. therefore, in reference to hemd and other epigenetic databases, we developed a relatively comprehensive database for human epigenetic drugs. the human epigenetic drug database (hedd) focuses on the storage and integration of epigenetic drug datasets obtained from laboratory experiments and manually curated information. the latest release of hedd incorporates five kinds of datasets: (i) drug, (ii) target, (iii) disease, (vi) high-throughput and (v) complex. in order to facilitate data extraction, flexible search options were built in hedd, which allowed an unlimited condition query for specific kinds of datasets using drug names, diseases and experiment types.”
Herppich, S., Toker, A., Pietzsch, B., Kitagawa, Y., Ohkura, N., Miyao, T., … Huehn, J.. (2019). Dynamic Imprinting of the Treg Cell-Specific Epigenetic Signature in Developing Thymic Regulatory T Cells. Frontiers in Immunology
Plain numerical DOI: 10.3389/fimmu.2019.02382
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“Regulatory t (treg) cells mainly develop within the thymus and arise from cd25+foxp3− (cd25+ tregp) or cd25−foxp3+ (foxp3+ tregp) treg cell precursors resulting in treg cells harboring distinct transcriptomic profiles and complementary t cell receptor repertoires. the stable and long-term expression of foxp3 in treg cells and their stable suppressive phenotype are controlled by the demethylation of treg cell-specific epigenetic signature genes including an evolutionarily conserved cpg-rich element within the foxp3 locus, the treg-specific demethylated region (tsdr). here we analyzed the dynamics of the imprinting of the treg cell-specific epigenetic signature genes in thymic treg cells. we could demonstrate that cd25+foxp3+ treg cells show a progressive demethylation of most signature genes during maturation within the thymus. interestingly, a partial demethylation of several treg cell-specific epigenetic signature genes was already observed in foxp3+ tregp but not in cd25+ tregp. furthermore, foxp3+ tregp were very transient in nature and arose at a more mature developmental stage when compared to cd25+ tregp. when the two treg cell precursors were cultured in presence of il-2, a factor known to be critical for thymic treg cell development, we observed a major impact of il-2 on the demethylation of the tsdr with a more pronounced effect on foxp3+ tregp. together, these results suggest that the establishment of the treg cell-specific hypomethylation pattern is a continuous process throughout thymic treg cell development and that the two known treg cell precursors display distinct dynamics for the imprinting of the treg cell-specific epigenetic signature genes.”
Yu, X., Mao, W., Zhai, Y., Tong, C., Liu, M., Ma, L., … Li, S.. (2017). Anti-tumor activity of metformin: From metabolic and epigenetic perspectives. Oncotarget
Plain numerical DOI: 10.18632/oncotarget.13639
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“Metformin has been used to treat type 2 diabetes for over 50 years. epidemiological, preclinical and clinical studies suggest that metformin treatment reduces cancer incidence in diabetes patients. due to its potential as an anti-cancer agent and its low cost, metformin has gained intense research interest. its traditional anti-cancer mechanisms involve both indirect and direct insulin-dependent pathways. here, we discussed the anti-tumor mechanism of metformin from the aspects of cell metabolism and epigenetic modifications. the effects of metformin on anti-cancer immunity and apoptosis were also described. understanding these mechanisms will shed lights on application of metformin in clinical trials and development of anti-cancer therapy.”
Lee, Y. C. G., & Karpen, G. H.. (2017). Pervasive epigenetic effects of drosophila euchromatic transposable elements impact their evolution. ELife
Plain numerical DOI: 10.7554/eLife.25762
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“Transposable elements (tes) are widespread genomic parasites, and their evolution has remained a critical question in evolutionary genomics. here, we study the relatively unexplored epigenetic impacts of tes and provide the first genome-wide quantification of such effects in d. melanogaster and d. simulans. surprisingly, the spread of repressive epigenetic marks (histone h3k9me2) to nearby dna occurs at >50% of euchromatic tes, and can extend up to 20 kb. this results in differential epigenetic states of genic alleles and, in turn, selection against tes. interestingly, the lower te content in d. simulans compared to d. melanogaster correlates with stronger epigenetic effects of tes and higher levels of host genetic factors known to promote epigenetic silencing. our study demonstrates that the epigenetic effects of euchromatic tes, and host genetic factors modulating such effects, play a critical role in the evolution of tes both within and between species.”
