Epigenomes doi: 10.3390/epigenomes8020012
Authors: Mohammad Nahian Ferdous Abrar Yu Jiang Hongmei Zhang Liang Li Hasan Arshad
The association between newborn DNA methylation (DNAm) and asthma acquisition (AA) during adolescence has been suggested. Lung function (LF) has been shown to be associated with asthma risk and its severity. However, the role of LF in the associations between DNAm and AA is unclear, and it is also unknown whether the association between DNAm and AA is consistent with that between DNAm and LF. We address this question through assessing newborn epigenetic features of preadolescence LF and of AA during adolescence, along with their biological pathways and processes. Our study’s primary medical significance lies in advancing the understanding of asthma’s early life origins. By investigating epigenetic markers in newborns and their association with lung function in preadolescence, we aim to uncover potential early biomarkers of asthma risk. This could facilitate earlier detection and intervention strategies. Additionally, exploring biological pathways linking early lung function to later asthma development can offer insights into the disease’s pathogenesis, potentially leading to novel therapeutic targets. Methods: The study was based on the Isle of Wight Birth cohort (IOWBC). Female subjects with DNAm data at birth and with no asthma at age 10 years were included (n = 249). The R package ttScreening was applied to identify CpGs potentially associated with AA from 10 to 18 years and with LF at age 10 (FEV1, FVC, and FEV1/FVC), respectively. Agreement in identified CpGs between AA and LF was examined, along with their biological pathways and processes via the R function gometh. We tested the findings in an independent cohort, the Avon Longitudinal Study of Parents and Children (ALSPAC), to examine overall replicability. Results: In IOWBC, 292 CpGs were detected with DNAm associated with AA and 1517 unique CpGs for LF (514 for FEV1, 436 for FVC, 408 for FEV1/FVC), with one overlapping CpG, cg23642632 (NCKAP1) between AA and LF. Among the IOWBC-identified CpGs, we further tested in ALSPAC and observed the highest agreement between the two cohorts in FVC with respect to the direction of association and statistical significance. Epigenetic enrichment analyses indicated non-specific connections in the biological pathways and processes between AA and LF. Conclusions: The present study suggests that FEV1, FVC, and FEV1/FVC (as objective measures of LF) and AA (incidence of asthma) are likely to have their own specific epigenetic features and biological pathways at birth. More replications are desirable to fully understand the complexity between DNAm, lung function, and asthma acquisition.
]]>Epigenomes doi: 10.3390/epigenomes8010011
Authors: Karolina Dulka Noémi Lajkó Kálmán Nacsa Karoly Gulya
Temporal and spatial epigenetic modifications in the brain occur during ontogenetic development, pathophysiological disorders, and aging. When epigenetic marks, such as histone methylations, in brain autopsies or biopsy samples are studied, it is critical to understand their postmortem/surgical stability. For this study, the frontal cortex and hippocampus of adult rats were removed immediately (controls) or after a postmortem delay of 15, 30, 60, 90, 120, or 150 min. The patterns of unmodified H3 and its trimethylated form H3K9me3 were analyzed in frozen samples for Western blot analysis and in formalin-fixed tissues embedded in paraffin for confocal microscopy. We found that both the unmodified H3 and H3K9me3 showed time-dependent but opposite changes and were altered differently in the frontal cortex and hippocampus with respect to postmortem delay. In the frontal cortex, the H3K9me3 marks increased approximately 450% with a slow parallel 20% decrease in the unmodified H3 histones after 150 min. In the hippocampus, the change was opposite, since H3K9me3 marks decreased steadily by approximately 65% after 150 min with a concomitant rapid increase of 20–25% in H3 histones at the same time. Confocal microscopy located H3K9me3 marks in the heterochromatic regions of the nuclei of all major cell types in the control brains: oligodendrocytes, astrocytes, neurons, and microglia. Therefore, epigenetic marks could be affected differently by postmortem delay in different parts of the brain.
]]>Epigenomes doi: 10.3390/epigenomes8010010
Authors: Jasmine Manji Jasmine Pipella Gabriel Brawerman Peter J. Thompson
Type 1 diabetes (T1D) is a metabolic disease resulting from progressive autoimmune destruction of insulin-producing pancreatic beta cells. Although the majority of beta cells are lost in T1D, a small subset undergoes senescence, a stress response involving growth arrest, DNA damage response, and activation of a senescence-associated secretory phenotype (SASP). SASP in beta cells of the nonobese diabetic (NOD) mouse model of T1D and primary human islets is regulated at the level of transcription by bromodomain extra-terminal (BET) proteins, but the mechanisms remain unclear. To explore how SASP is transcriptionally regulated in beta cells, we used the NOD beta cell line NIT-1 to model beta cell SASP and identified binding partners of BET protein Brd4 and explored the role of the cyclin-dependent kinase inhibitor p21. Brd4 interacted with a variety of proteins in senescent NIT-1 cells including subunits of the Ino80 chromatin remodeling complex, which was expressed in beta cells during T1D progression in NOD mice and in human beta cells of control, autoantibody-positive, and T1D donors as determined from single-cell RNA-seq data. RNAi knockdown of p21 during senescence in NIT-1 cells did not significantly impact viability or SASP. Taken together, these results suggest that Brd4 interacts with several protein partners during senescence in NIT-1 cells, some of which may play roles in SASP gene activation and that p21 is dispensable for the SASP in this beta cell model.
]]>Epigenomes doi: 10.3390/epigenomes8010009
Authors: Wiesława Leśniak
Epidermis is the outer skin layer built of specialized cells called keratinocytes. Keratinocytes undergo a unique differentiation process, also known as cornification, during which their gene expression pattern, morphology and other properties change remarkably to the effect that the terminally differentiated, cornified cells can form a physical barrier, which separates the underlying tissues from the environment. Many genes encoding proteins that are important for epidermal barrier formation are located in a gene cluster called epidermal differentiation complex (EDC). Recent data provided valuable information on the dynamics of the EDC locus and the network of interactions between EDC gene promoters, enhancers and other regions, during keratinocytes differentiation. These data, together with results concerning changes in epigenetic modifications, provide a valuable insight into the mode of regulation of EDC gene expression.
]]>Epigenomes doi: 10.3390/epigenomes8010008
Authors: Rebecca M. Malcore Sundeep Kalantry
The mammalian sexes are distinguished by the X and Y chromosomes. Whereas males harbor one X and one Y chromosome, females harbor two X chromosomes. To equalize X-linked gene expression between the sexes, therian mammals have evolved X-chromosome inactivation as a dosage compensation mechanism. During X-inactivation, most genes on one of the two X chromosomes in females are transcriptionally silenced, thus equalizing X-linked gene expression between the sexes. Two forms of X-inactivation characterize eutherian mammals, imprinted and random. Imprinted X-inactivation is defined by the exclusive inactivation of the paternal X chromosome in all cells, whereas random X-inactivation results in the silencing of genes on either the paternal or maternal X chromosome in individual cells. Both forms of X-inactivation have been studied intensively in the mouse model system, which undergoes both imprinted and random X-inactivation early in embryonic development. Stable imprinted and random X-inactivation requires the induction of the Xist long non-coding RNA. Following its induction, Xist RNA recruits proteins and complexes that silence genes on the inactive-X. In this review, we present a current understanding of the mechanisms of Xist RNA induction, and, separately, the establishment and maintenance of gene silencing on the inactive-X by Xist RNA during imprinted and random X-inactivation.
]]>Epigenomes doi: 10.3390/epigenomes8010007
Authors: Megan R. Dreier Jasmine Walia Ivana L. de la Serna
SWI/SNF enzymes are heterogeneous multi-subunit complexes that utilize the energy from ATP hydrolysis to remodel chromatin structure, facilitating transcription, DNA replication, and repair. In mammalian cells, distinct sub-complexes, including cBAF, ncBAF, and PBAF exhibit varying subunit compositions and have different genomic functions. Alterations in the SWI/SNF complex and sub-complex functions are a prominent feature in cancer, making them attractive targets for therapeutic intervention. Current strategies in cancer therapeutics involve the use of pharmacological agents designed to bind and disrupt the activity of SWI/SNF complexes or specific sub-complexes. Inhibitors targeting the catalytic subunits, SMARCA4/2, and small molecules binding SWI/SNF bromodomains are the primary approaches for suppressing SWI/SNF function. Proteolysis-targeting chimeras (PROTACs) were generated by the covalent linkage of the bromodomain or ATPase-binding ligand to an E3 ligase-binding moiety. This engineered connection promotes the degradation of specific SWI/SNF subunits, enhancing and extending the impact of this pharmacological intervention in some cases. Extensive preclinical studies have underscored the therapeutic potential of these drugs across diverse cancer types. Encouragingly, some of these agents have progressed from preclinical research to clinical trials, indicating a promising stride toward the development of effective cancer therapeutics targeting SWI/SNF complex and sub-complex functions.
]]>Epigenomes doi: 10.3390/epigenomes8010006
Authors: Samuel Jesus Luchsinger-Morcelle Joost Gribnau Hegias Mira-Bontenbal
Compensation for the gene dosage disequilibrium between sex chromosomes in mammals is achieved in female cells by repressing one of its X chromosomes through a process called X chromosome inactivation (XCI), exemplifying the control of gene expression by epigenetic mechanisms. A critical player in this mechanism is Xist, a long, non-coding RNA upregulated from a single X chromosome during early embryonic development in female cells. Over the past few decades, many factors involved at different levels in the regulation of Xist have been discovered. In this review, we hierarchically describe and analyze the different layers of Xist regulation operating concurrently and intricately interacting with each other to achieve asymmetric and monoallelic upregulation of Xist in murine female cells. We categorize these into five different classes: DNA elements, transcription factors, other regulatory proteins, long non-coding RNAs, and the chromatin and topological landscape surrounding Xist.
]]>Epigenomes doi: 10.3390/epigenomes8010005
Authors: Manal S. Fawzy Afaf T. Ibrahiem Dalia Mohammad Osman Amany I. Almars Maali Subhi Alshammari Layan Tariq Almazyad Noof Daif Allah Almatrafi Renad Tariq Almazyad Eman A. Toraih
The genotyping of long non-coding RNA (lncRNA)-related single-nucleotide polymorphisms (SNPs) could be associated with cancer risk and/or progression. This study aimed to analyze the angiogenesis-related lncRNAs MALAT1 (rs3200401) and MIAT (rs1061540) variants in patients with ovarian cancer (OC) using “Real-Time allelic discrimination polymerase chain reaction” in 182 formalin-fixed paraffin-embedded (FFPE) samples of benign, borderline, and primary malignant ovarian tissues. Differences in the genotype frequencies between low-grade ovarian epithelial tumors (benign/borderline) and malignant tumors and between high-grade malignant epithelial tumors and malignant epithelial tumors other than high-grade serous carcinomas were compared. Odds ratios (ORs)/95% confidence intervals were calculated as measures of the association strength. Additionally, associations of the genotypes with the available pathological data were analyzed. The heterozygosity of MALAT1 rs3200401 was the most common genotype (47.8%), followed by C/C (36.3%). Comparing the study groups, no significant differences were observed regarding this variant. In contrast, the malignant epithelial tumors had a higher frequency of the MIAT rs1061540 C/C genotype compared to the low-grade epithelial tumor cohorts (56.7% vs. 37.6, p = 0.031). The same genotype was significantly higher in high-grade serous carcinoma than its counterparts (69.4% vs. 43.8%, p = 0.038). Multivariate Cox regression analysis showed that the age at diagnosis was significantly associated with the risk of OC development. In contrast, the MIAT T/T genotype was associated with a low risk of malignant epithelial tumors under the homozygote comparison model (OR = 0.37 (0.16–0.83), p = 0.017). Also, MIAT T allele carriers were less likely to develop high-grade serous carcinoma under heterozygote (CT vs. CC; OR = 0.33 (0.12–0.88), p = 0.027) and homozygote (TT vs. CC; OR = 0.26 (0.07–0.90), p = 0.034) comparison models. In conclusion, our data provide novel evidence for a potential association between the lncRNA MIAT rs1061540 and the malignant condition of ovarian cancer, suggesting the involvement of such lncRNAs in OC development.
]]>Epigenomes doi: 10.3390/epigenomes8010003
Authors: Sarah M. Merrill Nicole Letourneau Gerald F. Giesbrecht Karlie Edwards Julia L. MacIsaac Jonathan W. Martin Amy M. MacDonald David W. Kinniburgh Michael S. Kobor Deborah Dewey Gillian England-Mason The APrON Study Team The APrON Study Team
Di(2-ethylhexyl) phthalate (DEHP) is a common plasticizer that can affect immune system development and susceptibility to infection. Aging processes (measured as epigenetic age acceleration (EAA)) may mediate the immune-related effects of prenatal exposure to DEHP. This study’s objective was to examine associations between prenatal DEHP exposure, EAA at three months of age, and the number of upper respiratory infections (URIs) from 12 to 18 months of age using a sample of 69 maternal–child pairs from a Canadian pregnancy cohort. Blood DNA methylation data were generated using the Infinium HumanMethylation450 BeadChip; EAA was estimated using Horvath’s pan-tissue clock. Robust regressions examined overall and sex-specific associations. Higher prenatal DEHP exposure (B = 6.52, 95% CI = 1.22, 11.81) and increased EAA (B = 2.98, 95% CI = 1.64, 4.32) independently predicted more URIs. In sex-specific analyses, some similar effects were noted for boys, and EAA mediated the association between prenatal DEHP exposure and URIs. In girls, higher prenatal DEHP exposure was associated with decreased EAA, and no mediation was noted. Higher prenatal DEHP exposure may be associated with increased susceptibility to early childhood URIs, particularly in boys, and aging biomarkers such as EAA may be a biological mechanism. Larger cohort studies examining the potential developmental immunotoxicity of phthalates are needed.
]]>Epigenomes doi: 10.3390/epigenomes8010004
Authors: Melanie Ehrlich Kenneth C. Ehrlich Michelle Lacey Carl Baribault Sagnik Sen Pierre-Olivier Estève Sriharsa Pradhan
While studying myoblast methylomes and transcriptomes, we found that CDH15 had a remarkable preference for expression in both myoblasts and cerebellum. To understand how widespread such a relationship was and its epigenetic and biological correlates, we systematically looked for genes with similar transcription profiles and analyzed their DNA methylation and chromatin state and accessibility profiles in many different cell populations. Twenty genes were expressed preferentially in myoblasts and cerebellum (Myob/Cbl genes). Some shared DNA hypo- or hypermethylated regions in myoblasts and cerebellum. Particularly striking was ZNF556, whose promoter is hypomethylated in expressing cells but highly methylated in the many cell populations that do not express the gene. In reporter gene assays, we demonstrated that its promoter’s activity is methylation sensitive. The atypical epigenetics of ZNF556 may have originated from its promoter’s hypomethylation and selective activation in sperm progenitors and oocytes. Five of the Myob/Cbl genes (KCNJ12, ST8SIA5, ZIC1, VAX2, and EN2) have much higher RNA levels in cerebellum than in myoblasts and displayed myoblast-specific hypermethylation upstream and/or downstream of their promoters that may downmodulate expression. Differential DNA methylation was associated with alternative promoter usage for Myob/Cbl genes MCF2L, DOK7, CNPY1, and ANK1. Myob/Cbl genes PAX3, LBX1, ZNF556, ZIC1, EN2, and VAX2 encode sequence-specific transcription factors, which likely help drive the myoblast and cerebellum specificity of other Myob/Cbl genes. This study extends our understanding of epigenetic/transcription associations related to differentiation and may help elucidate relationships between epigenetic signatures and muscular dystrophies or cerebellar-linked neuropathologies.
