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Epigenomes, Volume 4, Issue 3 (September 2020) – 12 articles

Cover Story (view full-size image): Enhancer of zeste homolog 2 (EZH2) is an epigenetic modulator that catalyzes trimethylation on lysine 27 of histone 3 (H3K27) in the chromatin, condensing its structure and inhibiting gene expression. Dysregulation of EZH2 in the uterus and other organs has been linked with pathologies that often involve aberrant cell proliferation. To understand the uterine role of EZH2, a conditional knockout mouse model lacking Ezh2 in progesterone receptor-positive cells has been developed, and these mice show uterine hypertrophy, cystic endometrial hyperplasia, aberrant epithelial proliferation, and altered estrogen responsiveness. This review discusses the roles of EZH2 in the uterus and placenta in health and disease. View this paper
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Review
Epigenetic Regulation of the Non-Coding Genome: Opportunities for Immuno-Oncology
Epigenomes 2020, 4(3), 22; https://0-doi-org.brum.beds.ac.uk/10.3390/epigenomes4030022 - 10 Sep 2020
Cited by 1 | Viewed by 1212
Abstract
The contribution of the non-coding genome to disease and its therapeutic potential have been largely unexplored. Recently, several epigenetic drugs developed for cancer treatment have been described to mediate therapeutic effects through the reactivation of the expression of transposable elements in cancer cells. [...] Read more.
The contribution of the non-coding genome to disease and its therapeutic potential have been largely unexplored. Recently, several epigenetic drugs developed for cancer treatment have been described to mediate therapeutic effects through the reactivation of the expression of transposable elements in cancer cells. This event activates innate immunity-related pathways and promotes the generation of neoantigens in tumor cells, improving the efficacy of immunotherapeutic treatments. This review focuses on the regulation of transposable elements by epigenetic inhibitors and its implications for immuno-oncology. Full article
(This article belongs to the Special Issue Targeting the Epigenetic Machinery to Enhance Cancer Immunotherapy)
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Review
Quantifying Genomic Imprinting at Tissue and Cell Resolution in the Brain
Epigenomes 2020, 4(3), 21; https://0-doi-org.brum.beds.ac.uk/10.3390/epigenomes4030021 - 04 Sep 2020
Viewed by 1531
Abstract
Imprinted genes are a group of ~150 genes that are preferentially expressed from one parental allele owing to epigenetic marks asymmetrically distributed on inherited maternal and paternal chromosomes. Altered imprinted gene expression causes human brain disorders such as Prader-Willi and Angelman syndromes and [...] Read more.
Imprinted genes are a group of ~150 genes that are preferentially expressed from one parental allele owing to epigenetic marks asymmetrically distributed on inherited maternal and paternal chromosomes. Altered imprinted gene expression causes human brain disorders such as Prader-Willi and Angelman syndromes and additional rare brain diseases. Research data principally obtained from the mouse model revealed how imprinted genes act in the normal and pathological brain. However, a better understanding of imprinted gene functions calls for building detailed maps of their parent-of-origin-dependent expression and of associated epigenetic signatures. Here we review current methods for quantifying genomic imprinting at tissue and cell resolutions, with a special emphasis on methods to detect parent-of-origin dependent expression and their applications to the brain. We first focus on bulk RNA-sequencing, the main method to detect parent-of-origin-dependent expression transcriptome-wide. We discuss the benefits and caveats of bulk RNA-sequencing and provide a guideline to use it on F1 hybrid mice. We then review methods for detecting parent-of-origin-dependent expression at cell resolution, including single-cell RNA-seq, genetic reporters, and molecular probes. Finally, we provide an overview of single-cell epigenomics technologies that profile additional features of genomic imprinting, including DNA methylation, histone modifications and chromatin conformation and their combination into sc-multimodal omics approaches, which are expected to yield important insights into genomic imprinting in individual brain cells. Full article
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Review
The Roles of the Histone Protein Modifier EZH2 in the Uterus and Placenta
Epigenomes 2020, 4(3), 20; https://0-doi-org.brum.beds.ac.uk/10.3390/epigenomes4030020 - 02 Sep 2020
Viewed by 1374
Abstract
Epigenetic modifications regulate normal physiological, as well as pathological processes in various organs, including the uterus and placenta. Both organs undergo dramatic and rapid restructuring that depends upon precise orchestration of events. Epigenetic changes that alter transcription and translation of gene-sets regulate such [...] Read more.