Zhu, T., Zheng, S. C., Paul, D. S., Horvath, S., & Teschendorff, A. E.. (2018). Cell and tissue type independent age-associated DNA methylation changes are not rare but common. Aging
Plain numerical DOI: 10.18632/aging.101666
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“Age-associated dna methylation changes have been widely reported across many different tissue and cell types. epigenetic ‘clocks’ that can predict chronological age with a surprisingly high degree of accuracy appear to do so independently of tissue and cell-type, suggesting that a component of epigenetic drift is cell-type independent. however, the relative amount of age-associated dnam changes that are specific to a cell or tissue type versus the amount that occurs independently of cell or tissue type is unclear and a matter of debate, with a recent study concluding that most epigenetic drift is tissue-specific. here, we perform a novel comprehensive statistical analysis, including matched multi cell-type and multi-tissue dna methylation profiles from the same individuals and adjusting for cell-type heterogeneity, demonstrating that a substantial amount of epigenetic drift, possibly over 70%, is shared between significant numbers of different tissue/cell types. we further show that elovl2 is not unique and that many other cpg sites, some mapping to genes in the wnt and glutamate receptor signaling pathways, are altered with age across at least 10 different cell/tissue types. we propose that while most age-associated dnam changes are shared between cell-types that the putative functional effect is likely to be tissue-specific.”
Zhou, Z., Lin, Z., Pang, X., Tariq, M. A., Ao, X., Li, P., & Wang, J.. (2018). Epigenetic regulation of long non-coding RNAs in gastric cancer. Oncotarget
Plain numerical DOI: 10.18632/oncotarget.23821
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“Gastric cancer is one of the most common cancers and is the second leading cause of cancer mortality worldwide. therefore, it is urgent to explore new molecular biomarkers for early diagnosis, early treatment and prognosis for gastric cancer patients. recently, increasing evidence has shown that epigenetic changes, such as aberrant dna methylation, histone modifications, and noncoding rnas (ncrnas) expression, play substantial roles in the development and progression of malignancies. among these changes, long non-coding rnas (lncrnas), a novel class of ncrnas, are emerging as highly versatile actors in a variety of cellular processes by regulating gene expression at the epigenetic level as well as at the transcriptional and posttranscriptional levels. hundreds of lncrnas become dysregulated in the various pathological processes of gastric cancer, and multiple lncrnas have been reported to function as tumor-suppressors or oncogenes, although the underlying mechanisms are still under investigation. here, we provide an overview of the epigenetic regulation of chromatin and the molecular functions of lncrnas; we focus on lncrna-mediated epigenetic regulation of cancer-related gene expression in gastric cancer, as well as discuss the clinical implications of lncrnas on epigenetic-related cancer treatments, which may contribute helpful approaches for the development of new potential strategies for future diagnosis and therapeutic intervention in human cancers.”
Eimer, H., Sureshkumar, S., Singh Yadav, A., Kraupner-Taylor, C., Bandaranayake, C., Seleznev, A., … Balasubramanian, S.. (2018). RNA-Dependent Epigenetic Silencing Directs Transcriptional Downregulation Caused by Intronic Repeat Expansions. Cell
Plain numerical DOI: 10.1016/j.cell.2018.06.044
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“Transcriptional downregulation caused by intronic triplet repeat expansions underlies diseases such as friedreich’s ataxia. this downregulation of gene expression is coupled with epigenetic changes, but the underlying mechanisms are unknown. here, we show that an intronic gaa/ttc triplet expansion within the iil1 gene of arabidopsis thaliana results in accumulation of 24-nt short interfering rnas (sirnas) and repressive histone marks at the iil1 locus, which in turn causes its transcriptional downregulation and an associated phenotype. knocking down dicer like-3 (dcl3), which produces 24-nt sirnas, suppressed transcriptional downregulation of iil1 and the triplet expansion-associated phenotype. furthermore, knocking down additional components of the rna-dependent dna methylation (rddm) pathway also suppressed both transcriptional downregulation of iil1 and the repeat expansion-associated phenotype. thus, our results show that triplet repeat expansions can lead to local sirna biogenesis, which in turn downregulates transcription through an rddm-dependent epigenetic modification. triplet expansions within an arabidopsis gene leads to local sirna biogenesis and consequent transcriptional downregulation, suggesting how intronic repeat expansions may affect gene expression in other systems.”
Hanniford, D., Ulloa-Morales, A., Karz, A., Berzoti-Coelho, M. G., Moubarak, R. S., Sánchez-Sendra, B., … Hernando, E.. (2020). Epigenetic Silencing of CDR1as Drives IGF2BP3-Mediated Melanoma Invasion and Metastasis. Cancer Cell
Plain numerical DOI: 10.1016/j.ccell.2019.12.007
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“Investigating the role of circular rnas (circrna) in metastasis, hanniford et al. observe epigenetic silencing of circrna cdr1as in melanoma progression. depletion of cdr1as promotes melanoma metastasis via an igf2bp3-mediated mechanism that is independent of its well-characterized regulation of mir-7.”