]]>Epigenomes doi: 10.3390/epigenomes8010002
Authors: Carlos de Tomás Carlos M. Vicient
Transposable elements (TEs) are major components of plant genomes with the ability to change their position in the genome or to create new copies of themselves in other positions in the genome. These can cause gene disruption and large-scale genomic alterations, including inversions, deletions, and duplications. Host organisms have evolved a set of mechanisms to suppress TE activity and counter the threat that they pose to genome integrity. These includes the epigenetic silencing of TEs mediated by a process of RNA-directed DNA methylation (RdDM). In most cases, the silencing machinery is very efficient for the vast majority of TEs. However, there are specific circumstances in which TEs can evade such silencing mechanisms, for example, a variety of biotic and abiotic stresses or in vitro culture. Hybridization is also proposed as an inductor of TE proliferation. In fact, the discoverer of the transposons, Barbara McClintock, first hypothesized that interspecific hybridization provides a “genomic shock” that inhibits the TE control mechanisms leading to the mobilization of TEs. However, the studies carried out on this topic have yielded diverse results, showing in some cases a total absence of mobilization or being limited to only some TE families. Here, we review the current knowledge about the impact of interspecific hybridization on TEs in plants and the possible implications of changes in the epigenetic mechanisms.
]]>Epigenomes doi: 10.3390/epigenomes8010001
Authors: Maria C. Ow Sarah E. Hall
While reports on the generational inheritance of a parental response to stress have been widely reported in animals, the molecular mechanisms behind this phenomenon have only recently emerged. The booming interest in epigenetic inheritance has been facilitated in part by the discovery that small non-coding RNAs are one of its principal conduits. Discovered 30 years ago in the Caenorhabditis elegans nematode, these small molecules have since cemented their critical roles in regulating virtually all aspects of eukaryotic development. Here, we provide an overview on the current understanding of epigenetic inheritance in animals, including mice and C. elegans, as it pertains to stresses such as temperature, nutritional, and pathogenic encounters. We focus on C. elegans to address the mechanistic complexity of how small RNAs target their cohort mRNAs to effect gene expression and how they govern the propagation or termination of generational perdurance in epigenetic inheritance. Presently, while a great amount has been learned regarding the heritability of gene expression states, many more questions remain unanswered and warrant further investigation.
]]>Epigenomes doi: 10.3390/epigenomes7040032
Authors: Bowen Yan Qingchen Yuan Olga A. Guryanova
Hematopoietic stem cells (HSCs) are essential for maintaining overall health by continuously generating blood cells throughout an individual’s lifespan. However, as individuals age, the hematopoietic system undergoes significant functional decline, rendering them more susceptible to age-related diseases. Growing research evidence has highlighted the critical role of epigenetic regulation in this age-associated decline. This review aims to provide an overview of the diverse epigenetic mechanisms involved in the regulation of normal HSCs during the aging process and their implications in aging-related diseases. Understanding the intricate interplay of epigenetic mechanisms that contribute to aging-related changes in the hematopoietic system holds great potential for the development of innovative strategies to delay the aging process. In fact, interventions targeting epigenetic modifications have shown promising outcomes in alleviating aging-related phenotypes and extending lifespan in various animal models. Small molecule-based therapies and reprogramming strategies enabling epigenetic rejuvenation have emerged as effective approaches for ameliorating or even reversing aging-related conditions. By acquiring a deeper understanding of these epigenetic mechanisms, it is anticipated that interventions can be devised to prevent or mitigate the rates of hematologic aging and associated diseases later in life. Ultimately, these advancements have the potential to improve overall health and enhance the quality of life in aging individuals.
]]>Epigenomes doi: 10.3390/epigenomes7040031
Authors: Stephanie Tuminello Emelie Nguyen Nedim Durmus Ramazan Alptekin Muhammed Yilmaz Maria Cecilia Crisanti Matija Snuderl Yu Chen Yongzhao Shao Joan Reibman Emanuela Taioli Alan A. Arslan
Introduction: Known carcinogens in the dust and fumes from the destruction of the World Trade Center (WTC) towers on 9 November 2001 included metals, asbestos, and organic pollutants, which have been shown to modify epigenetic status. Epigenome-wide association analyses (EWAS) using uniform (Illumina) methodology have identified novel epigenetic profiles of WTC exposure. Methods: We reviewed all published data, comparing differentially methylated gene profiles identified in the prior EWAS studies of WTC exposure. This included DNA methylation changes in blood-derived DNA from cases of cancer-free “Survivors” and those with breast cancer, as well as tissue-derived DNA from “Responders” with prostate cancer. Emerging molecular pathways related to the observed DNA methylation changes in WTC-exposed groups were explored and summarized. Results: WTC dust exposure appears to be associated with DNA methylation changes across the genome. Notably, WTC dust exposure appears to be associated with increased global DNA methylation; direct dysregulation of cancer genes and pathways, including inflammation and immune system dysregulation; and endocrine system disruption, as well as disruption of cholesterol homeostasis and lipid metabolism. Conclusion: WTC dust exposure appears to be associated with biologically meaningful DNA methylation changes, with implications for carcinogenesis and development of other chronic diseases.
]]>Epigenomes doi: 10.3390/epigenomes7040030
Authors: Dustin J. Van Hofwegen Carolyn J. Hovde Scott A. Minnich
Pathogenic bacteria recognize environmental cues to vary gene expression for host adaptation. Moving from ambient to host temperature, Yersinia enterocolitica responds by immediately repressing flagella synthesis and inducing the virulence plasmid (pYV)-encoded type III secretion system. In contrast, shifting from host to ambient temperature requires 2.5 generations to restore motility, suggesting a link to the cell cycle. We hypothesized that differential DNA methylation contributes to temperature-regulated gene expression. We tested this hypothesis by comparing single-molecule real-time (SMRT) sequencing of Y. enterocolitica DNA from cells growing exponentially at 22 °C and 37 °C. The inter-pulse duration ratio rather than the traditional QV scoring was the kinetic metric to compare DNA from cells grown at each temperature. All 565 YenI restriction sites were fully methylated at both temperatures. Among the 27,118 DNA adenine methylase (Dam) sites, 42 had differential methylation patterns, while 17 remained unmethylated regardless of the temperature. A subset of the differentially methylated Dam sites localized to promoter regions of predicted regulatory genes including LysR-type and PadR-like transcriptional regulators and a cyclic-di-GMP phosphodiesterase. The unmethylated Dam sites localized with a bias to the replication terminus, suggesting they were protected from Dam methylase. No cytosine methylation was detected at Dcm sites.
]]>Epigenomes doi: 10.3390/epigenomes7040029
Authors: Samantha B. Peeters Bronwyn J. Posynick Carolyn J. Brown
The silencing of all but one X chromosome in mammalian cells is a remarkable epigenetic process leading to near dosage equivalence in X-linked gene products between the sexes. However, equally remarkable is the ability of a subset of genes to continue to be expressed from the otherwise inactive X chromosome—in some cases constitutively, while other genes are variable between individuals, tissues or cells. In this review we discuss the advantages and disadvantages of the approaches that have been used to identify escapees. The identity of escapees provides important clues to mechanisms underlying escape from XCI, an arena of study now moving from correlation to functional studies. As most escapees show greater expression in females, the not-so-inactive X chromosome is a substantial contributor to sex differences in humans, and we highlight some examples of such impact.
]]>Epigenomes doi: 10.3390/epigenomes7040028
Authors: Corinne Kaufmann Anton Wutz
For about 30 years, SPEN has been the subject of research in many different fields due to its variety of functions and its conservation throughout a wide spectrum of species, like worms, arthropods, and vertebrates. To date, 216 orthologues have been documented. SPEN had been studied for its role in gene regulation in the context of cell signaling, including the NOTCH or nuclear hormone receptor signaling pathways. More recently, SPEN has been identified as a major regulator of initiation of chromosome-wide gene silencing during X chromosome inactivation (XCI) in mammals, where its function remains to be fully understood. Dependent on the biological context, SPEN functions via mechanisms which include different domains. While some domains of SPEN are highly conserved in sequence and secondary structure, species-to-species differences exist that might lead to mechanistic differences. Initiation of XCI appears to be different between humans and mice, which raises additional questions about the extent of generalization of SPEN’s function in XCI. In this review, we dissect the mechanism of SPEN in XCI. We discuss its subregions and domains, focusing on its role as a major regulator. We further highlight species-related research, specifically of mouse and human SPEN, with the aim to reveal and clarify potential species-to-species differences in SPEN’s function.
]]>Epigenomes doi: 10.3390/epigenomes7040027
Authors: Veronica Barcelona Sameera Abuaish Seonjoo Lee Sarah Harkins Ashlie Butler Benjamin Tycko Andrea A. Baccarelli Kate Walsh Catherine E. Monk
Latinas experience physical and psychological stressors in pregnancy leading to increased morbidity and higher risk for adverse birth outcomes. Epigenetic changes, including DNA methylation (DNAm), have been proposed as markers to create more refined risk stratification, yet few of these studies have examined these changes in Latinas. We conducted a secondary analysis of stored blood leukocytes of Latina women (n = 58) enrolled in a larger National Institutes of Health funded R01 project (2011–2016). We examined DNAm on eight candidate stress genes to compare physically and psychologically stressed participants to healthy (low stress) participants. We found unique CpGs that were differentially methylated in stressed women early- and mid-pregnancy compared to the healthy group, though none remained significant after FDR correction. Both physical and psychological stress were associated with hypomethylation at two consecutive CpG sites on NR3C1 in early pregnancy and one CpG site on NR3C1 in mid-pregnancy before adjustment. Stress was also associated with hypomethylation at two CpG sites on FKBP5 in early and mid-pregnancy but were no longer significant after FDR adjustment. Though we did not find statistically significant differences in DNAm during pregnancy between stressed and healthy women in this sample, signals were consistent with previous findings. Future work in larger samples should further examine the associations between stress and DNAm in pregnancy as this mechanism may explain underlying perinatal health inequities.
]]>Epigenomes doi: 10.3390/epigenomes7040026
Authors: Rowshan Ara Islam Charalampos Rallis
23. Akirtava, C.; May, G.E.; McManus, C.J. False-Positive IRESes from Hoxa9 andOther Genes Resulting from Errors in Mam-malian 5’ UTR Annotations [...]
]]>Epigenomes doi: 10.3390/epigenomes7040025
Authors: Fani Konstantinidou Martina Placidi Giovanna Di Emidio Liborio Stuppia Carla Tatone Valentina Gatta Paolo Giovanni Artini
While the use of follicle-stimulating hormone (FSH) in ovarian stimulation for in vitro fertilization (IVF) is an established practice, the use of luteinizing hormone (LH) remains debatable. MicroRNAs (miRNAs) are short, endogenous, non-coding transcripts that control a variety of cellular functions, such as gonadotrophin production and follicular development. The goal of this pilot study was to investigate whether the employment of recombinant LH (rLH) in ovarian stimulation protocols results in changes in the miRNA profiles in human oocytes. Patients were divided into two groups: seven received recombinant FSH (rFSH, 225 IU), and six received rFSH (150 IU) plus rLH (75 IU). MiRNA predesigned panels and real-time PCR technology were used to analyze the oocytes retrieved from the follicular ovarian retrieval. Among the miRNAs evaluated, a series of them evidenced upregulation or downregulation in their expression in the FSH plus LH group compared to the FSH group. Considering the results obtained from the functional and network analysis, the different maternal miRNA profiles in the two groups revealed a differential modulation of pathways involved in numerous biological functions. Overall, based on the pathways associated with most of these maternal miRNAs, the presence of LH may result in a different modulation of pathways regulating survival under the control of a Tp53-related mechanism. Interestingly, among the miRNAs differentially expressed in oocytes of the two groups, we have found miRNAs already investigated at ovarian, follicular, oocyte, and embryonic levels: hsa-miR-484, hsa-miR-222, hsa-miR-520d-5p, hsa-miRNA-17, hsa-miR-548, and hsa-miR-140. Thus, investigation into the role of these miRNAs in oocyte molecular pathways may help determine how LH affects oocyte competence and eventually leads to the clinical improvement of IVF.
]]>Epigenomes doi: 10.3390/epigenomes7040024
Authors: Georgios Androutsopoulos Ioanna Styliara Evgenia Zarogianni Nadia Lazurko George Valasoulis Georgios Michail Georgios Adonakis
Endometrial cancer (EC) is the second most common malignancy of the female reproductive system worldwide. The updated EC classification emphasizes the significant role of various signaling pathways such as PIK3CA-PIK3R1-PTEN and RTK/RAS/β-catenin in EC pathogenesis. Some of these pathways are part of the EGF system signaling network, which becomes hyperactivated by various mechanisms and participates in cancer pathogenesis. In EC, the expression of ErbB receptors is significantly different, compared with the premenopausal and postmenopausal endometrium, mainly because of the increased transcriptional activity of ErbB encoding genes in EC cells. Moreover, there are some differences in ErbB-2 receptor profile among EC subgroups that could be explained by the alterations in pathophysiology and clinical behavior of various EC histologic subtypes. The fact that ErbB-2 receptor expression is more common in aggressive EC histologic subtypes (papillary serous and clear cell) could indicate a future role of ErbB-targeted therapies in well-defined EC subgroups with overexpression of ErbB receptors.
]]>Epigenomes doi: 10.3390/epigenomes7040023
Authors: Ekaterina D. Griazeva Daria M. Fedoseeva Elizaveta I. Radion Pavel V. Ershov Ivan O. Meshkov Alexandra V. Semyanihina Anna S. Makarova Valentin V. Makarov Vladimir S. Yudin Anton A. Keskinov Sergey A. Kraevoy
Epigenetic therapy is a promising tool for the treatment of a wide range of diseases. Several fundamental epigenetic approaches have been proposed. Firstly, the use of small molecules as epigenetic effectors, as the most developed pharmacological method, has contributed to the introduction of a number of drugs into clinical practice. Secondly, various innovative epigenetic approaches based on dCas9 and the use of small non-coding RNAs as therapeutic agents are also under extensive research. In this review, we present the current state of research in the field of epigenetic therapy, considering the prospects for its application and possible limitations.
]]>Epigenomes doi: 10.3390/epigenomes7030022
Authors: Yashpal Ramakrishnaiah Adam P. Morris Jasbir Dhaliwal Melcy Philip Levin Kuhlmann Sonika Tyagi
Long non-coding RNAs (lncRNAs), comprising a significant portion of the human transcriptome, serve as vital regulators of cellular processes and potential disease biomarkers. However, the function of most lncRNAs remains unknown, and furthermore, existing approaches have focused on gene-level investigation. Our work emphasizes the importance of transcript-level annotation to uncover the roles of specific transcript isoforms. We propose that understanding the mechanisms of lncRNA in pathological processes requires solving their structural motifs and interactomes. A complete lncRNA annotation first involves discriminating them from their coding counterparts and then predicting their functional motifs and target bio-molecules. Current in silico methods mainly perform primary-sequence-based discrimination using a reference model, limiting their comprehensiveness and generalizability. We demonstrate that integrating secondary structure and interactome information, in addition to using transcript sequence, enables a comprehensive functional annotation. Annotating lncRNA for newly sequenced species is challenging due to inconsistencies in functional annotations, specialized computational techniques, limited accessibility to source code, and the shortcomings of reference-based methods for cross-species predictions. To address these challenges, we developed a pipeline for identifying and annotating transcript sequences at the isoform level. We demonstrate the effectiveness of the pipeline by comprehensively annotating the lncRNA associated with two specific disease groups. The source code of our pipeline is available under the MIT licensefor local use by researchers to make new predictions using the pre-trained models or to re-train models on new sequence datasets. Non-technical users can access the pipeline through a web server setup.
