Epigenomes

30 pages, 2028 KB

Open AccessReview

MicroRNA Regulation in Kidney Interstitial Fibrosis

by Hirofumi Sakuma, Satoshi Kawaguchi, Yuya Kobayashi, Akiko Koizumi and Naoki Nakagawa

Epigenomes 2026, 10(1), 21; https://doi.org/10.3390/epigenomes10010021 - 16 Mar 2026

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MicroRNAs (miRNAs) are small non-coding RNAs that play central roles in post-transcriptional gene regulation and cellular homeostasis maintenance. Dysregulation of miRNA expression is increasingly recognized as a key contributor to tissue injury during the acute phase and to disease progression in the chronic [...] Read more.

MicroRNAs (miRNAs) are small non-coding RNAs that play central roles in post-transcriptional gene regulation and cellular homeostasis maintenance. Dysregulation of miRNA expression is increasingly recognized as a key contributor to tissue injury during the acute phase and to disease progression in the chronic phase. Chronic kidney disease (CKD) commonly progresses and ultimately leads to kidney failure through interstitial fibrosis, which is the final common pathway of CKD progression. Interstitial fibrosis is driven not only by fibroblast activation but also by phenotypic transitions in injured tubular epithelial cells, infiltrating macrophages, and peritubular capillary cells. These multifaceted cellular pathways induce and exacerbate interstitial fibrosis, and several miRNAs have been identified as important regulators of these pathways. In addition to fibrotic pathophysiological features, disease-specific dysregulation of miRNAs has been increasingly detected in various causes of CKD, including diabetic kidney disease, chronic glomerulonephritis, and nephrosclerosis. In this review, we provide an integrated overview of miRNA-mediated regulation in CKD, with particular emphasis on cell lineage functions within fibrotic pathways and disease-specific roles. Finally, we discuss the emerging potential of miRNAs as biomarkers and therapeutic targets for CKD and highlight future research directions. Full article

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25 pages, 968 KB

Open AccessArticle

Epigenetics of Genes Displaying High and Preferential Expression in Myoblasts

by Kenneth C. Ehrlich, Michelle Lacey, Sriharsa Pradhan and Melanie Ehrlich

Epigenomes 2026, 10(1), 20; https://doi.org/10.3390/epigenomes10010020 - 13 Mar 2026

Viewed by 364

Abstract

Background/Objectives: Genome-wide studies of differential DNA methylation often focus on its role in turning transcription on or off. Here we report some atypical epigenetic/transcription relationships for 92 genes that are highly and preferentially expressed in primary human myoblasts relative to heterologous cell cultures. [...] Read more.

Background/Objectives: Genome-wide studies of differential DNA methylation often focus on its role in turning transcription on or off. Here we report some atypical epigenetic/transcription relationships for 92 genes that are highly and preferentially expressed in primary human myoblasts relative to heterologous cell cultures. Methods: We compared methylomes and myoblast-specific differentially methylated regions (DMRs) with methylomes, chromatin profiles, and transcriptomes for many different cell populations. Results: We found that myoblast-associated promoter hypomethylation was unusually prevalent among the 92 myoblast-preferential genes. Sometimes this promoter hypomethylation was seen as a myoblast-associated extension of their constitutively unmethylated region at a CpG island. All 92 genes showed some myoblast-specific hypomethylation, including 32 genes at tissue-specific super-enhancers or broad H3K4-trimethylated promoters. Myoblast hypermethylated DMRs were also associated with almost half of the myoblast-preferential genes. These hypermethylated DMRs were often in intragenic locations embedded in H3K36-trimethylated chromatin in myoblasts. Conclusions: Our analysis suggests that some of the hypermethylated DMRs repress cryptic, alternative, or adjacent promoters. Myoblast hypermethylated DMRs may also downmodulate expression in myoblasts to avoid yet higher RNA levels found in adult or fetal skeletal muscle tissue. The epigenetic insights that were obtained can help elucidate the transcription regulation of some of these genes (e.g., MUSK, RAPSN, HEYL, SYNPO2, SYNPO2L, STAC3, PITX2, and TPPP3) that are implicated in congenital myasthenic syndromes, myasthenia gravis, muscle repair, heart dysfunction, or cancer. This study supports cell type-specific roles for DNA hypo- and hypermethylation as a modulator of transcription levels, in addition to being an on–off switch during differentiation. Full article