Luna, R. C. P., De Oliveira, Y., Lisboa, J. V. C., Chaves, T. R., De Araújo, T. A. M., De Sousa, E. E., … De Brito Alves, J. L.. (2018). Insights on the epigenetic mechanisms underlying pulmonary arterial hypertension. Brazilian Journal of Medical and Biological Research
Plain numerical DOI: 10.1590/1414-431X20187437
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“Pulmonary arterial hypertension (pah), characterized by localized increased arterial blood pressure in the lungs, is a slow developing long-term disease that can be fatal. pah is characterized by inflammation, vascular tone imbalance, pathological pulmonary vascular remodeling, and right-sided heart failure. current treatments for pah are palliative and development of new therapies is necessary. recent and relevant studies have demonstrated that epigenetic processes may exert key influences on the pathogenesis of pah and may be promising therapeutic targets in the prevention and/or cure of this condition. the aim of the present mini-review is to summarize the occurrence of epigenetic-based mechanisms in the context of pah physiopathology, focusing on the roles of dna methylation, histone post-translational modifications and non-coding rnas. we also discuss the potential of epigenetic-based therapies for pah.”
Lehrner, A., & Yehuda, R.. (2018). Cultural trauma and epigenetic inheritance. Development and Psychopathology
Plain numerical DOI: 10.1017/S0954579418001153
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“The question of whether and how the effects of cultural trauma can be transmitted intergenerationally from parents to offspring, or even to later generations, has evoked interest and controversy in academic and popular forums. recent methodological advances have spurred investigations of potential epigenetic mechanisms for this inheritance, representing an exciting area of emergent research. epigenetics has been described as the means through which environmental influences get under the skin, directing transcriptional activity and influencing the expression or suppression of genes. over the past decade, this complex environment-biology interface has shown increasing promise as a potential pathway for the intergenerational transmission of the effects of trauma. this article reviews challenges facing research on cultural trauma, biological findings in trauma and posttraumatic stress disorder, and putative epigenetic mechanisms for transmission of trauma effects, including through social, intrauterine, and gametic pathways. implications for transmission of cultural trauma effects are discussed, focused on the relevance of cultural narratives and the possibilities of resilience and adaptivity.”
Wu, S., Zhang, J., Li, F., Du, W., Zhou, X., Wan, M., … Zhou, Y.. (2019). One-carbon metabolism links nutrition intake to embryonic development via epigenetic mechanisms. Stem Cells International
Plain numerical DOI: 10.1155/2019/3894101
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“Beyond energy production, nutrient metabolism plays a crucial role in stem cell lineage determination. changes in metabolism based on nutrient availability and dietary habits impact stem cell identity. evidence suggests a strong link between metabolism and epigenetic mechanisms occurring during embryonic development and later life of offspring. metabolism regulates epigenetic mechanisms such as modifications of dna, histones, and micrornas. in turn, these epigenetic mechanisms regulate metabolic pathways to modify the metabolome. one-carbon metabolism (ocm) is a crucial metabolic process involving transfer of the methyl groups leading to regulation of multiple cellular activities. ocm cycles and its related micronutrients are ubiquitously present in stem cells and feed into the epigenetic mechanisms. in this review, we briefly introduce the ocm process and involved micronutrients and discuss ocm-associated epigenetic modifications, including dna methylation, histone modification, and micrornas. we further consider the underlying ocm-mediated link between nutrition and epigenetic modifications in embryonic development.”
Jablonka, E., & Lamb, M. J.. (2015). The inheritance of acquired epigenetic variations. International Journal of Epidemiology
Plain numerical DOI: 10.1093/ije/dyv020
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“There is evidence that the functional history of a gene in one generation can influence its expression in the next. in somatic cells, changes in gene activity are frequently associated with changes in the pattern of methylation of the cytosines in dna; these methylation patterns are stably inherited. recent work suggests that information about patterns of methylation and other epigenetic states can also be transmitted from parents to offspring. this evidence is the basis of a model for the inheritance of acquired epigenetic variations. according to the model, an environmental stimulus can induce heritable chromatin modifications which are very specific and predictable, and might result in an adaptive response to the stimulus. this type of response probably has most significance for adaptive evolution in organisms such as fungi and plants, which lack distinct segregation of the soma and germ line. however, in all organisms, the accumulation of specific and random chromatin modifications in the germ line may be important in speciation, because these modifications could lead to reproductive isolation between populations. heritable chromatin variations may also alter the frequency and distribution of classical mutations and meiotic recombination. therefore, inherited epigenetic changes in the structure of chromatin can influence neo-darwinian evolution as well as cause a type of ‘lamarckian’ inheritance.”
Eirin-Lopez, J. M., & Putnam, H. M.. (2019). Marine environmental epigenetics. Annual Review of Marine Science
Plain numerical DOI: 10.1146/annurev-marine-010318-095114
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“Marine organisms’ persistence hinges on the capacity for acclimatization and adaptation to the myriad of interacting environmental stressors associated with global climate change. in this context, epigenetics – mechanisms that facilitate phenotypic variation through genotype-environment interactions – are of great interest ecologically and evolutionarily. our comprehensive review of marine environmental epigenetics guides our recommendations of four key areas for future research: the dynamics of wash-in and wash-out of epigenetic effects, the mechanistic understanding of the interplay of different epigenetic marks and the interaction with the microbiome, the capacity for and mechanisms of transgenerational epigenetic inheritance, and the evolutionary implications of the interaction of genetic and epigenetic features. emerging insights in marine environmental epigenetics can be applied to critical issues such as aquaculture, biomonitoring, and biological invasions, thereby improving our ability to explain and predict the responses of marine taxa to global climate change.”