]]>Epigenomes doi: 10.3390/epigenomes7030021
Authors: Bambarendage P. U. Perera Frédéric Silvestre
Research in epigenetics has dramatically risen during the last decade to include aspects of environmental biology. However, many questions remain regarding the effects of environmental stressors on the epigenome, incorporating the particular role of epigenetic mechanisms in the adaptation and evolution of organisms in changing environments. Epigenetics is commonly defined as mitotically and/or meiotically heritable changes in gene function that occur without altering the underlying DNA sequence. It encompasses DNA (hydroxy)methylation, histone modifications, chromatin structure, and non-coding RNAs that may be inherited across generations under certain circumstances. Epigenetic mechanisms are perfect candidates to extend our understanding of the impact of environmental stressors on organisms and to explain the rapid phenomenon of adaptive evolution. Existing evidence shows that environmental cues can affect the epigenome and modify gene expression accordingly. These changes can then induce phenotypic modifications that are morphological, physiological, or behavioral at the organismal level. In this Special Issue focusing on environmental epigenetics, we provide an overview of influences to the epigenome that are driven by various environmental and evolutionary factors, with a particular focus on DNA methylation (DNAm). Five research groups have contributed insightful studies or reviews on (1) DNAm and demethylation events affected by the exposome; (2) DNAm as a potential biomarker to determine cardiometabolic risk early in life; (3) consequences of DNAm across multiple generations; (4) DNAm variation within natural animal populations; and (5) epigenetic mechanisms in genetically uniform organisms. Collectively, the articles from this Special Issue consistently support that environmental changes can induce long-lasting epigenetic effects within a given organism pertaining to individual risk for disease, or multi-generational impacts that ultimately impact evolution.
]]>Epigenomes doi: 10.3390/epigenomes7030020
Authors: Toshiyuki Murai Satoru Matsuda
Neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, are caused by a combination of multiple events that damage neuronal function. A well-characterized biomarker of neurodegeneration is the accumulation of proteinaceous aggregates in the brain. However, the gradually worsening symptoms of neurodegenerative diseases are unlikely to be solely due to the result of a mutation in a single gene, but rather a multi-step process involving epigenetic changes. Recently, it has been suggested that a fraction of epigenetic alternations may be correlated to neurodegeneration in the brain. Unlike DNA mutations, epigenetic alterations are reversible, and therefore raise the possibilities for therapeutic intervention, including dietary modifications. Additionally, reactive oxygen species may contribute to the pathogenesis of Alzheimer’s disease and Parkinson’s disease through epigenetic alternation. Given that the antioxidant properties of plant-derived phytochemicals are likely to exhibit pleiotropic effects against ROS-mediated epigenetic alternation, dietary intervention may be promising for the management of neurodegeneration in these diseases. In this review, the state-of-the-art applications using single-cell multimodal omics approaches, including epigenetics, and dietary approaches for the identification of novel biomarkers and therapeutic approaches for the treatment of neurodegenerative diseases are discussed.
]]>Epigenomes doi: 10.3390/epigenomes7030019
Authors: Majid Nikpay
Understanding the epigenome paths through which smoking contributes to cardiometabolic traits is important for downstream applications. In this study, an SNP-based analytical pipeline was used to integrate several publicly available datasets in order to identify CpG sites that mediate the impact of smoking on cardiometabolic traits and to investigate the underlying molecular mechanisms. After applying stringent statistical criteria, 11 CpG sites were detected that showed significant association (p < 5 × 10−8) with cardiometabolic traits at both the discovery and replication stages. By integrating eQTL data, I found genes behind a number of these associations. cg05228408 was hypomethylated in smokers and contributed to higher blood pressure by lowering the expression of the CLCN6 gene. cg08639339 was hypermethylated in smokers and lowered the metabolic rate by increasing the expression of RAB29; furthermore, I noted TMEM120A mediated the impact of smoking-cg17325771 on LDL, and LTBP3 mediated the smoking-cg07029024 effect on heart rate. The pathway analysis identified processes through which the identified genes impact their traits. This study provides a list of CpG sites that mediates the impact of smoking on cardiometabolic traits and a framework to investigate the underlying molecular paths using publicly available data.
]]>Epigenomes doi: 10.3390/epigenomes7030018
Authors: Perla Pizzi Argentato João Victor da Silva Guerra Liania Alves Luzia Ester Silveira Ramos Mariana Maschietto Patrícia Helen de Carvalho Rondó
Background: Changes in body weight are associated with the regulation of DNA methylation (DNAm). In this study, we investigated the associations between maternal gestational weight gain-related DNAm and foetal and neonatal body composition. Methods: Brazilian pregnant women from the Araraquara Cohort Study were followed up during pregnancy, delivery, and after hospital discharge. Women with normal pre-pregnancy BMI were allocated into two groups: adequate gestational weight gain (AGWG, n = 45) and excessive gestational weight gain (EGWG, n = 30). Foetal and neonatal body composition was evaluated via ultrasound and plethysmography, respectively. DNAm was assessed in maternal blood using Illumina Infinium MethylationEPIC BeadChip arrays. Linear regression models were used to explore the associations between DNAm and foetal and neonatal body composition. Results: Maternal weight, GWG, neonatal weight, and fat mass were higher in the EGWG group. Analysis of DNAm identified 46 differentially methylated positions and 11 differentially methylated regions (DMRs) between the EGWG and AGWG groups. Nine human phenotypes were enriched for these 11 DMRs located in 13 genes (EMILIN1, HOXA5, CPT1B, CLDN9, ZFP57, BRCA1, POU5F1, ANKRD33, HLA-B, RANBP17, ZMYND11, DIP2C, TMEM232), highlighting the terms insulin resistance, and hyperglycaemia. Maternal DNAm was associated with foetal total thigh and arm tissues and subcutaneous thigh and arm fat, as well as with neonatal fat mass percentage and fat mass. Conclusion: The methylation pattern in the EGWG group indicated a risk for developing chronic diseases and involvement of maternal DNAm in foetal lean and fat mass and in neonatal fat mass.
]]>Epigenomes doi: 10.3390/epigenomes7030017
Authors: Rowshan Ara Islam Charalampos Rallis
Although reported in the literature, ribosome heterogeneity is a phenomenon whose extent and implications in cell and organismal biology is not fully appreciated. This has been the case due to the lack of the appropriate techniques and approaches. Heterogeneity can arise from alternative use and differential content of protein and RNA constituents, as well as from post-transcriptional and post-translational modifications. In the few examples we have, it is apparent that ribosomal heterogeneity offers an additional level and potential for gene expression regulation and might be a way towards tuning metabolism, stress, and growth programs to external and internal stimuli and needs. Here, we introduce ribosome biogenesis and discuss ribosomal heterogeneity in various reported occasions. We conclude that a systematic approach in multiple organisms will be needed to delineate this biological phenomenon and its contributions to growth, aging, and disease. Finally, we discuss ribosome mutations and their roles in disease.
]]>Epigenomes doi: 10.3390/epigenomes7030016
Authors: Jéssika Aline do Nascimento Medeiros Ayane Cristine Alves Sarmento Emanuelly Bernardes-Oliveira Ronnier de Oliveira Maysa Eunice Grigorio Bezerra Lima Ana Katherine Gonçalves Deyse de Souza Dantas Janaina Cristiana de Oliveira Crispim
Different studies show that small non-coding RNAs, such as microRNAs (miRNAs) obtained from exosomes, are considered potential biomarkers in several types of cancer, including cervical cancer (CC). Therefore, the present study seeks to present an overview of the role of circulating exosomal miRNAs with the potential to act as biomarkers for the diagnosis and prognosis of CC and to analyze the presence of these miRNAs according to the stage of CC. For this purpose, a review was developed, with articles consulted from the electronic databases MEDLINE/PubMed, Scopus, and Web of Science published between 2015 and 2021. Seven articles were included after a selection of studies according to the eligibility criteria. In addition to the methods used for sample analysis, detection, and isolation of miRNAs in each article, clinical data were also extracted from the patients studied, such as the stage of cancer. After analyzing the network of the seven miRNAs, they were associated with the immune system, CC progression and staging, and cisplatin resistance. With the belief that studies on miRNAs in cervical cancer would have major clinical implications, in this review, we have attempted to summarize the current situation and potential development prospects.
]]>Epigenomes doi: 10.3390/epigenomes7030015
Authors: Svetlana Salamaikina Vitaly Korchagin Ekaterina Kulabukhova Konstantin Mironov Vera Zimina Alexey Kravtchenko Vasily Akimkin
Genetic factors in the HIV-background may play a significant role in the susceptibility to secondary diseases, like tuberculosis, which is the leading cause in mortality of HIV-positive people. Toll-like receptors (TLRs) are considered to be receptors for adaptive immunity, and polymorphisms in TLR genes can influence the activity of the immune response to infection. We conducted a case–control study of the association of TLR gene polymorphisms with the risk of tuberculosis coinfection in a multi-country sample of HIV-positive participants. Our study revealed certain associations between TLR4 and TLR6 polymorphisms and HIV–tuberculosis coinfection. We also found that the analyzed TLR1 and TLR4 polymorphisms were linked with the decline in CD4+ cell count, which is a predictor of disease progression in HIV-infected individuals. Our findings confirm that TLR gene polymorphisms are factors that may contribute to development of HIV–tuberculosis coinfection. However, the essence of the observed associations remains unclear, since it can also include both environmental factors and epigenetic mechanisms of gene expression regulation.
]]>Epigenomes doi: 10.3390/epigenomes7030014
Authors: Fátima Duarte-Aké Rosa Us-Camas Clelia De-la-Peña
Epigenetic regulation has the potential to revolutionize plant breeding and improve crop yields by regulating gene expression in plants. DNA methylation and histone modifications are key epigenetic modifications that can impact plant development, stress responses, productivity, and yields. Higher-yielding crops not only generate greater profits for farmers and seed producers, but also require less land, water, fuel, and fertilizer than traditional crops for equivalent yields. The use of heterosis in crops can influence productivity and food quality, but producing hybrids with superior agronomic traits to their parents remains challenging. However, epigenetic markers, such as histone methylation and acetylation, may help select parental and hybrid combinations with better performances than the parental plants. This review assesses the potential applications of epigenetics in crop breeding and improvement, rendering agriculture more efficient, sustainable, and adaptable to changing environmental conditions.
]]>Epigenomes doi: 10.3390/epigenomes7030013
Authors: Dylan Wrede Mika Bordak Yeabtsega Abraham Masfique Mehedi
Epigenetics generally involves genetic control by factors other than our own DNA sequence. Recent research has focused on delineating the mechanisms of two major epigenetic phenomena: DNA methylation and histone modification. As epigenetics involves many cellular processes, it is no surprise that it can also influence disease-associated gene expression. A direct link between respiratory infections, host cell epigenetic regulations, and chronic lung diseases is still unknown. Recent studies have revealed bacterium- or virus-induced epigenetic changes in the host cells. In this review, we focused on respiratory pathogens (viruses, bacteria, and fungi) induced epigenetic modulations (DNA methylation and histone modification) that may contribute to lung disease pathophysiology by promoting host defense or allowing pathogen persistence.
]]>Epigenomes doi: 10.3390/epigenomes7030012
Authors: Fallon Gallimore Tamer E. Fandy
Azanucleosides, such as 5-azacytidine and decitabine, are DNA demethylating agents used in the treatment of acute myeloid leukemia and myelodysplastic syndromes. Researchers continue to explore their utility in the treatment of other hematologic and solid tumors. Based on the capacity of the compounds to inhibit DNA methyltransferase enzymes and the important role of DNA methylation in health and disease, it is essential to understand the molecular changes that azanucleosides induce and how these changes may improve treatment outcomes in subsets of patients. This review summarizes the molecular and therapeutic actions of azanucleosides and discusses recent clinical trials of these compounds as single agents or in combination therapy for the treatment of cancer and related conditions.
]]>Epigenomes doi: 10.3390/epigenomes7020011
Authors: Daniel R. A. Cox Tess McClure Fan Zhang Boris Ka Leong Wong Adam Testro Su Kah Goh Vijayaragavan Muralidharan Alexander Dobrovic
Background: Graft-derived cell-free DNA (gdcfDNA) analysis has shown promise as a non-invasive tool for monitoring organ health following solid organ transplantation. A number of gdcfDNA analysis techniques have been described; however, the majority rely on sequencing or prior genotyping to detect donor-recipient mis-matched genetic polymorphisms. Differentially methylated regions of DNA can be used to identify the tissue-of-origin of cell-free DNA (cfDNA) fragments. In this study, we aimed to directly compare the performance of gdcfDNA monitoring using graft-specific DNA methylation analysis and donor-recipient genotyping techniques in a pilot cohort of clinical samples from patients post-liver transplantation. Results: 7 patients were recruited prior to LT, 3 developed early, biopsy-proven TCMR in the first 6 weeks post-LT. gdcfDNA was successfully quantified in all samples using both approaches. There was a high level of technical correlation between results using the two techniques (Spearman testing, rs = 0.87, p < 0.0001). gdcfDNA levels quantified using the genotyping approach were significantly greater across all timepoints in comparison to the tissue-specific DNA methylation-based approach: e.g., day 1 post-LT median 31,350 copies/mL (IQR 6731–64,058) vs. 4133 copies/mL (IQR 1100–8422), respectively. Qualitative trends in gdcfDNA levels for each patient were concordant between the two assays. Acute TCMR was preceded by significant elevations in gdcfDNA as quantified by both techniques. Elevations in gdcfDNA, using both techniques, were suggestive of TCMR in this pilot study with a 6- and 3-day lead-time prior to histological diagnosis in patients 1 and 2. Conclusions: Both the graft-specific methylation and genotyping techniques successfully quantified gdcfDNA in patients post-LT with statistically significant concordance. A direct comparison of these two techniques is not only important from a technical perspective for orthogonal validation, but significantly adds weight to the evidence that gdcfDNA monitoring reflects the underlying biology. Both techniques identified LT recipients who developed acute TCMR, with several days lead-time in comparison to conventional diagnostic workflows. Whilst the two assays performed comparably, gdcfDNA monitoring based on graft-specific DNA methylation patterns in cfDNA offers major practical advantages over the donor-recipient genotyping, and hence enhances the potential to translate this emerging technology into clinical practice.
]]>Epigenomes doi: 10.3390/epigenomes7020010
Authors: Rashmi Srivastava Rubi Singh Shaurya Jauhari Niraj Lodhi Rakesh Srivastava
Epigenetic modifications are heritable, reversible changes in histones or the DNA that control gene functions, being exogenous to the genomic sequence itself. Human diseases, particularly cancer, are frequently connected to epigenetic dysregulations. One of them is histone methylation, which is a dynamically reversible and synchronously regulated process that orchestrates the three-dimensional epigenome, nuclear processes of transcription, DNA repair, cell cycle, and epigenetic functions, by adding or removing methylation groups to histones. Over the past few years, reversible histone methylation has become recognized as a crucial regulatory mechanism for the epigenome. With the development of numerous medications that target epigenetic regulators, epigenome-targeted therapy has been used in the treatment of malignancies and has shown meaningful therapeutic potential in preclinical and clinical trials. The present review focuses on the recent advances in our knowledge on the role of histone demethylases in tumor development and modulation, in emphasizing molecular mechanisms that control cancer cell progression. Finally, we emphasize current developments in the advent of new molecular inhibitors that target histone demethylases to regulate cancer progression.