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20 pages, 3145 KB

Open AccessArticle

Mutant KRAS Heterogeneity Shapes Nuclear Architecture During Pancreatic Cancer Initiation

by Gareth Pollin, Angela J. Mathison, Elise N. Leverence, Thiago Milech De Assuncao, Juan Iovanna, Johnny C. Hong, Michael T. Zimmermann, Raul Urrutia and Gwen Lomberk

Epigenomes 2026, 10(1), 19; https://doi.org/10.3390/epigenomes10010019 - 10 Mar 2026

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Abstract

Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) arises predominantly from activating KRAS mutations, yet individual genetic variants differ markedly in signaling output and clinical impact. G12D, the most prevalent variant, strongly drives oncogenic programs, whereas G12R signals less efficiently through the AKT and ERK pathways [...] Read more.

Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) arises predominantly from activating KRAS mutations, yet individual genetic variants differ markedly in signaling output and clinical impact. G12D, the most prevalent variant, strongly drives oncogenic programs, whereas G12R signals less efficiently through the AKT and ERK pathways and is associated with longer patient survival than G12D-driven PDAC. Methods: To elucidate how these differences influence early cellular transformation, we expressed a panel of KRAS mutants in non-cancerous pancreatic ductal epithelial cells as a model of early PDAC initiation and profiled transcriptional and phospho-proteomic responses. We next examined whether epigenetic differences translate into mutation-specific changes in nuclear organization using quantitative imaging of G12D- and G12R-expressing nuclei at 24 and 48 h. Results: Each variant established a unique regulatory program enriched for chromatin remodelers, histone modifiers, and nuclear structural factors, indicating that variant-specific KRAS signaling rapidly develops divergent epigenetic states. Integrated transcriptomic and phospho-proteomic analyses identified G12D and G12R as the most divergent variants. G12D induced pronounced nuclear remodeling, including increased nuclear size, irregular morphology, and reorganization of the nucleolus and spliceosome, consistent with extensive chromatin and transcriptional reprogramming. In contrast, G12R elicited a weaker response, with minimal or delayed structural changes. Conclusions: Together, these findings demonstrate that KRAS mutational context in pancreatic ductal epithelial cells shapes early transcriptional reprogramming that actively remodels nuclear architecture and nuclear sub-compartments. This work establishes nuclear structural remodeling as a structural state of KRAS-driven epigenetic dysregulation during PDAC initiation. Full article

(This article belongs to the Special Issue Epigenetic Signatures in Metabolic Health and Cancer)

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13 pages, 790 KB

Open AccessArticle

Changes in Blood DNA CpG Methylation Levels in Response to Methadone Maintenance Treatment: Epigenome-Wide Longitudinal Study

by Orna Levran, Yuli Kim, Justin Li, Anat Sason, Miriam Adelson and Einat Peles

Epigenomes 2026, 10(1), 18; https://doi.org/10.3390/epigenomes10010018 - 5 Mar 2026

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Abstract

Background/Objectives: Methadone maintenance treatment (MMT) is one of the major pharmacotherapies for opioid use disorder. The underlying mechanisms of addiction and the treatment response are only partially understood. The study’s main goal was to identify differential DNA CpG methylation that occurred in response [...] Read more.

Background/Objectives: Methadone maintenance treatment (MMT) is one of the major pharmacotherapies for opioid use disorder. The underlying mechanisms of addiction and the treatment response are only partially understood. The study’s main goal was to identify differential DNA CpG methylation that occurred in response to MMT. Methods: Toward this goal, we have conducted a longitudinal epigenome-wide study of blood samples from 64 patients at the beginning and after 1–3 years of MMT, using a linear mixed model. Results: A total of 1881 differentially methylated probes (DMPs) were identified (FDR < 0.05), controlling for sex, age, estimates of blood cell proportions, and the first two principal components based on genome-wide SNP genotypes. Among the genes annotated to the top DMPs are DGLUCY, NXNL2, SOX10, and NPAS3. Several genes associated with substance use disorder were annotated by the identified DMPs, including ADORA2A, BDNF, CACNA1D, CREB1, CRHR1, CRY1, DNMT3B, GABRD, GNAS, GRIP1, OXR1, PRKACB, SCN2A, and SCN3A. The most overrepresented pathway is the small GTPase-mediated signal transduction pathway, and the most overrepresented process is the actin cytoskeleton organization. Conclusions: The study provides preliminary insight into the epigenetic effect of MMT. Future studies will have to confirm the DMPs, assess their impact on gene expression, and determine their clinical relevance. Full article