Bocklandt, S., Lin, W., Sehl, M. E., Sánchez, F. J., Sinsheimer, J. S., Horvath, S., & Vilain, E.. (2011). Epigenetic predictor of age. PLoS ONE
Plain numerical DOI: 10.1371/journal.pone.0014821
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“From the moment of conception, we begin to age. a decay of cellular structures, gene regulation, and dna sequence ages cells and organisms. dna methylation patterns change with increasing age and contribute to age related disease. here we identify 88 sites in or near 80 genes for which the degree of cytosine methylation is significantly correlated with age in saliva of 34 male identical twin pairs between 21 and 55 years of age. furthermore, we validated sites in the promoters of three genes and replicated our results in a general population sample of 31 males and 29 females between 18 and 70 years of age. the methylation of three sites-in the promoters of the edaradd, tom1l1, and nptx2 genes-is linear with age over a range of five decades. using just two cytosines from these loci, we built a regression model that explained 73% of the variance in age, and is able to predict the age of an individual with an average accuracy of 5.2 years. in forensic science, such a model could estimate the age of a person, based on a biological sample alone. furthermore, a measurement of relevant sites in the genome could be a tool in routine medical screening to predict the risk of age-related diseases and to tailor interventions based on the epigenetic bio-age instead of the chronological age. © 2011 bocklandt et al.”
Jühling, F., Hamdane, N., Crouchet, E., Li, S., El Saghire, H., Mukherji, A., … Baumert, T. F.. (2021). Targeting clinical epigenetic reprogramming for chemoprevention of metabolic and viral hepatocellular carcinoma. Gut
Plain numerical DOI: 10.1136/gutjnl-2019-318918
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“Objective hepatocellular carcinoma (hcc) is the fastest-growing cause of cancer-related mortality with chronic viral hepatitis and non-alcoholic steatohepatitis (nash) as major aetiologies. treatment options for hcc are unsatisfactory and chemopreventive approaches are absent. chronic hepatitis c (chc) results in epigenetic alterations driving hcc risk and persisting following cure. here, we aimed to investigate epigenetic modifications as targets for liver cancer chemoprevention. design liver tissues from patients with nash and chc were analysed by chip-seq (h3k27ac) and rna-seq. the liver disease-specific epigenetic and transcriptional reprogramming in patients was modelled in a liver cell culture system. perturbation studies combined with a targeted small molecule screen followed by in vivo and ex vivo validation were used to identify chromatin modifiers and readers for hcc chemoprevention. results in patients, chc and nash share similar epigenetic and transcriptomic modifications driving cancer risk. using a cell-based system modelling epigenetic modifications in patients, we identified chromatin readers as targets to revert liver gene transcription driving clinical hcc risk. proof-of-concept studies in a nash-hcc mouse model showed that the pharmacological inhibition of chromatin reader bromodomain 4 inhibited liver disease progression and hepatocarcinogenesis by restoring transcriptional reprogramming of the genes that were epigenetically altered in patients. conclusion our results unravel the functional relevance of metabolic and virus-induced epigenetic alterations for pathogenesis of hcc development and identify chromatin readers as targets for chemoprevention in patients with chronic liver diseases.”
Report, A.. (
2019).
व ा र ् ष ि क प ् रत ि व े दन Annual Report Annual Report.
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“A growing body of evidence points towards epigenetic mechanisms being responsible for a wide range of biological phenomena, from the plasticity of plant growth and development to the nutritional control of caste determination in honeybees and the etiology of human disease (e.g., cancer). with the (partial) elucidation of the molecular basis of epigenetic variation and the heritability of certain of these changes, the field of evolutionary epigenetics is flourishing. despite this, the role of epigenetics in shaping host–pathogen interactions has received comparatively little attention. yet there is plenty of evidence supporting the implication of epigenetic mechanisms in the modulation of the biological interaction between hosts and pathogens. the phenotypic plasticity of many key parasite life-history traits appears to be under epigenetic control. moreover, pathogen-induced effects in host phenotype may have transgenerational consequences, and the bases of these changes and their heritability probably have an epigenetic component. the significance of epigenetic modifications may, however, go beyond providing a mechanistic basis for host and pathogen plasticity. epigenetic epidemiology has recently emerged as a promising area for future research on infectious diseases. in addition, the incorporation of epigenetic inheritance and epigenetic plasticity mechanisms to evolutionary models and empirical studies of host–pathogen interactions will provide new insights into the evolution and coevolution of these associations. here, we review the evidence available for the role epigenetics on host–pathogen interactions, and the utility and versatility of the epigenetic technologies available that can be cross-applied to host–pathogen studies. we conclude with recommendations and directions for future research on the burgeoning field of epigenetics as applied to host–pathogen interactions.”