]]>Epigenomes doi: 10.3390/epigenomes7020009
Authors: Fatemeh Vand-Rajabpour Meghan Savage Rachel L. Belote Robert L. Judson-Torres
MicroRNAs are non-coding RNAs fundamental to metazoan development and disease. Although the aberrant regulation of microRNAs during mammalian tumorigenesis is well established, investigations into the contributions of individual microRNAs are wrought with conflicting observations. The underlying cause of these inconsistencies is often attributed to context-specific functions of microRNAs. We propose that consideration of both context-specific factors, as well as underappreciated fundamental concepts of microRNA biology, will permit a more harmonious interpretation of ostensibly diverging data. We discuss the theory that the biological function of microRNAs is to confer robustness to specific cell states. Through this lens, we then consider the role of miR-211-5p in melanoma progression. Using literature review and meta-analyses, we demonstrate how a deep understating of domain-specific contexts is critical for moving toward a concordant understanding of miR-211-5p and other microRNAs in cancer biology.
]]>Epigenomes doi: 10.3390/epigenomes7010008
Authors: Mariya A. Smetanina Valeria A. Korolenya Alexander E. Kel Ksenia S. Sevostyanova Konstantin A. Gavrilov Andrey I. Shevela Maxim L. Filipenko
Epigenomic changes in the venous cells exerted by oscillatory shear stress towards the endothelium may result in consolidation of gene expression alterations upon vein wall remodeling during varicose transformation. We aimed to reveal such epigenome-wide methylation changes. Primary culture cells were obtained from non-varicose vein segments left after surgery of 3 patients by growing the cells in selective media after magnetic immunosorting. Endothelial cells were either exposed to oscillatory shear stress or left at the static condition. Then, other cell types were treated with preconditioned media from the adjacent layer’s cells. DNA isolated from the harvested cells was subjected to epigenome-wide study using Illumina microarrays followed by data analysis with GenomeStudio (Illumina), Excel (Microsoft), and Genome Enhancer (geneXplain) software packages. Differential (hypo-/hyper-) methylation was revealed for each cell layer’s DNA. The most targetable master regulators controlling the activity of certain transcription factors regulating the genes near the differentially methylated sites appeared to be the following: (1) HGS, PDGFB, and AR for endothelial cells; (2) HGS, CDH2, SPRY2, SMAD2, ZFYVE9, and P2RY1 for smooth muscle cells; and (3) WWOX, F8, IGF2R, NFKB1, RELA, SOCS1, and FXN for fibroblasts. Some of the identified master regulators may serve as promising druggable targets for treating varicose veins in the future.
]]>Epigenomes doi: 10.3390/epigenomes7010007
Authors: Nando Dulal Das Hideaki Niwa Takashi Umehara
The dynamic regulation of histone methylation and demethylation plays an important role in the regulation of gene expression. Aberrant expression of histone lysine demethylases has been implicated in various diseases including intractable cancers, and thus lysine demethylases serve as promising therapeutic targets. Recent studies in epigenomics and chemical biology have led to the development of a series of small-molecule demethylase inhibitors that are potent, specific, and have in vivo efficacy. In this review, we highlight emerging small-molecule inhibitors targeting the histone lysine demethylases and their progress toward drug discovery.
]]>Epigenomes doi: 10.3390/epigenomes7010006
Authors: Ayoung Kim Kyumin Mo Hyeonseok Kwon Soohyun Choe Misung Park Woori Kwak Hyunho Yoon
Breast cancer remains a common cause of cancer-related death in women. Therefore, further studies are necessary for the comprehension of breast cancer and the revolution of breast cancer treatment. Cancer is a heterogeneous disease that results from epigenetic alterations in normal cells. Aberrant epigenetic regulation is strongly associated with the development of breast cancer. Current therapeutic approaches target epigenetic alterations rather than genetic mutations due to their reversibility. The formation and maintenance of epigenetic changes depend on specific enzymes, including DNA methyltransferases and histone deacetylases, which are promising targets for epigenetic-based therapy. Epidrugs target different epigenetic alterations, including DNA methylation, histone acetylation, and histone methylation, which can restore normal cellular memory in cancerous diseases. Epigenetic-targeted therapy using epidrugs has anti-tumor effects on malignancies, including breast cancer. This review focuses on the importance of epigenetic regulation and the clinical implications of epidrugs in breast cancer.
]]>Epigenomes doi: 10.3390/epigenomes7010005
Authors: Ekaterina Yu. Fedotova Elena V. Iakovenko Natalia Yu. Abramycheva Sergey N. Illarioshkin
In recent years, epigenetic mechanisms have been implicated in the development of multifactorial diseases including neurodegenerative disorders. In Parkinson’s disease (PD), as a synucleinopathy, most studies focused on DNA methylation of SNCA gene coding alpha-synuclein but obtained results were rather contradictory. In another neurodegenerative synucleinopathy, multiple system atrophy (MSA), very few studies investigated the epigenetic regulation. This study included patients with PD (n = 82), patients with MSA (n = 24), and a control group (n = 50). In three groups, methylation levels of CpG and non-CpG sites in regulatory regions of the SNCA gene were analyzed. We revealed hypomethylation of CpG sites in the SNCA intron 1 in PD and hypermethylation of predominantly non-CpG sites in the SNCA promoter region in MSA. In PD patients, hypomethylation in the intron 1 was associated with earlier age at the disease onset. In MSA patients, hypermethylation in the promotor was associated with shorter disease duration (before examination). These results showed different patterns of the epigenetic regulation in two synucleinopathies—PD and MSA.
]]>Epigenomes doi: 10.3390/epigenomes7010004
Authors: Abeer A. Aljahdali Jaclyn M. Goodrich Dana C. Dolinoy Hyungjin M. Kim Edward A. Ruiz-Narváez Ana Baylin Alejandra Cantoral Libni A. Torres-Olascoaga Martha M. Téllez-Rojo Karen E. Peterson
DNA methylation (DNAm) is a plausible mechanism underlying cardiometabolic abnormalities, but evidence is limited among youth. This analysis included 410 offspring of the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) birth cohort followed up to two time points in late childhood/adolescence. At Time 1, DNAm was quantified in blood leukocytes at long interspersed nuclear elements (LINE-1), H19, and 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD-2), and at Time 2 in peroxisome proliferator-activated receptor alpha (PPAR-α). At each time point, cardiometabolic risk factors were assessed including lipid profiles, glucose, blood pressure, and anthropometry. Linear mixed effects models were used for LINE-1, H19, and 11β-HSD-2 to account for the repeated-measure outcomes. Linear regression models were conducted for the cross-sectional association between PPAR-α with the outcomes. DNAm at LINE-1 was associated with log glucose at site 1 [β = −0.029, p = 0.0006] and with log high-density lipoprotein cholesterol at site 3 [β = 0.063, p = 0.0072]. 11β-HSD-2 DNAm at site 4 was associated with log glucose (β = −0.018, p = 0.0018). DNAm at LINE-1 and 11β-HSD-2 was associated with few cardiometabolic risk factors among youth in a locus-specific manner. These findings underscore the potential for epigenetic biomarkers to increase our understanding of cardiometabolic risk earlier in life.
]]>Epigenomes doi: 10.3390/epigenomes7010003
Authors: Epigenomes Editorial Office Epigenomes Editorial Office
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]]>Epigenomes doi: 10.3390/epigenomes7010002
Authors: Elena Tomeva Ulrike D. B. Krammer Olivier J. Switzeny Alexander G. Haslberger Berit Hippe
Dysregulation of epigenetic mechanisms has been recognized to play a crucial role in cancer development, but these mechanisms vary between sexes. Therefore, we focused on sex-specific differences in the context of cancer-based data from a recent study. A total of 12 cell-free DNA methylation targets in CpG-rich promoter regions and 48 miRNAs were analyzed by qPCR in plasma samples from 8 female and 7 male healthy controls as well as 48 female and 80 male subjects with solid tumors of the bladder, brain, colorectal region (CRC), lung, stomach, pancreas, and liver. Due to the small sample size in some groups and/or the non-balanced distribution of men and women, sex-specific differences were evaluated statistically only in healthy subjects, CRC, stomach or pancreas cancer patients, and all cancer subjects combined (n female/male—8/7, 14/14, 8/15, 6/6, 48/80, respectively). Several miRNAs with opposing expressions between the sexes were observed for healthy subjects (miR-17-5p, miR-26b-5p); CRC patients (miR-186-5p, miR-22-3p, miR-22-5p, miR-25-3p, miR-92a-3p, miR-16-5p); stomach cancer patients (miR-133a-3p, miR-22-5p); and all cancer patients combined (miR-126-3p, miR-21-5p, miR-92a-3p, miR-183-5p). Moreover, sex-specific correlations that were dependent on cancer stage were observed in women (miR-27a-3p) and men (miR-17-5p, miR-20a-5p). Our results indicate the complex and distinct role of epigenetic regulation, particularly miRNAs, depending not only on the health status but also on the sex of the patient. The same miRNAs could have diverse effects in different tissues and opposing effects between the biological sexes, which should be considered in biomarker research.
]]>Epigenomes doi: 10.3390/epigenomes7010001
Authors: Günter Vogt
Organisms adapt to different environments by selection of the most suitable phenotypes from the standing genetic variation or by phenotypic plasticity, the ability of single genotypes to produce different phenotypes in different environments. Because of near genetic identity, asexually reproducing populations are particularly suitable for the investigation of the potential and molecular underpinning of the latter alternative in depth. Recent analyses on the whole-genome scale of differently adapted clonal animals and plants demonstrated that epigenetic mechanisms such as DNA methylation, histone modifications and non-coding RNAs are among the molecular pathways supporting phenotypic plasticity and that epigenetic variation is used to stably adapt to different environments. Case studies revealed habitat-specific epigenetic fingerprints that were maintained over subsequent years pointing at the existence of epigenetic ecotypes. Environmentally induced epimutations and corresponding gene expression changes provide an ideal means for fast and directional adaptation to changing or new conditions, because they can synchronously alter phenotypes in many population members. Because microorganisms inclusive of human pathogens also exploit epigenetically mediated phenotypic variation for environmental adaptation, this phenomenon is considered a universal biological principle. The production of different phenotypes from the same DNA sequence in response to environmental cues by epigenetic mechanisms also provides a mechanistic explanation for the “general-purpose genotype hypothesis” and the “genetic paradox of invasions”.
]]>Epigenomes doi: 10.3390/epigenomes6040043
Authors: Kenneth C. Ehrlich Michelle Lacey Carl Baribault Sagnik Sen Pierre Olivier Esteve Sriharsa Pradhan Melanie Ehrlich
TBX15, which encodes a differentiation-related transcription factor, displays promoter-adjacent DNA hypermethylation in myoblasts and skeletal muscle (psoas) that is absent from non-expressing cells in other lineages. By whole-genome bisulfite sequencing (WGBS) and enzymatic methyl-seq (EM-seq), these hypermethylated regions were found to border both sides of a constitutively unmethylated promoter. To understand the functionality of this DNA hypermethylation, we cloned the differentially methylated sequences (DMRs) in CpG-free reporter vectors and tested them for promoter or enhancer activity upon transient transfection. These cloned regions exhibited strong promoter activity and, when placed upstream of a weak promoter, strong enhancer activity specifically in myoblast host cells. In vitro CpG methylation targeted to the DMR sequences in the plasmids resulted in 86–100% loss of promoter or enhancer activity, depending on the insert sequence. These results as well as chromatin epigenetic and transcription profiles for this gene in various cell types support the hypothesis that DNA hypermethylation immediately upstream and downstream of the unmethylated promoter region suppresses enhancer/extended promoter activity, thereby downmodulating, but not silencing, expression in myoblasts and certain kinds of skeletal muscle. This promoter-border hypermethylation was not found in cell types with a silent TBX15 gene, and these cells, instead, exhibit repressive chromatin in and around the promoter. TBX18, TBX2, TBX3 and TBX1 display TBX15-like hypermethylated DMRs at their promoter borders and preferential expression in myoblasts. Therefore, promoter-adjacent DNA hypermethylation for downmodulating transcription to prevent overexpression may be used more frequently for transcription regulation than currently appreciated.
]]>Epigenomes doi: 10.3390/epigenomes6040042
Authors: Lucy Anne Doyle Firuze Unlu Bektas Eleftheria Chatzantonaki Charlotte Repton Alexandra Derrien Robert Scott Illingworth
During mammalian neurodevelopment, signaling pathways converge upon transcription factors (TFs) to establish appropriate gene expression programmes leading to the production of distinct neural and glial cell types. This process is partially regulated by the dynamic modulation of chromatin states by epigenetic systems, including the polycomb group (PcG) family of co-repressors. PcG proteins form multi-subunit assemblies that sub-divide into distinct, yet functionally related families. Polycomb repressive complexes 1 and 2 (PRC1 and 2) modify the chemical properties of chromatin by covalently modifying histone tails via H2A ubiquitination (H2AK119ub1) and H3 methylation, respectively. In contrast to the PRCs, the Polycomb repressive deubiquitinase (PR-DUB) complex removes H2AK119ub1 from chromatin through the action of the C-terminal hydrolase BAP1. Genetic screening has identified several PcG mutations that are causally associated with a range of congenital neuropathologies associated with both localised and/or systemic growth abnormalities. As PRC1 and PR-DUB hold opposing functions to control H2AK119ub1 levels across the genome, it is plausible that such neurodevelopmental disorders arise through a common mechanism. In this review, we will focus on advancements regarding the composition and opposing molecular functions of mammalian PRC1 and PR-DUB, and explore how their dysfunction contributes to the emergence of neurodevelopmental disorders.
]]>Epigenomes doi: 10.3390/epigenomes6040041
Authors: Xiaodong Liu Xiao-Jiang Li Li Lin
Profiling of 5-hydroxymethylcytosine (5hmC) in the brain regions of rhesus monkey at different ages reveals accumulation and tissue-specific patterns of 5hmC with aging. Region-specific differentially hydroxymethylated regions (DhMRs) are involved in neuronal functions and signal transduction. These data suggest that 5hmC may be a key regulator of gene transcription in neurodevelopment and thus a potential candidate for the epigenetic clock. Importantly, non-human primates are the ideal animal models for investigation of human aging and diseases not only because they are more genetically similar to humans but also epigenetically.
]]>Epigenomes doi: 10.3390/epigenomes6040040
Authors: Ibani Kapur Elodie L. Boulier Nicole J. Francis
The Polycomb group (PcG) complex PRC1 localizes in the nucleus in condensed structures called Polycomb bodies. The PRC1 subunit Polyhomeotic (Ph) contains an oligomerizing sterile alpha motif (SAM) that is implicated in both PcG body formation and chromatin organization in Drosophila and mammalian cells. A truncated version of Ph containing the SAM (mini-Ph) forms phase-separated condensates with DNA or chromatin in vitro, suggesting that PcG bodies may form through SAM-driven phase separation. In cells, Ph forms multiple small condensates, while mini-Ph typically forms a single large nuclear condensate. We therefore hypothesized that sequences outside of mini-Ph, which are predicted to be intrinsically disordered, are required for proper condensate formation. We identified three distinct low-complexity regions in Ph based on sequence composition. We systematically tested the role of each of these sequences in Ph condensates using live imaging of transfected Drosophila S2 cells. Each sequence uniquely affected Ph SAM-dependent condensate size, number, and morphology, but the most dramatic effects occurred when the central, glutamine-rich intrinsically disordered region (IDR) was removed, which resulted in large Ph condensates. Like mini-Ph condensates, condensates lacking the glutamine-rich IDR excluded chromatin. Chromatin fractionation experiments indicated that the removal of the glutamine-rich IDR reduced chromatin binding and that the removal of either of the other IDRs increased chromatin binding. Our data suggest that all three IDRs, and functional interactions among them, regulate Ph condensate size and number. Our results can be explained by a model in which tight chromatin binding by Ph IDRs antagonizes Ph SAM-driven phase separation. Our observations highlight the complexity of regulation of biological condensates housed in single proteins.