Epigenetic modifications regulate normal physiological, as well as pathological processes in various organs, including the uterus and placenta. Both organs undergo dramatic and rapid restructuring that depends upon precise orchestration of events. Epigenetic changes that alter transcription and translation of gene-sets regulate such responses. Histone modifications alter the chromatin structure, thereby affecting transcription factor access to gene promoter regions. Binding of histones to DNA is regulated by addition or removal of subunit methyl and other groups, which can inhibit or stimulate transcription. Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of polycomb repressive complex 2 (PRC2) that catalyzes tri-methylation of histone H3 at Lys 27 (H3K27me3) and subsequently suppresses transcription of genes bound by such histones. Uterine EZH2 expression exerts a critical role in development and function of this organ with deletion of this gene resulting in uterine hyperplasia and expression of cancer-associated transcripts. Elucidating the roles of EZH2 in uterus and placenta is essential as EZH2 dysregulation is associated with several uterine and placental pathologies. Herein, we discuss EZH2 functions in uterus and placenta, emphasizing its physiological and pathological importance. Full article
(This article belongs to the Collection Histone Demethylases)
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Article
Genome-Wide DNA Methylation and LncRNA-Associated DNA Methylation in Metformin-Treated and -Untreated Diabetes
Epigenomes 2020, 4(3), 19; https://0-doi-org.brum.beds.ac.uk/10.3390/epigenomes4030019 - 01 Sep 2020
Viewed by 1495
Abstract
Metformin, which is used as a first line treatment for type 2 diabetes mellitus (T2DM), has been shown to affect epigenetic patterns. In this study, we investigated the DNA methylation and potential lncRNA modifications in metformin-treated and newly diagnosed adults with T2DM. Genome-wide [...] Read more.
Metformin, which is used as a first line treatment for type 2 diabetes mellitus (T2DM), has been shown to affect epigenetic patterns. In this study, we investigated the DNA methylation and potential lncRNA modifications in metformin-treated and newly diagnosed adults with T2DM. Genome-wide DNA methylation and lncRNA analysis were performed from the peripheral blood of 12 screen-detected and 12 metformin-treated T2DM individuals followed by gene ontology (GO) and KEGG pathway analysis. Differentially methylated regions (DMRs) observed showed 22 hypermethylated and 11 hypomethylated DMRs between individuals on metformin compared to screen-detected subjects. Amongst the hypomethylated DMR regions were the SLC gene family, specifically, SLC25A35 and SLC28A1. Fifty-seven lncRNA-associated DNA methylation regions included the mitochondrial ATP synthase-coupling factor 6 (ATP5J). Functional gene mapping and pathway analysis identified regions in the axon initial segment (AIS), node of Ranvier, cell periphery, cleavage furrow, cell surface furrow, and stress fiber. In conclusion, our study has identified a number of DMRs and lncRNA-associated DNA methylation regions in metformin-treated T2DM that are potential targets for therapeutic monitoring in patients with diabetes. Full article
(This article belongs to the Special Issue Complex Disease Epigenetics)
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Editorial
New Aspects of the Epigenetics of Pancreatic Carcinogenesis
Epigenomes 2020, 4(3), 18; https://0-doi-org.brum.beds.ac.uk/10.3390/epigenomes4030018 - 31 Aug 2020
Viewed by 1138
Abstract
Pancreatic cancer remains among the deadliest forms of cancer with a 5 year survival rate less than 10%. With increasing numbers being observed, there is an urgent need to elucidate the pathogenesis of pancreatic cancer. While both contribute to disease progression, neither genetic [...] Read more.
Pancreatic cancer remains among the deadliest forms of cancer with a 5 year survival rate less than 10%. With increasing numbers being observed, there is an urgent need to elucidate the pathogenesis of pancreatic cancer. While both contribute to disease progression, neither genetic nor environmental factors completely explain susceptibility or pathogenesis. Defining the links between genetic and environmental events represents an opportunity to understand the pathogenesis of pancreatic cancer. Epigenetics, the study of mitotically heritable changes in genome function without a change in nucleotide sequence, is an emerging field of research in pancreatic cancer. The main epigenetic mechanisms include DNA methylation, histone modifications and RNA interference, all of which are altered by changes to the environment. Epigenetic mechanisms are being investigated to clarify the underlying pathogenesis of pancreatic cancer including an increasing number of studies examining the role as possible diagnostic and prognostic biomarkers. These mechanisms also provide targets for promising new therapeutic approaches for this devastating malignancy. Full article
(This article belongs to the Special Issue Epigenetics of Pancreatic Cancer 2.0)
Review
Functions of Polycomb Proteins on Active Targets
Epigenomes 2020, 4(3), 17; https://0-doi-org.brum.beds.ac.uk/10.3390/epigenomes4030017 - 17 Aug 2020
Cited by 1 | Viewed by 1479
Abstract
Chromatin regulators of the Polycomb group of genes are well-known by their activities as transcriptional repressors. Characteristically, their presence at genomic sites occurs with specific histone modifications and sometimes high-order chromatin structures correlated with silencing of genes involved in cell differentiation. However, evidence [...] Read more.