Chauvistré, H., & Seré, K.. (2020). Epigenetic aspects of DC development and differentiation. Molecular Immunology
Plain numerical DOI: 10.1016/j.molimm.2020.10.011
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“In this review we introduce the basic principles of epigenetic gene regulation and discuss them in the context of dendritic cell (dc) development and differentiation. epigenetic mechanisms control the accessibility of chromatin for dna binding proteins and thus they control gene expression. these mechanisms comprise chemical modifications of dna and histones, chromatin remodeling and chromatin conformation. the variety of epigenetic mechanisms allow high-end fine tuning and flexibility of gene expression, a prerequisite in the process of dc lineage development.”
Lester, B. M., & Marsit, C. J.. (2018). Epigenetic mechanisms in the placenta related to infant neurodevelopment. Epigenomics
Plain numerical DOI: 10.2217/epi-2016-0171
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“As the ‘third brain’ the placenta links the developing fetal brain and the maternal brain enabling study of epigenetic process in placental genes that affect infant neurodevelopment. we described the characteristics and findings of the 17 studies on epigenetic processes in placental genes and human infant neurobehavior. studies showed consistent findings in the same cohort of term healthy infants across epigenetic processes (dna methylation, genome wide, gene and mirna expression) genomic region (single and multiple genes, imprinted genes and mirnas) using candidate gene and genome wide approaches and across biobehavioral systems (neurobehavior, cry acoustics and neuroendocrine). despite limitations, studies support future work on molecular processes in placental genes related to neurodevelopmental trajectories including implications for intervention.”
Babenko, O., Kovalchuk, I., & Metz, G. A. S.. (2015). Stress-induced perinatal and transgenerational epigenetic programming of brain development and mental health. Neuroscience and Biobehavioral Reviews
Plain numerical DOI: 10.1016/j.neubiorev.2014.11.013
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“Research efforts during the past decades have provided intriguing evidence suggesting that stressful experiences during pregnancy exert long-term consequences on the future mental wellbeing of both the mother and her baby. recent human epidemiological and animal studies indicate that stressful experiences in utero or during early life may increase the risk of neurological and psychiatric disorders, arguably via altered epigenetic regulation. epigenetic mechanisms, such as mirna expression, dna methylation, and histone modifications are prone to changes in response to stressful experiences and hostile environmental factors. altered epigenetic regulation may potentially influence fetal endocrine programming and brain development across several generations. only recently, however, more attention has been paid to possible transgenerational effects of stress. in this review we discuss the evidence of transgenerational epigenetic inheritance of stress exposure in human studies and animal models. we highlight the complex interplay between prenatal stress exposure, associated changes in mirna expression and dna methylation in placenta and brain and possible links to greater risks of schizophrenia, attention deficit hyperactivity disorder, autism, anxiety- or depression-related disorders later in life. based on existing evidence, we propose that prenatal stress, through the generation of epigenetic alterations, becomes one of the most powerful influences on mental health in later life. the consideration of ancestral and prenatal stress effects on lifetime health trajectories is critical for improving strategies that support healthy development and successful aging.”
Pant, R., Firmal, P., Shah, V. K., Alam, A., & Chattopadhyay, S.. (2021). Epigenetic Regulation of Adipogenesis in Development of Metabolic Syndrome. Frontiers in Cell and Developmental Biology
Plain numerical DOI: 10.3389/fcell.2020.619888
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“Obesity is one of the biggest public health concerns identified by an increase in adipose tissue mass as a result of adipocyte hypertrophy and hyperplasia. pertaining to the importance of adipose tissue in various biological processes, any alteration in its function results in impaired metabolic health. in this review, we discuss how adipose tissue maintains the metabolic health through secretion of various adipokines and inflammatory mediators and how its dysfunction leads to the development of severe metabolic disorders and influences cancer progression. impairment in the adipocyte function occurs due to individuals’ genetics and/or environmental factor(s) that largely affect the epigenetic profile leading to altered gene expression and onset of obesity in adults. moreover, several crucial aspects of adipose biology, including the regulation of different transcription factors, are controlled by epigenetic events. therefore, understanding the intricacies of adipogenesis is crucial for recognizing its relevance in underlying disease conditions and identifying the therapeutic interventions for obesity and metabolic syndrome.”