]]>Epigenomes doi: 10.3390/epigenomes6040039
Authors: Shivangi Shukla Ashutosh Kumar
The centromere is a specialized DNA locus that ensures the faithful segregation of chromosomes during cell division. It does so by directing the assembly of an essential proteinaceous structure called the kinetochore. The centromere identity is primarily epigenetically defined by a nucleosome containing an H3 variant called CENP-A as well as by the interplay of several factors such as differential chromatin organization driven by CENP-A and H2A.Z, centromere-associated proteins, and post-translational modifications. At the centromere, CENP-A is not just a driving force for kinetochore assembly but also modifies the structural and dynamic properties of the centromeric chromatin, resulting in a distinctive chromatin organization. An additional level of regulation of the centromeric chromatin conformation is provided by post-translational modifications of the histones in the CENP-A nucleosomes. Further, H2A.Z is present in the regions flanking the centromere for heterochromatinization. In this review, we focus on the above-mentioned factors to describe how they contribute to the organization of the centromeric chromatin: CENP-A at the core centromere, post-translational modifications that decorate CENP-A, and the variant H2A.Z.
]]>Epigenomes doi: 10.3390/epigenomes6040038
Authors: Ubah Dominic Babah Ubah Korawin Triyasakorn Brandon Roan Minsyusheen Conlin James C. K. Lai Prabha S. Awale
This study was initiated as an attempt to clarify some of the apparent conflicting data regarding the so-called anti-inflammatory versus proinflammatory properties of histone deacetylase inhibitors (HDACis). In cell culture, typically, chronic pretreatment with the HDACi valproic acid (VPA) and trichostatin A (TSA) exhibits an anti-inflammatory effect. However, the effect of acute treatment with VPA and TSA on the levels of inflammatory cytokines in J774A.1 macrophage cell line is unknown. Therefore, this study investigated the effect of acute treatment with VPA and TSA on levels of key inflammatory cytokines in maximally stimulated J774A.1 cells. J774A.1 macrophages were treated with either VPA or TSA for 1 h (acute treatment), followed by maximal stimulation with LPS + IFNγ for 24 h. ELISA was used to measure the levels of proinflammatory cytokines TNFα, NO and IL-1β from the culture medium. Acute treatment with VPA showed a dose-dependent increase in levels of all three cytokines. Similar to VPA, TSA also showed a dose-dependent increase in levels of IL-1β alone. This study sheds new light on the conflicting data in the literature that may partly be explained by acute or short-term exposure versus chronic or long-term exposure to HDACi.
]]>Epigenomes doi: 10.3390/epigenomes6040037
Authors: Sophie Kogut Hana Paculova Princess Rodriguez Joseph Boyd Alyssa Richman Amrita Palaria Hilde Schjerven Seth Frietze
The hematopoietic transcription factor Ikaros (IKZF1) regulates normal B cell development and functions as a tumor suppressor in precursor B cell acute lymphoblastic leukemia (B-ALL). MicroRNAs (miRNAs) are small regulatory RNAs that through post-transcriptional gene regulation play critical roles in intracellular processes including cell growth in cancer. However, the role of Ikaros in the regulation of miRNA expression in developing B cells is unknown. In this study, we examined the Ikaros-regulated miRNA targets using human IKZF1-mutated Ph+ B-ALL cell lines. Inducible expression of wild-type Ikaros (the Ik1 isoform) caused B-ALL growth arrest and exit from the cell cycle. Global miRNA expression analysis revealed a total of 31 miRNAs regulated by IK1, and ChIP-seq analysis showed that Ikaros bound to several Ik1-responsive miRNA genes. Examination of the prognostic significance of miRNA expression in B-ALL indicate that the IK1-regulated miRNAs hsa-miR-26b, hsa-miR-130b and hsa-miR-4649 are significantly associated with outcome in B-ALL. Our findings establish a potential regulatory circuit between the tumor-suppressor Ikaros and the oncogenic miRNA networks in IKZF1-mutated B-ALL. These results indicate that Ikaros regulates the expression of a subset of miRNAs, of which several may contribute to B-ALL growth.
]]>Epigenomes doi: 10.3390/epigenomes6040036
Authors: Anindita Dutta Apurba Das Deepa Bisht Vijendra Arya Rohini Muthuswami
Cells respond to oxidative stress by elevating the levels of antioxidants, signaling, and transcriptional regulation, often implemented by chromatin remodeling proteins. The study presented here shows that the expression of PICH, a Rad54-like helicase belonging to the ATP-dependent chromatin remodeling protein family, is upregulated during oxidative stress in HeLa cells. We also show that PICH regulates the expression of Nrf2, a transcription factor regulating antioxidant response in both the absence and presence of oxidative stress. The overexpression of PICH in PICH-depleted cells restored Nrf2 as well as antioxidant gene expression. In turn, Nrf2 regulated the expression of PICH in the presence of oxidative stress. ChIP experiments showed that PICH is present on the Nrf2 as well as antioxidant gene promoters, suggesting that the protein might be regulating the expression of these genes directly by binding to the DNA sequences. In addition, Nrf2 and histone acetylation (H3K27ac) also played a role in activating transcription in the presence of oxidative stress. Both Nrf2 and H3K27ac were found to be present on PICH and antioxidant promoters. Their occupancy was dependent on the PICH expression as fold enrichment was found to be decreased in PICH-depleted cells. PICH ablation led to the reduced expression of Nrf2 and impaired antioxidant response, leading to increased ROS content and thus showing PICH is essential for the cell to respond to oxidative stress.
]]>Epigenomes doi: 10.3390/epigenomes6040035
Authors: Anna Fiselier Boseon Byeon Yaroslav Ilnytskyy Olga Kovalchuk Igor Kovalchuk
Non-coding RNA fragments (ncRFs) are small RNA fragments processed from non-coding RNAs (ncRNAs). ncRFs have various functions and are commonly tissue-specific, and their processing is altered by exposure to stress. Information about ncRFs in the brain is scarce. Recently, we reported the brain region-specific and sex-specific expression of ncRNAs and their processing into ncRFs. Here, we analyzed the expression of ncRFs in the frontal cortex (FC), hippocampus (HIP), and cerebellum (CER) of male and female rats exposed to scatter radiation. We found multiple brain region- and sex-specific changes in response to scatter radiation. Specifically, we observed decreased miRNA expression and the increased expression of ra-ncRNA reads in HIP and CER, as well as an increased number of mtR-NA-associated reads in HIP. We also observed the appearance of sense-intronic ncRNAs—in females, in HIP and FC, and in males, in CER. In this work, we also show that tRNA-GlyGCC and tRNA-GlyCCC are most frequently processed to tRFs, in CER in females, as compared to males. An analysis of the targeted pathways revealed that tRFs and snoRFs in scatter radiation samples mapped to genes in several pathways associated with various neuronal functions. While in HIP and CER these pathways were underrepresented, in FC, they were overrepresented. Such changes may play an important role in pathologies that develop in response to scatter radiation, the effect known as “radio-brain”, and may in part explain the sex-specific differences observed in animals and humans exposed to radiation and scatter radiation.
]]>Epigenomes doi: 10.3390/epigenomes6040034
Authors: Philippe Johann to Berens Geoffrey Schivre Marius Theune Jackson Peter Salimata Ousmane Sall Jérôme Mutterer Fredy Barneche Clara Bourbousse Jean Molinier
The combination of ever-increasing microscopy resolution with cytogenetical tools allows for detailed analyses of nuclear functional partitioning. However, the need for reliable qualitative and quantitative methodologies to detect and interpret chromatin sub-nuclear organization dynamics is crucial to decipher the underlying molecular processes. Having access to properly automated tools for accurate and fast recognition of complex nuclear structures remains an important issue. Cognitive biases associated with human-based curation or decisions for object segmentation tend to introduce variability and noise into image analysis. Here, we report the development of two complementary segmentation methods, one semi-automated (iCRAQ) and one based on deep learning (Nucl.Eye.D), and their evaluation using a collection of A. thaliana nuclei with contrasted or poorly defined chromatin compartmentalization. Both methods allow for fast, robust and sensitive detection as well as for quantification of subtle nucleus features. Based on these developments, we highlight advantages of semi-automated and deep learning-based analyses applied to plant cytogenetics.
]]>Epigenomes doi: 10.3390/epigenomes6040033
Authors: Haley E. Hanson Andrea L. Liebl
DNA methylation is an epigenetic modification with wide-ranging consequences across the life of an organism. This modification can be stable, persisting through development despite changing environmental conditions. However, in other contexts, DNA methylation can also be flexible, underlying organismal phenotypic plasticity. One underappreciated aspect of DNA methylation is that it is a potent mutagen; methylated cytosines mutate at a much faster rate than other genetic motifs. This mutagenic property of DNA methylation has been largely ignored in eco-evolutionary literature, despite its prevalence. Here, we explore how DNA methylation induced by environmental and other factors could promote mutation and lead to evolutionary change at a more rapid rate and in a more directed manner than through stochastic genetic mutations alone. We argue for future research on the evolutionary implications of DNA methylation driven mutations both within the lifetime of organisms, as well as across timescales.
]]>Epigenomes doi: 10.3390/epigenomes6040032
Authors: Florestan Courant Gwenola Bougras-Cartron Caroline Abadie Jean-Sébastien Frenel Pierre-François Cartron
Background: Deregulation of DNA methylation/demethylation reactions may be the source of C > T mutation via active deamination of 5-methylcytosine to thymine. Exposome, that is to say, the totality of exposures to which an individual is subjected during their life, can deregulate these reactions. Thus, one may wonder whether the exposome can induce C > T mutations in the breast cancer-predisposing gene PALB2. Methods: Our work is based on the exposure of MCF10A mammary epithelial cells to seven compounds of our exposome (folate, Diuron, glyphosate, PFOA, iron, zinc, and ascorbic acid) alone or in cocktail. The qMSRE and RMS techniques were used to study the impact of these exposures on the level of methylation and mutation of the PALB2 gene. Results: Here, we have found that exposome compounds (nutriments, ions, pollutants) promoting the cytosine methylation and the 5-methylcytosine deamination have the ability to promote a specific C > T mutation in the PALB2 gene. Interestingly, we also noted that the addition of exposome compounds promoting the TET-mediated conversion of 5-methylcytosine (Ascorbic acid and iron) abrogates the presence of C > T mutation in the PALB2 gene. Conclusions: Our study provides a proof of concept supporting the idea that exposomes can generate genetic mutation by affecting DNA methylation/demethylation.
]]>Epigenomes doi: 10.3390/epigenomes6040031
Authors: Valentine Chapelle Frédéric Silvestre
Population epigenetics explores the extent of epigenetic variation and its dynamics in natural populations encountering changing environmental conditions. In contrast to population genetics, the basic concepts of this field are still in their early stages, especially in animal populations. Epigenetic variation may play a crucial role in phenotypic plasticity and local adaptation as it can be affected by the environment, it is likely to have higher spontaneous mutation rate than nucleotide sequences do, and it may be inherited via non-mendelian processes. In this review, we aim to bring together natural animal population epigenetic studies to generate new insights into ecological epigenetics and its evolutionary implications. We first provide an overview of the extent of DNA methylation variation and its autonomy from genetic variation in wild animal population. Second, we discuss DNA methylation dynamics which create observed epigenetic population structures by including basic population genetics processes. Then, we highlight the relevance of DNA methylation variation as an evolutionary mechanism in the extended evolutionary synthesis. Finally, we suggest new research directions by highlighting gaps in the knowledge of the population epigenetics field. As for our results, DNA methylation diversity was found to reveal parameters that can be used to characterize natural animal populations. Some concepts of population genetics dynamics can be applied to explain the observed epigenetic structure in natural animal populations. The set of recent advancements in ecological epigenetics, especially in transgenerational epigenetic inheritance in wild animal population, might reshape the way ecologists generate predictive models of the capacity of organisms to adapt to changing environments.
]]>Epigenomes doi: 10.3390/epigenomes6040030
Authors: Le Zhang Emma M. Rath Yuen Yee Cheng
The last few decades have brought tremendous advances in the mechanisms of epigenetic regulation, with DNA methylation, histone methylation and acetylation, microRNAs and other noncoding RNAs being among the most prominent [...]
]]>Epigenomes doi: 10.3390/epigenomes6030029
Authors: Susana M. Contreras Romina T. Zambrano Siri Elías M. Rivera Constanza Cristaldi Laura Kamenetzky Kami Kim Marina Clemente Josefina Ocampo Laura Vanagas Sergio O. Angel
Subtelomeres (ST) are chromosome regions that separate telomeres from euchromatin and play relevant roles in various biological processes of the cell. While their functions are conserved, ST structure and genetic compositions are unique to each species. This study aims to identify and characterize the subtelomeric regions of the 13 Toxoplasma gondii chromosomes of the Me49 strain. Here, STs were defined at chromosome ends based on poor gene density. The length of STs ranges from 8.1 to 232.4 kbp, with a gene density of 0.049 genes/kbp, lower than the Me49 genome (0.15 kbp). Chromatin organization showed that H3K9me3, H2A.X, and H3.3 are highly enriched near telomeres and the 5′ end of silenced genes, decaying in intensity towards euchromatin. H3K4me3 and H2A.Z/H2B.Z are shown to be enriched in the 5′ end of the ST genes. Satellite DNA was detected in almost all STs, mainly the sat350 family and a novel satellite named sat240. Beyond the STs, only short dispersed fragments of sat240 and sat350 were found. Within STs, there were 12 functional annotated genes, 59 with unknown functions (Hypothetical proteins), 15 from multigene FamB, and 13 from multigene family FamC. Some genes presented low interstrain synteny associated with the presence of satellite DNA. Orthologues of FamB and FamC were also detected in Neospora caninum and Hammondia hammondi. A re-analysis of previous transcriptomic data indicated that ST gene expression is strongly linked to the adaptation to different situations such as extracellular passage (evolve and resequencing study) and changes in metabolism (lack of acetyl-CoA cofactor). In conclusion, the ST region of the T. gondii chromosomes was defined, the STs genes were determined, and it was possible to associate them with high interstrain plasticity and a role in the adaptability of T. gondii to environmental changes.
]]>Epigenomes doi: 10.3390/epigenomes6030028
Authors: Beatriz German Leigh Ellis
The polycomb group (PcG) proteins are a subset of transcription regulators highly conserved throughout evolution. Their principal role is to epigenetically modify chromatin landscapes and control the expression of master transcriptional programs to determine cellular identity. The two mayor PcG protein complexes that have been identified in mammals to date are Polycomb Repressive Complex 1 (PRC1) and 2 (PRC2). These protein complexes selectively repress gene expression via the induction of covalent post-translational histone modifications, promoting chromatin structure stabilization. PRC2 catalyzes the histone H3 methylation at lysine 27 (H3K27me1/2/3), inducing heterochromatin structures. This activity is controlled by the formation of a multi-subunit complex, which includes enhancer of zeste (EZH2), embryonic ectoderm development protein (EED), and suppressor of zeste 12 (SUZ12). This review will summarize the latest insights into how PRC2 in mammalian cells regulates transcription to orchestrate the temporal and tissue-specific expression of genes to determine cell identity and cell-fate decisions. We will specifically describe how PRC2 dysregulation in different cell types can promote phenotypic plasticity and/or non-mutational epigenetic reprogramming, inducing the development of highly aggressive epithelial neuroendocrine carcinomas, including prostate, small cell lung, and Merkel cell cancer. With this, EZH2 has emerged as an important actionable therapeutic target in such cancers.
