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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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
DOI URL
directSciHub download
Show/hide publication abstract
“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