Nadhamuni, V. S., & Korbonits, M.. (2020). Novel insights into pituitary tumorigenesis: Genetic and epigenetic mechanisms. Endocrine Reviews
Plain numerical DOI: 10.1210/endrev/bnaa006
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“Substantial advances have been made recently in the pathobiology of pituitary tumors. similar to many other endocrine tumors, over the last few years we have recognized the role of germline and somatic mutations in a number of syndromic or nonsyndromic conditions with pituitary tumor predisposition. these include the identification of novel germline variants in patients with familial or simplex pituitary tumors and establishment of novel somatic variants identified through next generation sequencing. advanced techniques have allowed the exploration of epigenetic mechanisms mediated through dna methylation, histone modifications and noncoding rnas, such as microrna, long noncoding rnas and circular rnas. these mechanisms can influence tumor formation, growth, and invasion. while genetic and epigenetic mechanisms often disrupt similar pathways, such as cell cycle regulation, in pituitary tumors there is little overlap between genes altered by germline, somatic, and epigenetic mechanisms. the interplay between these complex mechanisms driving tumorigenesis are best studied in the emerging multiomics studies. here, we summarize insights from the recent developments in the regulation of pituitary tumorigenesis. (endocrine reviews 41: 1 – 26, 2020).”
Morris, B. J., Willcox, B. J., & Donlon, T. A.. (2019). Genetic and epigenetic regulation of human aging and longevity. Biochimica et Biophysica Acta – Molecular Basis of Disease
Plain numerical DOI: 10.1016/j.bbadis.2018.08.039
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“Here we summarize the latest data on genetic and epigenetic contributions to human aging and longevity. whereas environmental and lifestyle factors are important at younger ages, the contribution of genetics appears more important in reaching extreme old age. genome-wide studies have implicated ~57 gene loci in lifespan. epigenomic changes during aging profoundly affect cellular function and stress resistance. dysregulation of transcriptional and chromatin networks is likely a crucial component of aging. large-scale bioinformatic analyses have revealed involvement of numerous interaction networks. as the young well-differentiated cell replicates into eventual senescence there is drift in the highly regulated chromatin marks towards an entropic middle-ground between repressed and active, such that genes that were previously inactive ‘leak’. there is a breakdown in chromatin connectivity such that topologically associated domains and their insulators weaken, and well-defined blocks of constitutive heterochromatin give way to generalized, senescence-associated heterochromatin, foci. together, these phenomena contribute to aging.”
Lee, J., You, J. H., Kim, M. S., & Roh, J. L.. (2020). Epigenetic reprogramming of epithelial-mesenchymal transition promotes ferroptosis of head and neck cancer. Redox Biology
Plain numerical DOI: 10.1016/j.redox.2020.101697
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“Condensed abstract: expression of epithelial-mesenchymal transition (emt) markers was closely related to susceptibility to ferroptosis inducers. epigenetic reprogramming of emt to gain a mesenchymal phenotype, such as sirt1 activation or mir-200 family inhibition, promoted ferroptosis in head and neck cancer cells retaining relatively high epithelial traits and low sensitivity to ferroptosis inducers.”
Wilting, R. H., & Dannenberg, J. H.. (2012). Epigenetic mechanisms in tumorigenesis, tumor cell heterogeneity and drug resistance. Drug Resistance Updates
Plain numerical DOI: 10.1016/j.drup.2012.01.008
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“Resistance of cancer cells to chemotherapeutics and emerging targeted drugs is a devastating problem in the treatment of cancer patients. multiple mechanisms contribute to drug resistance such as increased drug efflux, altered drug metabolism, secondary mutations in drug targets, and activation of downstream or parallel signal transduction pathways. the rapid kinetics, the reversibility of acquired drug resistance and the absence of genetic mutations suggest an epigenetic basis for drug insensitivity. similar to the cellular variance seen in the human body, epigenetic mechanisms, through reversible histone modifications and dna methylation patterns, generate a variety of transcriptional states resulting in a dynamic heterogeneous tumor cell population. consequently, epigenomes favoring survival in the presence of a drug by aberrant transcription of drug transporters, dna-repair enzymes and pro-apoptotic factors render cytotoxic and targeted drugs ineffective and allow selection of rare drug-resistant tumor cells. recent advances in charting cancer genomes indeed strongly indicate a role for epigenetic regulators in driving cancer, which may result in the acquisition of additional (epi)genetic modifications leading to drug resistance. these observations have important clinical consequences as they provide an opportunity for ‘epigenetic drugs’ to change reversible drug-resistance-associated epigenomes to prevent or reverse non-responsiveness to anti-cancer drugs. © 2012 elsevier ltd.”
Mongelli, A., Atlante, S., Bachetti, T., Martelli, F., Farsetti, A., & Gaetano, C.. (2020). Epigenetic signaling and RNA regulation in cardiovascular diseases. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms21020509
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“RNA epigenetics is perhaps the most recent field of interest for translational epigeneticists. rna modifications create such an extensive network of epigenetically driven combinations whose role in physiology and pathophysiology is still far from being elucidated. not surprisingly, some of the players determining changes in rna structure are in common with those involved in dna and chromatin structure regulation, while other molecules seem very specific to rna. it is envisaged, then, that new small molecules, acting selectively on rna epigenetic changes, will be reported soon, opening new therapeutic interventions based on the correction of the rna epigenetic landscape. in this review, we shall summarize some aspects of rna epigenetics limited to those in which the potential clinical translatability to cardiovascular disease is emerging.”