]]>Epigenomes doi: 10.3390/epigenomes6030027
Authors: Catherine A. Dennen Kenneth Blum Abdalla Bowirrat Jag Khalsa Panayotis K. Thanos David Baron Rajendra D. Badgaiyan Ashim Gupta Eric R. Braverman Mark S. Gold
Cannabis is one of the most commonly used and abused illicit drugs in the world today. The United States (US) currently has the highest annual prevalence rate of cannabis consumption in the world, 17.9% in individuals aged 12 or older, and it is on the rise. With increasing cannabis use comes the potential for an increase in abuse, and according to the Substance Abuse and Mental Health Services Administration (SAMHSA), approximately 5.1% of Americans had Cannabis Use Disorder (CUD) in 2020. Research has shown that genetics and epigenetics play a significant role in cannabis use and CUD. In fact, approximately 50–70% of liability to CUD and 40–48% of cannabis use initiation have been found to be the result of genetic factors. Cannabis usage and CUD have also been linked to an increased risk of psychiatric disorders and Reward Deficiency Syndrome (RDS) subsets like schizophrenia, depression, anxiety, and substance use disorder. Comprehension of the genetic and epigenetic aspects of cannabinoids is necessary for future research, treatment plans, and the production of pure cannabinoid compounds, which will be essential for FDA approval. In conclusion, having a better understanding of the epigenetic and genetic underpinnings of cannabis use, CUD, and the endocannabinoid system as a whole will aid in the development of effective FDA-approved treatment therapies and the advancement of personalized medicine.
]]>Epigenomes doi: 10.3390/epigenomes6030026
Authors: Yasuhiro Fujiwara Mary Ann Handel Yuki Okada
Meiosis is specialized cell division during gametogenesis that produces genetically unique gametes via homologous recombination. Meiotic homologous recombination entails repairing programmed 200–300 DNA double-strand breaks generated during the early prophase. To avoid interference between meiotic gene transcription and homologous recombination, mammalian meiosis is thought to employ a strategy of exclusively transcribing meiotic or post-meiotic genes before their use. Recent studies have shown that R-loops, three-stranded DNA/RNA hybrid nucleotide structures formed during transcription, play a crucial role in transcription and genome integrity. Although our knowledge about the function of R-loops during meiosis is limited, recent findings in mouse models have suggested that they play crucial roles in meiosis. Given that defective formation of an R-loop can cause abnormal transcription and transcription-coupled DNA damage, the precise regulatory network of R-loops may be essential in vivo for the faithful progression of mammalian meiosis and gametogenesis.
]]>Epigenomes doi: 10.3390/epigenomes6030025
Authors: Itzel Alejandra Hernández-Romero Victor Julian Valdes
Every cell of an organism shares the same genome; even so, each cellular lineage owns a different transcriptome and proteome. The Polycomb group proteins (PcG) are essential regulators of gene repression patterning during development and homeostasis. However, it is unknown how the repressive complexes, PRC1 and PRC2, identify their targets and elicit new Polycomb domains during cell differentiation. Classical recruitment models consider the pre-existence of repressive histone marks; still, de novo target binding overcomes the absence of both H3K27me3 and H2AK119ub. The CpG islands (CGIs), non-core proteins, and RNA molecules are involved in Polycomb recruitment. Nonetheless, it is unclear how de novo targets are identified depending on the physiological context and developmental stage and which are the leading players stabilizing Polycomb complexes at domain nucleation sites. Here, we examine the features of de novo sites and the accessory elements bridging its recruitment and discuss the first steps of Polycomb domain formation and transcriptional regulation, comprehended by the experimental reconstruction of the repressive domains through time-resolved genomic analyses in mammals.
]]>Epigenomes doi: 10.3390/epigenomes6030024
Authors: Deepa Ramasamy Arunagiri Kuha Deva Magendhra Rao Thangarajan Rajkumar Samson Mani
Cytosine methylation adjacent to adenine, thymine, and cytosine residues but not guanine of the DNA is distinctively known as non-CpG methylation. This CA/CT/CC methylation accounts for 15% of the total cytosine methylation and varies among different cell and tissue types. The abundance of CpG methylation has largely concealed the role of non-CpG methylation. Limitations in the early detection methods could not distinguish CpG methylation from non-CpG methylation. Recent advancements in enrichment strategies and high throughput sequencing technologies have enabled the detection of non-CpG methylation. This review discusses the advanced experimental and computational approaches to detect and describe the genomic distribution and function of non-CpG methylation. We present different approaches such as enzyme-based and antibody-based enrichment, which, when coupled, can also improve the sensitivity and specificity of non-CpG detection. We also describe the current bioinformatics pipelines and their specific application in computing and visualizing the imbalance of CpG and non-CpG methylation. Enrichment modes and the computational suites need to be further developed to ease the challenges of understanding the functional role of non-CpG methylation.
]]>Epigenomes doi: 10.3390/epigenomes6030023
Authors: Chet H. Loh Gert Jan C. Veenstra
Embryonic development is a highly intricate and complex process. Different regulatory mechanisms cooperatively dictate the fate of cells as they progress from pluripotent stem cells to terminally differentiated cell types in tissues. A crucial regulator of these processes is the Polycomb Repressive Complex 2 (PRC2). By catalyzing the mono-, di-, and tri-methylation of lysine residues on histone H3 tails (H3K27me3), PRC2 compacts chromatin by cooperating with Polycomb Repressive Complex 1 (PRC1) and represses transcription of target genes. Proteomic and biochemical studies have revealed two variant complexes of PRC2, namely PRC2.1 which consists of the core proteins (EZH2, SUZ12, EED, and RBBP4/7) interacting with one of the Polycomb-like proteins (MTF2, PHF1, PHF19), and EPOP or PALI1/2, and PRC2.2 which contains JARID2 and AEBP2 proteins. MTF2 and JARID2 have been discovered to have crucial roles in directing and recruiting PRC2 to target genes for repression in embryonic stem cells (ESCs). Following these findings, recent work in the field has begun to explore the roles of different PRC2 variant complexes during different stages of embryonic development, by examining molecular phenotypes of PRC2 mutants in both in vitro (2D and 3D differentiation) and in vivo (knock-out mice) assays, analyzed with modern single-cell omics and biochemical assays. In this review, we discuss the latest findings that uncovered the roles of different PRC2 proteins during cell-fate and lineage specification and extrapolate these findings to define a developmental roadmap for different flavors of PRC2 regulation during mammalian embryonic development.
]]>Epigenomes doi: 10.3390/epigenomes6030022
Authors: Shoko Sato Mariko Dacher Hitoshi Kurumizaka
In eukaryotes, genomic DNA is bound with histone proteins and packaged into chromatin. The nucleosome, a fundamental unit of chromatin, regulates the accessibility of DNA to enzymes involved in gene regulation. During the past few years, structural analyses of chromatin architectures have been limited to evolutionarily related organisms. The amino acid sequences of histone proteins are highly conserved from humans to yeasts, but are divergent in the deeply branching protozoan groups, including human parasites that are directly related to human health. Certain large DNA viruses, as well as archaeal organisms, contain distant homologs of eukaryotic histone proteins. The divergent sequences give rise to unique and distinct nucleosome architectures, although the fundamental principles of histone folding and DNA contact are highly conserved. In this article, we review the structures and biophysical properties of nucleosomes containing histones from the human parasites Giardia lamblia and Leishmania major, and histone-like proteins from the Marseilleviridae amoeba virus family. The presented data confirm the sharing of the overall DNA compaction system among evolutionally distant species and clarify the deviations from the species-specific nature of the nucleosome.
]]>Epigenomes doi: 10.3390/epigenomes6030021
Authors: Beatriz Martinez-Delgado Maria J. Barrero
Rare diseases affect more than 300 million people worldwide. Diagnosing rare diseases is a major challenge as they have different causes and etiologies. Careful assessment of clinical symptoms often leads to the testing of the most common genetic alterations that could explain the disease. Patients with negative results for these tests frequently undergo whole exome or genome sequencing, leading to the identification of the molecular cause of the disease in 50% of patients at best. Therefore, a significant proportion of patients remain undiagnosed after sequencing their genome. Recently, approaches based on functional aspects of the genome, including transcriptomics and epigenomics, are beginning to emerge. Here, we will review these approaches, including studies that have successfully provided diagnoses for complex undiagnosed cases.
]]>Epigenomes doi: 10.3390/epigenomes6030020
Authors: Keishi Shintomi
Mitotic chromosome assembly is an essential preparatory step for accurate transmission of the genome during cell division. During the past decades, biochemical approaches have uncovered the molecular basis of mitotic chromosomes. For example, by using cell-free assays of frog egg extracts, the condensin I complex central for the chromosome assembly process was first identified, and its functions have been intensively studied. A list of chromosome-associated proteins has been almost completed, and it is now possible to reconstitute structures resembling mitotic chromosomes with a limited number of purified factors. In this review, I introduce how far we have come in understanding the mechanism of chromosome assembly using cell-free assays and reconstitution assays, and I discuss their potential applications to solve open questions.
]]>Epigenomes doi: 10.3390/epigenomes6030019
Authors: Ryszard Maleszka
This report summarizes the proceedings of the inaugural Clinical Epigenetics Conference that was held in Szczecin, Poland, from 8 June 2022. With focus on epigenetic diseases whose causes, progression, and prognosis are associated with aberrant epigenomic alterations, the meeting was a timely forum to discuss recent progress in this rapidly evolving field and consider avenues for converting experimental data into clinical reality that would be beneficial for patients. The wealth of the presented data was an impressive showcase of the enormous challenges faced by researchers in their quest for understanding the benefits and limitations of the available information in the medical context. A shared view among the participants was that merging the current state of knowledge with clinical applications will be promptly achieved.
]]>Epigenomes doi: 10.3390/epigenomes6030018
Authors: Takashi Umehara
Epigenomic modifications are unique in the type and amount of chemical modification at each chromosomal location, can vary from cell to cell, and can be externally modulated by small molecules. In recent years, genome-wide epigenomic modifications have been revealed, and rapid progress has been made in the identification of proteins responsible for epigenomic modifications and in the development of compounds that regulate them. This Special Issue on “Epidrugs: Toward Understanding and Treating Diverse Diseases” aims to provide insights into various aspects of the biology and development of epigenome-regulating compounds.
]]>Epigenomes doi: 10.3390/epigenomes6030017
Authors: Tighe Bloskie Kenneth B. Storey
Transcriptional suppression is characteristic of extreme stress responses, speculated to preserve energetic resources in the maintenance of hypometabolism. In recent years, epigenetic regulation has become heavily implicated in stress adaptation of many animals, including supporting freeze tolerance of the wood frog (Rana sylvatica). However, nervous tissues are frequently lacking in these multi-tissue analyses which warrants investigation. The present study examines the role of DNA methylation, a core epigenetic mechanism, in the response of wood frog brains to freezing. We use immunoblot analysis to track the relative expression of DNA methyltransferases (DNMT), methyl-CpG-binding domain (MBD) proteins and ten-eleven-translocation (TET) demethylases across the freeze-thaw cycle in R. sylvatica brain, including selected comparisons to freeze-associated sub-stresses (anoxia and dehydration). Global methyltransferase activities and 5-hmC content were also assessed. The data show coordinated evidence for DNA hypomethylation in wood frog brains during freeze-recovery through the combined roles of depressed DNMT3A/3L expression driving lowered DNMT activity and increased TET2/3 levels leading to elevated 5-hmC genomic content (p < 0.05). Raised levels of DNMT1 during high dehydration were also noteworthy. The above suggest that alleviation of transcriptionally repressive 5-mC DNA methylation is a necessary component of the wood frog freeze-thaw cycle, potentially facilitating the resumption of a normoxic transcriptional state as frogs thaw and resume normal metabolic activities.
]]>Epigenomes doi: 10.3390/epigenomes6030016
Authors: Jorge Luis Batista-Roche Bruno Gómez-Gil Gertrud Lund César Alejandro Berlanga-Robles Alejandra García-Gasca
The Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) is the causal agent of COVID-19 (Coronavirus Disease-19). Both mutation and/or recombination events in the SARS-CoV-2 genome have resulted in variants that differ in transmissibility and severity. Furthermore, RNA methylation of the N6 position of adenosine (m6A) is known to be altered in cells infected with SARS-CoV-2. However, it is not known whether this epitranscriptomic modification differs across individuals dependent on the presence of infection with distinct SARS-CoV-2 variants, the viral load, or the vaccination status. To address this issue, we selected RNAs (n = 60) from SARS-CoV-2 sequenced nasopharyngeal samples (n = 404) of 30- to 60-year-old outpatients or hospitalized individuals from the city of Mazatlán (Mexico) between February 2021 and March 2022. Control samples were non-infected individuals (n = 10). SARS-CoV-2 was determined with real-time PCR, viral variants were determined with sequencing, and global m6A levels were determined by using a competitive immunoassay method. We identified variants of concern (VOC; alpha, gamma, delta, omicron), the variant of interest (VOI; epsilon), and the lineage B.1.1.519. Global m6A methylation differed significantly across viral variants (p = 3.2 × 10−7). In particular, we found that m6A levels were significantly lower in the VOC delta- and omicron-positive individuals compared to non-infected individuals (p = 2.541236 × 10−2 and 1.134411 × 10−4, respectively). However, we uncovered no significant correlation between global m6A levels and viral nucleocapsid (N) gene expression or age. Furthermore, individuals with complete vaccination schemes showed significantly lower m6A levels than unvaccinated individuals (p = 2.6 × 10−4), and differences in methylation levels across variants in unvaccinated individuals were significant (p = 3.068 × 10−3). These preliminary results suggest that SARS-CoV-2 variants show differences in global m6A levels.
]]>Epigenomes doi: 10.3390/epigenomes6020015
Authors: Asim A. Khogeer Iman S. AboMansour Dia A. Mohammed
According to recent findings, variances in autism spectrum disorder (ASD) risk factors might be determined by several factors, including molecular genetic variants. Accumulated evidence has also revealed the important role of biological and chemical pathways in ASD aetiology. In this paper, we assess several reviews with regard to their quality of evidence and provide a brief outline of the presumed mechanisms of the genetic, epigenetic, and environmental risk factors of ASD. We also review some of the critical literature, which supports the basis of each factor in the underlying and specific risk patterns of ASD. Finally, we consider some of the implications of recent research regarding potential molecular targets for future investigations.
]]>Epigenomes doi: 10.3390/epigenomes6020014
Authors: Zhou Zhang Wei Zhang
The centrosome plays a central role for cellular signaling and is critical for several fundamental cellular processes in human cells. Centrosome abnormalities have been linked to multiple solid tumors and hematological malignancies. We sought to explore the potential role of the DNA methylation, a critical epigenetic modification, of centrosome-related genes in different cancers. The 450K array DNA methylation data and RNA-seq data were downloaded for ~4000 tumor samples and ~500 normal controls from The Cancer Genome Atlas (TCGA) project, covering 11 major cancer types. Cancers with more than 30 normal controls were retained for analysis. Differentially modified CpGs of centrosome genes were identified, and cancer-specific epigenetic models were developed using a machine-learning algorithm for each cancer type. The association between the methylation level of differential CpGs and the corresponding gene expression, as well as the co-localization of the differential CpGs and cis-regulatory elements were evaluated. In total, 2761 CpGs located on 160 centrosome genes for 6 cancers were included in the analysis. Cancer-specific models demonstrated a high accuracy in terms of the area under the receiver operating characteristic (ROC) curve (AUC > 0.9) in five cancers and showed tissue specificity. This study enhanced our understanding of the epigenetic mechanisms underlying the DNA methylation of centrosome-related genes in cancers, and showed the potential of these epigenetic modifications as novel cancer biomarkers.