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15 pages, 1759 KB

Open AccessBrief Report

CpG Methylation of Protein Prenyltransferase Genes FNTA, FNTB, PGGT1B and RABGGTA in Cancer Cell Lines

by Dominik Jung, Daniel Diehl, Anna Hagemann and Hagen Sjard Bachmann

Epigenomes 2026, 10(1), 17; https://doi.org/10.3390/epigenomes10010017 - 4 Mar 2026

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Abstract

Background: Protein prenylation is crucial for the function of hundreds of proteins. Aberrant protein prenylation can be caused by the aberrant expression of prenyltransferases (PTases), which has been reported for multiple cancer entities. The reasons for aberrant PTase expression in cancer have not [...] Read more.

Background: Protein prenylation is crucial for the function of hundreds of proteins. Aberrant protein prenylation can be caused by the aberrant expression of prenyltransferases (PTases), which has been reported for multiple cancer entities. The reasons for aberrant PTase expression in cancer have not yet been investigated. Methods: We analyzed CpG methylation within promoter-associated CpG islands of the PTase genes FNTA, FNTB, PGGT1B, and RABGGTA via bisulfite conversion and pyrosequencing to assess its role in PTase expression and gain deeper insight into the regulation of protein prenylation in cancer. We used DNA from three benign controls (whole blood samples, peripheral blood mononuclear cells, and HEK293) and 19 human cancer cell lines from various origins to assess DNA methylation within PTase gene promoter-associated CpG islands. For a subset of these cell lines, we measured mRNA expression via qPCR and correlated it with DNA methylation. Results: Methylation across all PTase genes ranged from 1.9 ± 0.9% to 11.4 ± 4.0% (mean methylation ± standard deviation) in benign cells, and 2.3 ± 1.0% to 16.0 ± 5.4% in cancer cells. DNA methylation and mRNA expression of PGGT1B correlated inversely (PCC = −0.75; p = 0.005). Conclusions: We saw no general differences between benign and malignant cells, but observed significant differences between non-malignant controls and multiple individual cancer cell lines regarding the methylation of PTase genes. This was prominently seen in PGGT1B in Caki-1 cells, raising the possibility that DNA methylation is involved in the dysregulation of PTase expression in cancer. Full article

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17 pages, 2958 KB

Open AccessArticle

Integrative Analysis Reveals Conserved R-Loop Features in Mouse Embryonic Stem Cells

by Ohbeom Kwon, Hyeonwoo La, Seonho Yoo, Hyeonji Lee, Heeji Lee, Hoseong Lim, Chanhyeok Park, Dong Wook Han, Jeong-Tae Do, Hyuk Song, Youngsok Choi and Kwonho Hong

Epigenomes 2026, 10(1), 16; https://doi.org/10.3390/epigenomes10010016 - 2 Mar 2026

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Abstract

R-loops, three-stranded nucleic acid structures formed by an RNA-DNA hybrid, have emerged as important regulators of transcription and genome stability. Although advances in high-throughput sequencing have revealed widespread R-loop landscapes, platform-specific biases hinder the identification of conserved R-loops in specific cell types. Mouse [...] Read more.