Chromatin regulators of the Polycomb group of genes are well-known by their activities as transcriptional repressors. Characteristically, their presence at genomic sites occurs with specific histone modifications and sometimes high-order chromatin structures correlated with silencing of genes involved in cell differentiation. However, evidence gathered in recent years, on flies and mammals, shows that in addition to these sites, Polycomb products bind to a large number of active regulatory regions. Occupied sites include promoters and also intergenic regions, containing enhancers and super-enhancers. Contrasting with occupancies at repressed targets, characteristic histone modifications are low or undetectable. Functions on active targets are dual, restraining gene expression at some targets while promoting activity at others. Our aim here is to summarize the evidence available and discuss the convenience of broadening the scope of research to include Polycomb functions on active targets. Full article
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Article
Implication of m6A mRNA Methylation in Susceptibility to Inflammatory Bowel Disease
Epigenomes 2020, 4(3), 16; https://0-doi-org.brum.beds.ac.uk/10.3390/epigenomes4030016 - 03 Aug 2020
Cited by 1 | Viewed by 1319
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract that develops due to the interaction between genetic and environmental factors. More than 160 loci have been associated with IBD, but the functional implication of many of the associated genes [...] Read more.
Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract that develops due to the interaction between genetic and environmental factors. More than 160 loci have been associated with IBD, but the functional implication of many of the associated genes remains unclear. N6-Methyladenosine (m6A) is the most abundant internal modification in mRNA. m6A methylation regulates many aspects of mRNA metabolism, playing important roles in the development of several pathologies. Interestingly, SNPs located near or within m6A motifs have been proposed as possible contributors to disease pathogenesis. We hypothesized that certain IBD-associated SNPs could regulate the function of genes involved in IBD development via m6A-dependent mechanisms. We used online available GWAS, m6A and transcriptome data to find differentially expressed genes that harbored m6A-SNPs associated with IBD. Our analysis resulted in five candidate genes corresponding to two of the major IBD subtypes: UBE2L3 and SLC22A4 for Crohn’s Disease and TCF19, C6orf47 and SNAPC4 for Ulcerative Colitis. Further analysis using in silico predictions and co-expression analyses in combination with in vitro functional studies showed that our candidate genes seem to be regulated by m6A-dependent mechanisms. These findings provide the first indication of the implication of RNA methylation events in IBD pathogenesis. Full article
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Review
Epigenomic Remodeling in Huntington’s Disease—Master or Servant?
Epigenomes 2020, 4(3), 15; https://0-doi-org.brum.beds.ac.uk/10.3390/epigenomes4030015 - 31 Jul 2020
Cited by 1 | Viewed by 1210
Abstract
In light of our aging population, neurodegenerative disorders are becoming a tremendous challenge, that modern societies have to face. They represent incurable, progressive conditions with diverse and complex pathological features, followed by catastrophic occurrences of massive neuronal loss at the later stages of [...] Read more.
In light of our aging population, neurodegenerative disorders are becoming a tremendous challenge, that modern societies have to face. They represent incurable, progressive conditions with diverse and complex pathological features, followed by catastrophic occurrences of massive neuronal loss at the later stages of the diseases. Some of these disorders, like Huntington’s disease (HD), rely on defined genetic factors. HD, as an incurable, fatal hereditary neurodegenerative disorder characterized by its mid-life onset, is caused by the expansion of CAG trinucleotide repeats coding for glutamine (Q) in exon 1 of the huntingtin gene. Apart from the genetic defect, environmental factors are thought to influence the risk, onset and progression of HD. As epigenetic mechanisms are known to readily respond to environmental stimuli, they are proposed to play a key role in HD pathogenesis. Indeed, dynamic epigenomic remodeling is observed in HD patients and in brains of HD animal models. Epigenetic signatures, such as DNA methylation, histone variants and modifications, are known to influence gene expression and to orchestrate various aspects of neuronal physiology. Hence, deciphering their implication in HD pathogenesis might open up new paths for novel therapeutic concepts, which are discussed in this review. Full article
(This article belongs to the Special Issue Epigenetics of the Nervous System 2.0)
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Review
Influence of Prenatal Methamphetamine Abuse on the Brain
Epigenomes 2020, 4(3), 14; https://0-doi-org.brum.beds.ac.uk/10.3390/epigenomes4030014 - 14 Jul 2020
Viewed by 1221
Abstract
Methamphetamine (MA), a psychostimulant, has become a serious problem in recent years. It is one of the most widely abused psychostimulants in the world. In the Czech Republic, ecstasy is the most commonly used non-cannabis drug, followed by hallucinogenic fungi, LSD, MA, cocaine, [...] Read more.