]]>Epigenomes doi: 10.3390/epigenomes6020013
Authors: Shreya Sarkar Rwik Sen
Although few in number, studies on epigenome of the heart of COVID-19 patients show that epigenetic signatures such as DNA methylation are significantly altered, leading to changes in expression of several genes. It contributes to pathogenic cardiac phenotypes of COVID-19, e.g., low heart rate, myocardial edema, and myofibrillar disarray. DNA methylation studies reveal changes which likely contribute to cardiac disease through unknown mechanisms. The incidence of severe COVID-19 disease, including hospitalization, requiring respiratory support, morbidity, and mortality, is disproportionately higher in individuals with co-morbidities. This poses unprecedented strains on the global healthcare system. While their underlying conditions make patients more susceptible to severe COVID-19 disease, strained healthcare systems, lack of adequate support, or sedentary lifestyles from ongoing lockdowns have proved detrimental to their underlying health conditions, thus pushing them to severe risk of congenital heart disease (CHD) itself. Prophylactic vaccines against COVID-19 have ushered new hope for CHD. A common connection between COVID-19 and CHD is SARS-CoV-2’s host receptor ACE2, because ACE2 regulates and protects organs, including the heart, in various ways. ACE2 is a common therapeutic target against cardiovascular disease and COVID-19 which damages organs. Hence, this review explores the above regarding CHDs, cardiovascular damage, and cardiac epigenetics, in COVID-19 patients.
]]>Epigenomes doi: 10.3390/epigenomes6020012
Authors: Grace S. Lee Colin C. Conine
Epigenetic information is transmitted from one generation to the next, modulating the phenotype of offspring non-genetically in organisms ranging from plants to mammals. For intergenerational non-genetic inheritance to occur, epigenetic information must accumulate in germ cells. The three main carriers of epigenetic information—histone post-translational modifications, DNA modifications, and RNAs—all exhibit dynamic patterns of regulation during germ cell development. For example, histone modifications and DNA methylation are extensively reprogrammed and often eliminated during germ cell maturation and after fertilization during embryogenesis. Consequently, much attention has been given to RNAs, specifically small regulatory RNAs, as carriers of inherited epigenetic information. In this review, we discuss examples in which microRNAs have been implicated as key players in transmitting paternal epigenetic information intergenerationally.
]]>Epigenomes doi: 10.3390/epigenomes6020011
Authors: Anna Fiselier Boseon Byeon Yaroslav Ilnytskyy Igor Kovalchuk Olga Kovalchuk
Non-coding RNA fragments (ncRFs) are processed from various non-coding RNAs (ncRNAs), with the most abundant being those produced from tRNAs. ncRFs were reported in many animal and plant species. Many ncRFs exhibit tissue specificity or/and are affected by stress. There is, however, only a handful of reports that describe differential expression of ncRFs in the brain regions. In this work, we analyzed the abundance of ncRFs processed from four major ncRNAs, including tRNA (tRFs), snoRNA (snoRFs), snRNA (snRFs), and rRNA (rRFs) in the frontal cortex (FC), hippocampus (HIP), and cerebellum (CER) of male and female rats. We found brain-specific and sex-specific differences. Reads mapping to lincRNAs were significantly larger in CER as compared to HIP and CER, while those mapping to snRNAs and tRNA were smaller in HIP than in FC and CER. tRF reads were the most abundant among all ncRF reads, and FC had more reads than HIP and CER. Reads mapping to antisense ncRNAs were significantly larger in females than in males in FC. Additionally, males consistently had more tRF, snRF, and snoRF reads in all brain regions. rRFs were more abundant in males in FC and females in HIP. Several tRFs were significantly underrepresented, including tRF-ValCAC, tRF-ValACC, and tRF-LysCTT in all brain regions. We also found brain- and sex-specific differences in the number of brain function-related mRNA targets. To summarize, we found sex-specific differences in the expression of several ncRNA fragments in various brain regions of healthy rats.
]]>Epigenomes doi: 10.3390/epigenomes6010010
Authors: Megan R. Dreier Ivana L. de la Serna
Melanoma is an aggressive malignancy that arises from the transformation of melanocytes on the skin, mucosal membranes, and uvea of the eye. SWI/SNF chromatin remodeling enzymes are multi-subunit complexes that play important roles in the development of the melanocyte lineage and in the response to ultraviolet radiation, a key environmental risk factor for developing cutaneous melanoma. Exome sequencing has revealed frequent loss of function mutations in genes encoding SWI/SNF subunits in melanoma. However, some SWI/SNF subunits have also been demonstrated to have pro-tumorigenic roles in melanoma and to affect sensitivity to therapeutics. This review summarizes studies that have implicated SWI/SNF components in melanomagenesis and have evaluated how SWI/SNF subunits modulate the response to current therapeutics.
]]>Epigenomes doi: 10.3390/epigenomes6010009
Authors: Evan H. Lister-Shimauchi Benjamin McCarthy Michael Lippincott Shawn Ahmed
Transgenerational inheritance can occur at telomeres in distinct contexts. Deficiency for telomerase or telomere-binding proteins in germ cells can result in shortened or lengthened chromosome termini that are transmitted to progeny. In human families, altered telomere lengths can result in stem cell dysfunction or tumor development. Genetic inheritance of altered telomeres as well as mutations that alter telomeres can result in progressive telomere length changes over multiple generations. Telomeres of yeast can modulate the epigenetic state of subtelomeric genes in a manner that is mitotically heritable, and the effects of telomeres on subtelomeric gene expression may be relevant to senescence or other human adult-onset disorders. Recently, two novel epigenetic states were shown to occur at C. elegans telomeres, where very low or high levels of telomeric protein foci can be inherited for multiple generations through a process that is regulated by histone methylation.Together, these observations illustrate that information relevant to telomere biology can be inherited via genetic and epigenetic mechanisms, although the broad impact of epigenetic inheritance to human biology remains unclear.
]]>Epigenomes doi: 10.3390/epigenomes6010008
Authors: James Godwin Sara Farrona
Polycomb Repressive Complex 2 (PRC2) is arguably the best-known plant complex of the Polycomb Group (PcG) pathway, formed by a group of proteins that epigenetically represses gene expression. PRC2-mediated deposition of H3K27me3 has amply been studied in Arabidopsis and, more recently, data from other plant model species has also been published, allowing for an increasing knowledge of PRC2 activities and target genes. How PRC2 molecular functions are regulated and how PRC2 is recruited to discrete chromatin regions are questions that have brought more attention in recent years. A mechanism to modulate PRC2-mediated activity is through its interaction with other protein partners or accessory proteins. Current evidence for PRC2 interactors has demonstrated the complexity of its protein network and how far we are from fully understanding the impact of these interactions on the activities of PRC2 core subunits and on the formation of new PRC2 versions. This review presents a list of PRC2 interactors, emphasizing their mechanistic action upon PRC2 functions and their effects on transcriptional regulation.
]]>Epigenomes doi: 10.3390/epigenomes6010007
Authors: Helene A. Fachim Nagaraj Malipatil Kirk Siddals Rachelle Donn Gabriela Y. Cortés Caroline F. Dalton J. Martin Gibson Adrian H. Heald
BDNF signalling in hypothalamic neuronal circuits is thought to regulate mammalian food intake. In light of this, we investigated how a lifestyle intervention influenced serum levels and DNA methylation of BDNF gene in fat tissue and buffy coat of NDH individuals. In total, 20 participants underwent anthropometric measurements/fasting blood tests and adipose tissue biopsy pre-/post-lifestyle (6 months) intervention. DNA was extracted from adipose tissue and buffy coat, bisulphite converted, and pyrosequencing was used to determine methylation levels in exon IV of the BDNF gene. RNA was extracted from buffy coat for gene expression analysis and serum BDNF levels were measured by ELISA. No differences were found in BDNF serum levels, but buffy coat mean BDNF gene methylation decreased post-intervention. There were correlations between BDNF serum levels and/or methylation and cardiometabolic markers. (i) Pre-intervention: for BDNF methylation, we found positive correlations between mean methylation in fat tissue and waist-hip ratio, and negative correlations between mean methylation in buffy coat and weight. (ii) Post-intervention: we found correlations between BDNF mean methylation in buffy coat and HbA1c, BDNF methylation in buffy coat and circulating IGFBP-2, and BDNF serum and insulin. Higher BDNF % methylation levels are known to reduce BNDF expression. The fall in buffy coat mean BDNF methylation plus the association between lower BDNF methylation (so potentially higher BDNF) and higher HbA1c and serum IGFBP-2 (as a marker of insulin sensitivity) and between lower serum BDNF and higher circulating insulin are evidence for the degree of BDNF gene methylation being implicated in insulinisation and glucose homeostasis, particularly after lifestyle change in NDH individuals.
]]>Epigenomes doi: 10.3390/epigenomes6010006
Authors: Nicolas Constantin Abu Ali Ibn Sina Darren Korbie Matt Trau
The efficiency of conventional screening programs to identify early-stage malignancies can be limited by the low number of cancers recommended for screening as well as the high cumulative false-positive rate, and associated iatrogenic burden, resulting from repeated multimodal testing. The opportunity to use minimally invasive liquid biopsy testing to screen asymptomatic individuals at-risk for multiple cancers simultaneously could benefit from the aggregated diseases prevalence and a fixed specificity. Increasing both latter parameters is paramount to mediate high positive predictive value—a useful metric to evaluate a screening test accuracy and its potential harm-benefit. Thus, the use of a single test for multi-cancer early detection (stMCED) has emerged as an appealing strategy for increasing early cancer detection rate efficiency and benefit population health. A recent flurry of these stMCED technologies have been reported for clinical potential; however, their development is facing unique challenges to effectively improve clinical cost–benefit. One promising avenue is the analysis of circulating tumour DNA (ctDNA) for detecting DNA methylation biomarker fingerprints of malignancies—a hallmark of disease aetiology and progression holding the potential to be tissue- and cancer-type specific. Utilizing panels of epigenetic biomarkers could potentially help to detect earlier stages of malignancies as well as identify a tumour of origin from blood testing, useful information for follow-up clinical decision making and subsequent patient care improvement. Overall, this review collates the latest and most promising stMCED methodologies, summarizes their clinical performances, and discusses the specific requirements multi-cancer tests should meet to be successfully implemented into screening guidelines.
]]>Epigenomes doi: 10.3390/epigenomes6010005
Authors: Epigenomes Editorial Office Epigenomes Editorial Office
Rigorous peer-reviews are the basis of high-quality academic publishing [...]
]]>Epigenomes doi: 10.3390/epigenomes6010004
Authors: Emily M. Dennis David M. Garcia
Prions are proteins that can stably fold into alternative structures that frequently alter their activities. They can self-template their alternate structures and are inherited across cell divisions and generations. While they have been studied for more than four decades, their enigmatic nature has limited their discovery. In the last decade, we have learned just how widespread they are in nature, the many beneficial phenotypes that they confer, while also learning more about their structures and modes of inheritance. Here, we provide a brief review of the biochemical principles of prion proteins, including their sequences, characteristics and structures, and what is known about how they self-template, citing examples from multiple organisms. Prion-based inheritance is the most understudied segment of epigenetics. Here, we lay a biochemical foundation and share a framework for how to define these molecules, as new examples are unearthed throughout nature.
]]>Epigenomes doi: 10.3390/epigenomes6010003
Authors: Mallika Vijayanathan María Guadalupe Trejo-Arellano Iva Mozgová
Polycomb repressive complex 2 (PRC2) represents a group of evolutionarily conserved multi-subunit complexes that repress gene transcription by introducing trimethylation of lysine 27 on histone 3 (H3K27me3). PRC2 activity is of key importance for cell identity specification and developmental phase transitions in animals and plants. The composition, biochemistry, and developmental function of PRC2 in animal and flowering plant model species are relatively well described. Recent evidence demonstrates the presence of PRC2 complexes in various eukaryotic supergroups, suggesting conservation of the complex and its function. Here, we provide an overview of the current understanding of PRC2-mediated repression in different representatives of eukaryotic supergroups with a focus on the green lineage. By comparison of PRC2 in different eukaryotes, we highlight the possible common and diverged features suggesting evolutionary implications and outline emerging questions and directions for future research of polycomb repression and its evolution.
]]>Epigenomes doi: 10.3390/epigenomes6010002
Authors: Yasushi Hiraoka
Chromatin is a fundamental and highly conserved structure that carries genetic and epigenetic information in eukaryotic cells [...]
]]>Epigenomes doi: 10.3390/epigenomes6010001
Authors: Kenneth C. Ehrlich Hong-Wen Deng Melanie Ehrlich
Striated muscle has especially large energy demands. We identified 97 genes preferentially expressed in skeletal muscle and heart, but not in aorta, and found significant enrichment for mitochondrial associations among them. We compared the epigenomic and transcriptomic profiles of the 27 genes associated with striated muscle and mitochondria. Many showed strong correlations between their tissue-specific transcription levels, and their tissue-specific promoter, enhancer, or open chromatin as well as their DNA hypomethylation. Their striated muscle-specific enhancer chromatin was inside, upstream, or downstream of the gene, throughout much of the gene as a super-enhancer (CKMT2, SLC25A4, and ACO2), or even overlapping a neighboring gene (COX6A2, COX7A1, and COQ10A). Surprisingly, the 3′ end of the 1.38 Mb PRKN (PARK2) gene (involved in mitophagy and linked to juvenile Parkinson’s disease) displayed skeletal muscle/myoblast-specific enhancer chromatin, a myoblast-specific antisense RNA, as well as brain-specific enhancer chromatin. We also found novel tissue-specific RNAs in brain and embryonic stem cells within PPARGC1A (PGC-1α), which encodes a master transcriptional coregulator for mitochondrial formation and metabolism. The tissue specificity of this gene’s four alternative promoters, including a muscle-associated promoter, correlated with nearby enhancer chromatin and open chromatin. Our in-depth epigenetic examination of these genes revealed previously undescribed tissue-specific enhancer chromatin, intragenic promoters, regions of DNA hypomethylation, and intragenic noncoding RNAs that give new insights into transcription control for this medically important set of genes.
]]>Epigenomes doi: 10.3390/epigenomes5040028
Authors: W. Aline Ingelson-Filpula Kenneth B. Storey
The winter months are challenging for many animal species, which often enter a state of dormancy or hypometabolism to “wait out” the cold weather, food scarcity, reduced daylight, and restricted mobility that can characterize the season. To survive, many species use metabolic rate depression (MRD) to suppress nonessential metabolic processes, conserving energy and limiting tissue atrophy particularly of skeletal and cardiac muscles. Mammalian hibernation is the best recognized example of winter MRD, but some turtle species spend the winter unable to breathe air and use MRD to survive with little or no oxygen (hypoxia/anoxia), and various frogs endure the freezing of about two-thirds of their total body water as extracellular ice. These winter survival strategies are highly effective, but create physiological and metabolic challenges that require specific biochemical adaptive strategies. Gene-related processes as well as epigenetic processes can lower the risk of atrophy during prolonged inactivity and limited nutrient stores, and DNA modifications, mRNA storage, and microRNA action are enacted to maintain and preserve muscle. This review article focuses on epigenetic controls on muscle metabolism that regulate MRD to avoid muscle atrophy and support winter survival in model species of hibernating mammals, anoxia-tolerant turtles and freeze-tolerant frogs. Such research may lead to human applications including muscle-wasting disorders such as sarcopenia, or other conditions of limited mobility.