R-loops, three-stranded nucleic acid structures formed by an RNA-DNA hybrid, have emerged as important regulators of transcription and genome stability. Although advances in high-throughput sequencing have revealed widespread R-loop landscapes, platform-specific biases hinder the identification of conserved R-loops in specific cell types. Mouse embryonic stem cells, which are transcriptionally active, provide an ideal system for investigating the potential roles of stable R-loops in RNA biology. Here, we integrated 13 independent R-loop profiling datasets from four experimental platforms to define 27,950 Common R-loop regions in mouse embryonic stem cells and characterized their chromatin environment and associated biological functions. Common R-loop regions were reproducibly detected across methods and were preferentially localized to promoter-proximal and genic regions enriched in CpG islands. Genes associated with Common R-loops were highly and stably expressed, showing strong functional enrichment in RNA metabolic processes such as mRNA processing, RNA splicing, and ribonucleoprotein complex biogenesis. Chromatin state analysis revealed that Common R-loops are enriched in transcriptionally active and regulatory contexts. Sequence feature analysis further identified GC skew as a prominent signature of Common R-loops, particularly within transcribed chromatin states. Transcription factor motif analyses have identified distinct regulatory environments in Common R-loop regions, including pluripotency-associated OCT4-SOX2-TCF-NANOG motifs in enhancers, CTCF motifs in open chromatin, and YY1 motifs in promoters. Together, this study provides the first integrated analysis of conserved R-loop regions in mouse embryonic stem cells, revealing their preferential localization at regulatory loci linked to RNA metabolism and highlighting R-loops as structural and functional nodes in RNA biology. Full article

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27 pages, 880 KB

Open AccessReview

Histone Modifications in the Cell Cycle of C. elegans Embryogenesis: A Comparative Review

by Anati Alyaa Azhar and Hector Mendoza

Epigenomes 2026, 10(1), 15; https://doi.org/10.3390/epigenomes10010015 - 27 Feb 2026

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Abstract

Cell division is a highly regulated process that actively involves dynamic changes to the genetic material within the nucleus. DNA is faithfully replicated in the S-Phase of the cell cycle, being converted from loose, relaxed chromatin into tight, condensed chromosomes to be segregated [...] Read more.

Cell division is a highly regulated process that actively involves dynamic changes to the genetic material within the nucleus. DNA is faithfully replicated in the S-Phase of the cell cycle, being converted from loose, relaxed chromatin into tight, condensed chromosomes to be segregated in mitosis. In addition to scaffolding proteins that shape these mitotic chromosomes, post-translational modifications of histones within nucleosomes modulate chromosome dynamics throughout the cell cycle. In this review, we use a comparative approach to highlight some of the major epigenetic marks affected by the cell cycle during embryogenesis of Caenorhabditis elegans: H4K20me1, H3S10ph, H4S1ph, H2AS1ph, and H3T118ph. These five histone post-translational modifications will be specifically highlighted in the context of the mitotic cell cycle, as they are well documented in the C. elegans literature. Full article

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23 pages, 8863 KB

Open AccessArticle

Epigenetic Activity of Cancer Therapy Drugs Revealed by HeLa TI Cell-Based Assay

by Varvara Maksimova, Valeriia Popova, Alyona Kholodova, Julia Makus, Olga Usalka, Eugenia Lylova, Aleksandr Kudriashov, Gennady Belitsky, Marianna Yakubovskaya and Kirill Kirsanov

Epigenomes 2026, 10(1), 14; https://doi.org/10.3390/epigenomes10010014 - 23 Feb 2026

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Abstract

Background/Objectives: The aberrant epigenetic landscape of cancer cells has attracted wide attention, motivating the search for new epigenetically active drugs both for anticancer therapy and for overcoming the drug resistance promoted by epigenetic changes. The use of epi-drugs in cancer therapy requires consideration [...] Read more.

Background/Objectives: The aberrant epigenetic landscape of cancer cells has attracted wide attention, motivating the search for new epigenetically active drugs both for anticancer therapy and for overcoming the drug resistance promoted by epigenetic changes. The use of epi-drugs in cancer therapy requires consideration of the influence of applied treatment on epigenetic regulation of gene expression. Therefore, it is reasonable to screen epigenetically active compounds among the drugs widely used in clinical oncology. Methods: We applied the HeLa TI cell-based assay to analyze the epigenetic activity of 40 drugs including 22 chemotherapeutic, 2 immunotherapeutic, 13 targeted, and 3 palliative agents. Reactivation of the epigenetically silenced GFP reporter gene integrated into the genome of HeLa TI cells was assessed using flow cytometry. Results: Statistically significant increases in the proportions of GFP-positive cells were demonstrated for the alkylating agent chlorambucil; the antimetabolites cytarabine, fluorouracil, gemcitabine, and pemetrexed; the platinum-based compounds cisplatin, and oxaliplatin; the topoisomerase inhibitor topotecan; and the antimicrotubule agents docetaxel, vincristine, and eribulin. Epigenetic activity was also detected for the targeted-therapy agents AZD8055, wortmannin, and cetuximab, as well as for the corticosteroid dexamethasone. Thus, epigenetic activity was revealed for 15 drugs widely used in cancer therapy, which possess different modes of action. Conclusions: Our findings show that many anticancer therapy agents modulate the epigenetic landscape of cancer cells, providing a rationale for expanding their therapeutic applications and enhancing the efficacy of combination strategies by overcoming epigenetically driven chemoresistance. Full article