Sheikhpour, M., Maleki, M., Ebrahimi Vargoorani, M., & Amiri, V.. (2021). A review of epigenetic changes in asthma: methylation and acetylation. Clinical Epigenetics
Plain numerical DOI: 10.1186/s13148-021-01049-x
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“Several studies show that childhood and adulthood asthma and its symptoms can be modulated through epigenetic modifications. epigenetic changes are inheritable modifications that can modify the gene expression without changing the dna sequence. the most common epigenetic alternations consist of dna methylation and histone modifications. how these changes lead to asthmatic phenotype or promote the asthma features, in particular by immune pathways regulation, is an understudied topic. since external effects, like exposure to tobacco smoke, air pollution, and drugs, influence both asthma development and the epigenome, elucidating the role of epigenetic changes in asthma is of great importance. this review presents available evidence on the epigenetic process that drives asthma genes and pathways, with a particular focus on dna methylation, histone methylation, and acetylation. we gathered and assessed studies conducted in this field over the past two decades. our study examined asthma in different aspects and also shed light on the limitations and the important factors involved in the outcomes of the studies. to date, most of the studies in this area have been carried out on dna methylation. therefore, the need for diagnostic and therapeutic applications through this molecular process calls for more research on the histone modifications in this disease.”
De Rycke, M., Liebaers, I., & Van Steirteghem, A.. (2002). Epigenetic risks related to assisted reproductive technologies: Risk analysis and epigenetic inheritance. Human Reproduction
Plain numerical DOI: 10.1093/humrep/17.10.2487
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“A broad spectrum of assisted reproductive technologies has become available for couples with fertility problems. follow-up studies of children born as a result of assisted reproduction have shown that neonatal outcome and malformation rates are not different from those of the general population, except for a low birthweight and a slight increase in chromosomal abnormalities. the safety aspect of assisted reproduction at the epigenetic level has not been well studied. epigenetics refers to phenomena where modifications of dna methylation and/or chromatin structure underlie changes in gene expression and phenotype characteristics. this article intends to analyse epigenetic risks related to assisted reproduction on the basis of an overview of epigenetic reprogramming events in the gamete and early embryo. two epigenetic modifications, methylation and imprinting, are considered in more detail. the interference of in-vitro embryo culture, immature sperm cells and nuclear transfer with epigenetic reprogramming is discussed, as well as the possibility of epigenetic inheritance.”
Morlando, M., & Fatica, A.. (2018). Alteration of epigenetic regulation by long noncoding RNAs in cancer. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms19020570
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“Long noncoding rnas (lncrnas) are important regulators of the epigenetic status of the human genome. besides their participation to normal physiology, lncrna expression and function have been already associated to many diseases, including cancer. by interacting with epigenetic regulators and by controlling chromatin topology, their misregulation may result in an aberrant regulation of gene expression that may contribute to tumorigenesis. here, we review the functional role and mechanisms of action of lncrnas implicated in the aberrant epigenetic regulation that has characterized cancer development and progression.”
Torday, J. S., & Miller, W. B.. (2016). Phenotype as agent for epigenetic inheritance. Biology
Plain numerical DOI: 10.3390/biology5030030
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“The conventional understanding of phenotype is as a derivative of descent with modification through darwinian random mutation and natural selection. recent research has revealed lamarckian inheritance as a major transgenerational mechanism for environmental action on genomes whose extent is determined, in significant part, by germ line cells during meiosis and subsequent stages of embryological development. in consequence, the role of phenotype can productively be reconsidered. the possibility that phenotype is directed towards the effective acquisition of epigenetic marks in consistent reciprocation with the environment during the life cycle of an organism is explored. it is proposed that phenotype is an active agent in niche construction for the active acquisition of epigenetic marks as a dominant evolutionary mechanism rather than a consequence of darwinian selection towards reproductive success. the reproductive phase of the life cycle can then be appraised as a robust framework in which epigenetic inheritance is entrained to affect growth and development in continued reciprocal responsiveness to environmental stresses. furthermore, as first principles of physiology determine the limits of epigenetic inheritance, a coherent justification can thereby be provided for the obligate return of all multicellular eukaryotes to the unicellular state.”