]]>Epigenomes doi: 10.3390/epigenomes5040027
Authors: Maria Fortunata Lofiego Sara Cannito Carolina Fazio Francesca Piazzini Ornella Cutaia Laura Solmonese Francesco Marzani Carla Chiarucci Anna Maria Di Giacomo Luana Calabrò Sandra Coral Michele Maio Alessia Covre on behalf of the EPigenetic Immune-Oncology Consortium Airc (EPICA) Investigators on behalf of the EPigenetic Immune-Oncology Consortium Airc (EPICA) Investigators
Malignant pleural mesothelioma (MPM) is an aggressive malignancy with a severe prognosis, and with a long-standing need for more effective therapeutic approaches. However, treatment with immune checkpoint inhibitors is becoming an increasingly effective strategy for MPM patients. In this scenario, epigenetic modifications may negatively regulate the interplay between immune and malignant cells within the tumor microenvironment, thus contributing to the highly immunosuppressive contexture of MPM that may limit the efficacy of immunotherapy. Aiming to further improve prospectively the clinical efficacy of immunotherapeutic approaches in MPM, we investigated the immunomodulatory potential of different classes of epigenetic drugs (i.e., DNA hypomethylating agent (DHA) guadecitabine, histone deacetylase inhibitors VPA and SAHA, or EZH2 inhibitors EPZ-6438) in epithelioid, biphasic, and sarcomatoid MPM cell lines, by cytofluorimetric and real-time PCR analyses. We also characterized the effects of the DHA, guadecitabine, on the gene expression profiles (GEP) of the investigated MPM cell lines by the nCounter platform. Among investigated drugs, exposure of MPM cells to guadecitabine, either alone or in combination with VPA, SAHA and EPZ-6438 demonstrated to be the main driver of the induction/upregulation of immune molecules functionally crucial in host-tumor interaction (i.e., HLA class I, ICAM-1 and cancer testis antigens) in all three MPM subtypes investigated. Additionally, GEP demonstrated that treatment with guadecitabine led to the activation of genes involved in several immune-related functional classes mainly in the sarcomatoid subtype. Furthermore, among investigated MPM subtypes, DHA-induced CDH1 expression that contributes to restoring the epithelial phenotype was highest in sarcomatoid cells. Altogether, our results contribute to providing the rationale to develop new epigenetically-based immunotherapeutic approaches for MPM patients, potentially tailored to the specific histologic subtypes.
]]>Epigenomes doi: 10.3390/epigenomes5040026
Authors: Francesca Casciaro Giuseppe Persico Martina Rusin Stefano Amatori Claire Montgomery Jennifer Rutkowsky Jon Ramsey Gino Cortopassi Mirco Fanelli Marco Giorgio
Background: Women represent the majority of Alzheimer’s disease patients and show typical symptoms. Genetic, hormonal, and behavioral mechanisms have been proposed to explain sex differences in dementia prevalence. However, whether sex differences exist in the epigenetic landscape of neuronal tissue during the progression of the disease is still unknown. Methods: To investigate the differences of histone H3 modifications involved in transcription, we determined the genome-wide profiles of H3K4me3, H3K27ac, and H3K27me3 in brain cortexes of an Alzheimer mouse model (PSAPP). Gastrocnemius muscles were also tested since they are known to be different in the two sexes and are affected during the disease progression. Results: Correlation analysis distinguished the samples based on sex for H3K4me3 and H3K27me3 but not for H3K27ac. The analysis of transcription starting sites (TSS) signal distribution, and analysis of bounding sites revealed that gastrocnemius is more influenced than brain by sex for the three histone modifications considered, exception made for H3K27me3 distribution on the X chromosome which showed sex-related differences in promoters belonging to behavior and cellular or neuronal spheres in mice cortexes. Conclusions: H3K4me3, H3K27ac, and H3K27me3 signals are slightly affected by sex in brain, with the exception of H3K27me3, while a higher number of differences can be found in gastrocnemius.
]]>Epigenomes doi: 10.3390/epigenomes5040025
Authors: Vladimir Brukhin Emidio Albertini
Plants are exposed to highly fluctuating effects of light, temperature, weather conditions, and many other environmental factors throughout their life. As sessile organisms, unlike animals, they are unable to escape, hide, or even change their position. Therefore, the growth and development of plants are largely determined by interaction with the external environment. The success of this interaction depends on the ability of the phenotype plasticity, which is largely determined by epigenetic regulation. In addition to how environmental factors can change the patterns of genes expression, epigenetic regulation determines how genetic expression changes during the differentiation of one cell type into another and how patterns of gene expression are passed from one cell to its descendants. Thus, one genome can generate many ‘epigenomes’. Epigenetic modifications acquire special significance during the formation of gametes and plant reproduction when epigenetic marks are eliminated during meiosis and early embryogenesis and later reappear. However, during asexual plant reproduction, when meiosis is absent or suspended, epigenetic modifications that have arisen in the parental sporophyte can be transmitted to the next clonal generation practically unchanged. In plants that reproduce sexually and asexually, epigenetic variability has different adaptive significance. In asexuals, epigenetic regulation is of particular importance for imparting plasticity to the phenotype when, apart from mutations, the genotype remains unchanged for many generations of individuals. Of particular interest is the question of the possibility of transferring acquired epigenetic memory to future generations and its potential role for natural selection and evolution. All these issues will be discussed to some extent in this review.
]]>Epigenomes doi: 10.3390/epigenomes5040024
Authors: Tajbir Raihan Robert L. Geneve Sharyn E. Perry Carlos M. Rodriguez Lopez
In contrast to animals, adult organs in plants are not formed during embryogenesis but generated from meristematic cells as plants advance through development. Plant development involves a succession of different phenotypic stages and the transition between these stages is termed phase transition. Phase transitions need to be tightly regulated and coordinated to ensure they occur under optimal seasonal, environmental conditions. Polycarpic perennials transition through vegetative stages and the mature, reproductive stage many times during their lifecycles and, in both perennial and annual species, environmental factors and culturing methods can reverse the otherwise unidirectional vector of plant development. Epigenetic factors regulating gene expression in response to internal cues and external (environmental) stimuli influencing the plant’s phenotype and development have been shown to control phase transitions. How developmental and environmental cues interact to epigenetically alter gene expression and influence these transitions is not well understood, and understanding this interaction is important considering the current climate change scenarios, since epigenetic maladaptation could have catastrophic consequences for perennial plants in natural and agricultural ecosystems. Here, we review studies focusing on the epigenetic regulators of the vegetative phase change and highlight how these mechanisms might act in exogenously induced plant rejuvenation and regrowth following stress.
]]>Epigenomes doi: 10.3390/epigenomes5040023
Authors: Jessica L. Flesher David E. Fisher
Epigenetic regulation is a crucial component of DNA maintenance and cellular identity. As our understanding of the vast array of proteins that contribute to chromatin accessibility has advanced, the role of epigenetic remodelers in disease has become more apparent. G9a is a histone methyltransferase that contributes to immune cell differentiation and function, neuronal development, and has been implicated in diseases, including cancer. In melanoma, recurrent mutations and amplifications of G9a have led to its identification as a therapeutic target. The pathways that are regulated by G9a provide an insight into relevant biomarkers for patient stratification. Future work is aided by the breadth of literature on G9a function during normal differentiation and development, along with similarities to EZH2, another histone methyltransferase that forms a synthetic lethal relationship with members of the SWI/SNF complex in certain cancers. Here, we review the literature on G9a, its role in melanoma, and lessons from EZH2 inhibitor studies.
]]>Epigenomes doi: 10.3390/epigenomes5040022
Authors: Antonia Kalushkova Patrick Nylund Alba Atienza Párraga Andreas Lennartsson Helena Jernberg-Wiklund
Aberrant DNA methylation, dysregulation of chromatin-modifying enzymes, and microRNAs (miRNAs) play a crucial role in haematological malignancies. These epimutations, with an impact on chromatin accessibility and transcriptional output, are often associated with genomic instability and the emergence of drug resistance, disease progression, and poor survival. In order to exert their functions, epigenetic enzymes utilize cellular metabolites as co-factors and are highly dependent on their availability. By affecting the expression of metabolic enzymes, epigenetic modifiers may aid the generation of metabolite signatures that could be utilized as targets and biomarkers in cancer. This interdependency remains often neglected and poorly represented in studies, despite well-established methods to study the cellular metabolome. This review critically summarizes the current knowledge in the field to provide an integral picture of the interplay between epigenomic alterations and the cellular metabolome in haematological malignancies. Our recent findings defining a distinct metabolic signature upon response to enhancer of zeste homolog 2 (EZH2) inhibition in multiple myeloma (MM) highlight how a shift of preferred metabolic pathways may potentiate novel treatments. The suggested link between the epigenome and the metabolome in haematopoietic tumours holds promise for the use of metabolic signatures as possible biomarkers of response to treatment.
]]>Epigenomes doi: 10.3390/epigenomes5040021
Authors: Shailendra S. Maurya
Enhancers are cis-regulatory elements containing short DNA sequences that serve as binding sites for pioneer/regulatory transcription factors, thus orchestrating the regulation of genes critical for lineage determination. The activity of enhancer elements is believed to be determined by transcription factor binding, thus determining the cell state identity during development. Precise spatio-temporal control of the transcriptome during lineage specification requires the coordinated binding of lineage-specific transcription factors to enhancers. Thus, enhancers are the primary determinants of cell identity. Numerous studies have explored the role and mechanism of enhancers during development and disease, and various basic questions related to the functions and mechanisms of enhancers have not yet been fully answered. In this review, we discuss the recently published literature regarding the roles of enhancers, which are critical for various biological processes governing development. Furthermore, we also highlight that altered enhancer landscapes provide an essential context to understand the etiologies and mechanisms behind numerous complex human diseases, providing new avenues for effective enhancer-based therapeutic interventions.
]]>Epigenomes doi: 10.3390/epigenomes5040020
Authors: Joyce K. Thompson Filip Bednar
Pancreatic cancer is a molecularly heterogeneous disease. Epigenetic changes and epigenetic regulatory mechanisms underlie at least some of this heterogeneity and contribute to the evolution of aggressive tumor biology in patients and the tumor’s intrinsic resistance to therapy. Here we review our current understanding of epigenetic dysregulation in pancreatic cancer and how it is contributing to our efforts in early diagnosis, predictive and prognostic biomarker development and new therapeutic approaches in this deadly cancer.
]]>Epigenomes doi: 10.3390/epigenomes5030019
Authors: Louis Tirot Pauline E. Jullien Mathieu Ingouff
Cytosine methylation is an epigenetic mark present in most eukaryotic genomes that contributes to the regulation of gene expression and the maintenance of genome stability. DNA methylation mostly occurs at CG sequences, where it is initially deposited by de novo DNA methyltransferases and propagated by maintenance DNA methyltransferases (DNMT) during DNA replication. In this review, we first summarize the mechanisms maintaining CG methylation in mammals that involve the DNA Methyltransferase 1 (DNMT1) enzyme and its cofactor, UHRF1 (Ubiquitin-like with PHD and RING Finger domain 1). We then discuss the evolutionary conservation and diversification of these two core factors in the plant kingdom and speculate on potential functions of novel homologues typically observed in land plants but not in mammals.
]]>Epigenomes doi: 10.3390/epigenomes5030018
Authors: Kelsey Dawes Luke Sampson Rachel Reimer Shelly Miller Robert Philibert Allan Andersen
Alcohol and tobacco use are highly comorbid and exacerbate the associated morbidity and mortality of either substance alone. However, the relationship of alcohol consumption to the various forms of nicotine-containing products is not well understood. To improve this understanding, we examined the relationship of alcohol consumption to nicotine product use using self-report, cotinine, and two epigenetic biomarkers specific for smoking (cg05575921) and drinking (Alcohol T Scores (ATS)) in n = 424 subjects. Cigarette users had significantly higher ATS values than the other groups (p < 2.2 × 10−16). Using the objective biomarkers, the intensity of nicotine and alcohol consumption was correlated in both the cigarette and smokeless users (R = −0.66, p = 3.1 × 10−14; R2 = 0.61, p = 1.97 × 10−4). Building upon this idea, we used the objective nicotine biomarkers and age to build and test a Balanced Random Forest classification model for heavy alcohol consumption (ATS > 2.35). The model performed well with an AUC of 0.962, 89.3% sensitivity, and 85% specificity. We conclude that those who use non-combustible nicotine products drink significantly less than smokers, and cigarette and smokeless users drink more with heavier nicotine use. These findings further highlight the lack of informativeness of self-reported alcohol consumption and suggest given the public and private health burden of alcoholism, further research into whether using non-combustible nicotine products as a mode of treatment for dual users should be considered.
]]>Epigenomes doi: 10.3390/epigenomes5030017
Authors: Annick Dubois François Roudier
CRISPR-based epigenome editing uses dCas9 as a platform to recruit transcription or chromatin regulators at chosen loci. Despite recent and ongoing advances, the full potential of these approaches to studying chromatin functions in vivo remains challenging to exploit. In this review we discuss how recent progress in plants and animals provides new routes to investigate the function of chromatin regulators and address the complexity of associated regulations that are often interconnected. While efficient transcriptional engineering methodologies have been developed and can be used as tools to alter the chromatin state of a locus, examples of direct manipulation of chromatin regulators remain scarce in plants. These reports also reveal pitfalls and limitations of epigenome engineering approaches that are nevertheless informative as they are often associated with locus- and context-dependent features, which include DNA accessibility, initial chromatin and transcriptional state or cellular dynamics. Strategies implemented in different organisms to overcome and even take advantage of these limitations are highlighted, which will further improve our ability to establish the causality and hierarchy of chromatin dynamics on genome regulation.
]]>Epigenomes doi: 10.3390/epigenomes5030016
Authors: Sultana Mehbuba Hossain Chiemi F. Lynch-Sutherland Aniruddha Chatterjee Erin C. Macaulay Michael R. Eccles
Cancer is the second leading cause of mortality and morbidity in the developed world. Cancer progression involves genetic and epigenetic alterations, accompanied by aggressive changes, such as increased immune evasion, onset of metastasis, and drug resistance. Similar to cancer, DNA hypomethylation, immune suppression, and invasive cell behaviours are also observed in the human placenta. Mechanisms that lead to the acquisition of invasive behaviour, immune evasion, and drug and immunotherapy resistance are presently under intense investigations to improve patient outcomes. Here, we review current knowledge regarding the similarities between immune suppression and epigenome regulation, including the expression of repetitive elements (REs), endogenous retroviruses (ERVs) and transposable elements (TEs) in cells of the placenta and in cancer, which are associated with changes in immune regulation and invasiveness. We explore whether immune suppression and epigenome regulation in placenta offers novel insights into immunotherapy resistance in cancer, and we also discuss the implications and the knowledge gaps relevant to these findings, which are rapidly being accrued in these quite disparate research fields. Finally, we discuss potential linkages between TE, ERV and RE activation and expression, regarding mechanisms of immune regulation in placenta and cancer. A greater understanding of the role of immune suppression and associated epigenome regulation in placenta could help to elucidate some comparable mechanisms operating in cancer, and identify potential new therapeutic targets for treating cancer.
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