(This article belongs to the Special Issue Features Papers in Epigenomes 2025)

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28 pages, 1068 KB

Open AccessReview

The Epigenetic Battleground: Host Chromatin at the Core of Infection

by Fabrício Castro Machado and Nilmar Silvio Moretti

Epigenomes 2026, 10(1), 13; https://doi.org/10.3390/epigenomes10010013 - 15 Feb 2026

Cited by 1 | Viewed by 624

Abstract

Chromatin dynamics are usually modulated by histone epigenetic post-translational modifications, which rapidly and reversibly govern accessibility and transcriptional responsiveness. During microbial infection, this regulatory layer becomes a highly contested interface where host defense mechanisms and pathogen-driven subversion strategies converge and compete. Many infectious [...] Read more.

Chromatin dynamics are usually modulated by histone epigenetic post-translational modifications, which rapidly and reversibly govern accessibility and transcriptional responsiveness. During microbial infection, this regulatory layer becomes a highly contested interface where host defense mechanisms and pathogen-driven subversion strategies converge and compete. Many infectious agents exploit chromatin to reprogram gene expression, creating cellular environments that are conducive to infection, proliferation, and persistence. Diverse strategies have been described for viruses, bacteria, fungi, protozoa and nematodes, including the direct secretion of acetyltransferases and methyltransferases, interference with host chromatin-binding proteins, subcellular localization of transcriptional factors or epigenetic regulators, and metabolic availability manipulation. Concurrently, host cells activate immune and stress-response genes to mount rapid, adaptable antimicrobial responses. Recent advances in genome-wide, single-cell, and spatial omics profiling have begun to reveal the temporal and cell-type-specific dynamics of the host genome at the core of infection. This review synthesizes current insights into how chromatin is rewired by the major categories of pathogens during infection, highlighting representative case studies across infective agents and the functional consequences for immunity and cell fate. In addition, we discuss emerging techniques for epigenomic and transcriptomic data collection, and the potential of targeted host-directed therapeutic strategies. Chromatin regulation is thus a promising field of study and a possible target for next-generation interventions. Full article

(This article belongs to the Special Issue Epigenetics Meets Immunology: Mechanisms, Crosstalk, and Therapeutic Implications)

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16 pages, 2576 KB

Open AccessArticle

Preliminary Evidence of Blood DNA Methylation Changes in Pregnant Women Adhering to a Mediterranean Diet

by Grace Tavelli, Nikki Schultz, Joanna Brisbane, Nina Kresoje, Samantha Lodge, Jeremy K. Nicholson, Nicola J. Armstrong, Desiree Silva, Nina D’Vaz and David Martino

Epigenomes 2026, 10(1), 12; https://doi.org/10.3390/epigenomes10010012 - 13 Feb 2026

Viewed by 535

Abstract

Background/Objectives: Consumption of a Mediterranean diet (MD) has been associated with reduced incidence of non-communicable diseases and reduced overall mortality, with epigenomic effects representing plausible mediators. The aim of this pilot study was to explore potential epigenetic associations between DNA methylation markers in [...] Read more.