Wu, K. J.. (2020). The epigenetic roles of DNA N6-Methyladenine (6mA) modification in eukaryotes. Cancer Letters
Plain numerical DOI: 10.1016/j.canlet.2020.08.025
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“The dna n6-methyladenine (6ma) modification is a prevalent epigenetic mark in prokaryotes, but the low abundance of 6ma in eukaryotes has recently received attention. the possible role of 6ma as an epigenetic mark in eukaryotes is starting to be recognized. this review article addresses the epigenetic roles of 6ma in eukaryotes. the existence of 6ma in metazoans and plants, the correlation of 6ma with gene expression, the enzymes catalyzing the deposition and removal of the 6ma modification, the relationship of 6ma to nucleosome positioning, the 6ma interaction with chromatin, its role in tumorigenesis and other physiological conditions/diseases and technical issues in 6ma detection/profiling and bioinformatics analysis are described. new directions and unresolved issues (e.g., the base-pair-resolution 6ma-sequencing method and gene activation vs. repression) in 6ma research are discussed.”
Conte, M., Fontana, E., Nebbioso, A., & Altucci, L.. (2020). Marine-Derived Secondary Metabolites as Promising Epigenetic Bio-Compounds for Anticancer Therapy. Marine Drugs
Plain numerical DOI: 10.3390/md19010015
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“Sessile organisms such as seaweeds, corals, and sponges continuously adapt to both abiotic and biotic components of the ecosystem. this extremely complex and dynamic process often results in different forms of competition to ensure the maintenance of an ecological niche suitable for survival. a high percentage of marine species have evolved to synthesize biologically active molecules, termed secondary metabolites, as a defense mechanism against the external environment. these natural products and their derivatives may play modulatory roles in the epigenome and in disease-associated epigenetic machinery. epigenetic modifications also represent a form of adaptation to the environment and confer a competitive advantage to marine species by mediating the production of complex chemical molecules with potential clinical implications. bioactive compounds are able to interfere with epigenetic targets by regulating key transcriptional factors involved in the hallmarks of cancer through orchestrated molecular mechanisms, which also establish signaling interactions of the tumor microenvironment crucial to cancer phenotypes. in this review, we discuss the current understanding of secondary metabolites derived from marine organisms and their synthetic derivatives as epigenetic modulators, highlighting advantages and limitations, as well as potential strategies to improve cancer treatment.”
Dehennaut, V., Leprince, D., & Lefebvre, T.. (2014). O-GlcNAcylation, an epigenetic mark. Focus on the histone code, TET family proteins, and polycomb group proteins. Frontiers in Endocrinology
Plain numerical DOI: 10.3389/fendo.2014.00155
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“There are increasing evidences that dietary components and metabolic disorders affect gene expression through epigenetic mechanisms. these observations support the notion that epigenetic reprograming-linked nutrition is connected to the etiology of metabolic diseases and cancer. during the last 5 years, accumulating data revealed that the nutrient-sensing o-glcnac glycosylation (o-glcnacylation) may be pivotal in the modulation of chromatin remodeling and in the regulation of gene expression by being part of the ‘histone code,’ and by identifying ogt (o-glcnac transferase) as an interacting partner of the tet family proteins of dna hydroxylases and as a member of the polycomb group proteins. thus, it is suggested that o-glcnacylation is a post-translational modification that links nutrition to epigenetic. this review summarizes recent findings about the interplay between o-glcnacylation and the epigenome and enlightens the contribution of the glycosylation to epigenetic reprograming.”
Yang, M., & Pollard, P. J.. (2013). Succinate: A new epigenetic hacker. Cancer Cell
Plain numerical DOI: 10.1016/j.ccr.2013.05.015
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“Epigenetic reprogramming is a feature of many human cancers. in this issue of cancer cell, letouzé and colleagues describe dna hypermethylation in paragangliomas harboring mutations in succinate dehydrogenase genes. these tumors accumulate succinate, which inhibits 2-oxoglutarate-dependent histone and dna demethylase enzymes, resulting in epigenetic silencing that affects neuroendocrine differentiation. © 2013 elsevier inc.”
Arechederra, M., Recalde, M., Gárate‐rascón, M., Fernández‐barrena, M. G., Ávila, M. A., & Berasain, C.. (2021). Epigenetic biomarkers for the diagnosis and treatment of liver disease. Cancers
Plain numerical DOI: 10.3390/cancers13061265
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“Research in the last decades has demonstrated the relevance of epigenetics in controlling gene expression to maintain cell homeostasis, and the important role played by epigenome alterations in disease development. moreover, the reversibility of epigenetic marks can be harnessed as a therapeutic strategy, and epigenetic marks can be used as diagnosis biomarkers. epigenetic alterations in dna methylation, histone post‐translational modifications (ptms), and non‐coding rna (ncrna) expression have been associated with the process of hepatocarcinogenesis. here, we summarize epigenetic alterations involved in the pathogenesis of chronic liver disease (cld), particularly focusing on dna methylation. we also discuss their utility as epigenetic biomarkers in liquid biopsy for the diagnosis and prognosis of hepatocellular carcinoma (hcc). finally, we discuss the potential of epigenetic therapeutic strategies for hcc treatment.”