Methamphetamine (MA), a psychostimulant, has become a serious problem in recent years. It is one of the most widely abused psychostimulants in the world. In the Czech Republic, ecstasy is the most commonly used non-cannabis drug, followed by hallucinogenic fungi, LSD, MA, cocaine, and finally heroin. The prevalence of the usage of all addictive substances is highest in the age category of 15–34. Approximately 17.2% of registered drug addicts, both male and female, in the Czech Republic use MA as their first-choice drug. This group consists mostly of women who are unemployed and addicted to MA (85%). Almost half of the addicted women switched to MA from other drugs in the course of pregnancy. Psychostimulants such as amphetamine and its synthetic derivate MA induce feelings of calm and happiness by suppressing anxiety and depression. When MA is abused for longer periods, it mimics symptoms of mania and can lead to the development of psychosis. MA is often abused for its anorectic effect, its simple preparation, and compared to heroin and cocaine, its low price. There are significant differences in the susceptibility of users to the stimulant, with reactions to MA fluctuating from person to person. Molecular mechanisms related to the variable response among users might represent an explanation for increased addiction-associated bipolar disorder and psychosis. Currently, there is limited information regarding genetic mechanisms linked to these disorders and the transmission of drug addiction. As such, animal models of drug addiction represent significant sources of information and assets in the research of these issues. The aim of this review is to summarize the mechanism of action of methamphetamine and its effect on pregnant addicted women and their children, including a detailed description of the anatomical structures involved. Full article
(This article belongs to the Special Issue Epigenetics in Metabolic and Neurological Disorders 2.0)
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Review
Skin Color in Apple Fruit (Malus × domestica): Genetic and Epigenetic Insights
Epigenomes 2020, 4(3), 13; https://0-doi-org.brum.beds.ac.uk/10.3390/epigenomes4030013 - 13 Jul 2020
Viewed by 1266
Abstract
Apple skin color is an important trait for organoleptic quality. In fact, it has a major influence on consumer choice. Skin color is, thus, one of the most important criteria taken into account by breeders. For apples, most novel varieties are so-called “mutants” [...] Read more.
Apple skin color is an important trait for organoleptic quality. In fact, it has a major influence on consumer choice. Skin color is, thus, one of the most important criteria taken into account by breeders. For apples, most novel varieties are so-called “mutants” or “sports” that have been identified in clonal populations. Indeed, many “sports” exist that show distinct phenotypic differences compared to the varieties from which they originated. These differences affect a limited number of traits of economic importance, including skin color. Until recently, the detailed genetic or epigenetic changes resulting in heritable phenotypic changes in sports was largely unknown. Recent technological advances and the availability of several high-quality apple genomes now provide the bases to understand the exact nature of the underlying molecular changes that are responsible for the observed phenotypic changes observed in sports. The present review investigates the molecular nature of sports affected in apple skin color giving arguments in favor of the genetic or epigenetic explanatory models. Full article
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Communication
Epigenetic Dynamics of the Infant Immune System Reveals a Tumor Necrosis Factor Superfamily Signature in Early Human Life
Epigenomes 2020, 4(3), 12; https://0-doi-org.brum.beds.ac.uk/10.3390/epigenomes4030012 - 04 Jul 2020
Cited by 1 | Viewed by 1108
Abstract
DNA methylation (DNAm) is an essential mechanism governing normal development in humans. Although most DNAm patterns in blood cells are established in utero, the genes associated with immune function undergo postnatal DNAm modifications, and the characterization of this subset of genes is [...] Read more.
DNA methylation (DNAm) is an essential mechanism governing normal development in humans. Although most DNAm patterns in blood cells are established in utero, the genes associated with immune function undergo postnatal DNAm modifications, and the characterization of this subset of genes is incomplete. Accordingly, we used available longitudinal DNAm datasets from a large birth cohort in the U.S. to further identify postnatal DNAm variation in peripheral leukocytes from 105 children (n = 105) between birth and the first two years of life, as determined by postnatal changes in β values (with the percentage of methylation ranging from 0 to 1.0 at individual CpG sites). Our study is an extension of a previous analysis performed by our group and identified that: (1) as previously described, DNAm patterns at most CpG sites were established before birth and only a small group of genes underwent DNAm modifications postnatally, (2) this subset includes multiple immune genes critical for lymphocyte development, and (3) several members of the tumor necrosis factor receptor and cytokine superfamilies with essential roles in immune cell activation, survival, and lymphoid tissue development were among those with a larger postnatal variation. This study describes the precise epigenetic DNA methylation marks in important immune genes that change postnatally and raises relevant questions about the role of DNAm during postnatal immune development in early childhood. Full article
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Editorial
Epigenetic Control in Plants
Epigenomes 2020, 4(3), 11; https://0-doi-org.brum.beds.ac.uk/10.3390/epigenomes4030011 - 01 Jul 2020
Viewed by 977
Abstract
Epigenetic regulation in plants is an exciting field of research [...] Full article
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