Background/Objectives: Consumption of a Mediterranean diet (MD) has been associated with reduced incidence of non-communicable diseases and reduced overall mortality, with epigenomic effects representing plausible mediators. The aim of this pilot study was to explore potential epigenetic associations between DNA methylation markers in blood and adherence to an MD in pregnancy. Methods: Fifty-two pregnant women with high or low adherence to an MD throughout pregnancy, who participated in the BioMood ORIGINS study, were selected using an extremes-of-exposure design. DNA methylation (DNAm) profiles from whole blood were generated using the TWIST human methylome panel. We conducted both genome-wide and candidate gene-based differential methylation analyses to identify epigenetic variations between the study groups. Furthermore, we explored potential associations between blood methylation patterns and circulating inflammatory markers (GlycA, GlycB and SPC) previously observed to exhibit differential abundance in the same cohort of women. Results: There were no genome-wide significant differences in methylated dinucleotides between MD groups (p-value < 5 × 10⁻⁸); however, a region-based analysis identified 2210 differentially methylated regions (DMRs) (FDR < 0.05, absolute maximum logFC > 1) annotated to 1537 genes, significantly enriched in metabolic, inflammatory and neuronal signaling pathways. Leveraging publicly available data, we replicated nine novel DMR associations. Changes in circulating phospholipid inflammatory markers were significantly associated with a small methylation difference in Lipin-1 (LPIN1), albeit with a small effect size (p-value < 5 × 10⁻⁸). A look-up analysis of previously reported MD-associated genes in this cohort detected small but statistically significantly different methylation of CpGs located within collagen type XVIII alpha 1 (COL18A1) and peroxisome proliferator-activated receptor gamma, coactivator 1 beta (PPARGC1B) gene regions. Conclusions: We provide preliminary evidence for modest methylation changes in specific genes associated with adherence to an MD. Full article

(This article belongs to the Special Issue Epigenetic Signatures in Metabolic Health and Cancer)

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34 pages, 2503 KB

Open AccessArticle

Analysis of HERV-K (HML2) Expression in Colorectal Cancer Samples

by Valentina S. Obrezanenko, Polina M. Shulga, Anastasia G. Volkova, Anastasia A. Primova, Yulia A. Remizova, Ivan O. Meshkov, Alexandra D. Kikot, Daria A. Tarasova, Ekaterina S. Bolashova, Alexey A. Ivashechkin, Antonida V. Makhotenko, Ekaterina A. Snigir, Yulia A. Masyukova, Elizaveta I. Radion, Olesya A. Kuznetsova, Maria S. Cheporova, Michail Y. Fedyanin, Alexey A. Tryakin, Valentin V. Makarov, Vladimir S. Yudin, Anton A. Keskinov and Anna S. Makarova Show full author list Hide full author list

Epigenomes 2026, 10(1), 11; https://doi.org/10.3390/epigenomes10010011 - 12 Feb 2026

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Abstract

Background: HML-2 subgroup mobile genetic elements of the HERV-K family were described to participate in carcinogenesis processes, but their expression and epigenetic regulation in molecular subtypes of colorectal cancer (CRC) remain partly characterized. The present study aimed to evaluate the expression of HML-2 [...] Read more.

Background: HML-2 subgroup mobile genetic elements of the HERV-K family were described to participate in carcinogenesis processes, but their expression and epigenetic regulation in molecular subtypes of colorectal cancer (CRC) remain partly characterized. The present study aimed to evaluate the expression of HML-2 elements using RNA-sequencing data in paired tumor and normal intestinal tissue samples from 63 patients with CRC to identify patterns of the retrotransposons’ activity in different molecular subtypes (CMSs). Methods: RNA-sequencing and DNA methylation data were analyzed for paired CRC and normal tissue samples. HERV-K expression was assessed using three bioinformatics tools: Telescope (version 1.0.3), TEtranscripts (version 2.2.3), GeneTEFlow (version 2020). Molecular tumor subtypes were defined using the CMScaller (version 0.99.2) program. The results of the HML-2 loci expression analysis were supplemented with the HML-2 proteins expression data obtained by quantitative RT-PCR. Results: HML-2 expression assessment by GeneTEFlow (version 2020), TECount (version 2.2.3) and Telescope (version 1.0.3) showed high convergence: the Pearson correlation coefficient for each tool exceeded 0.88. Several HML-2 loci were identified as differentially expressed in CRC samples of different CMS. The PCR results confirmed an increase in HML-2 expression in tumor tissues. For all CMSs, an inverse association was detected between differential methylation of CpG sites and differential expression of HML-2 loci. Associations of HML-2 expressions with differentially expressed genes in which they are located were found, and for a number of such genes an inverse relationship between the expression level and the methylation level of their promoters were demonstrated, and data on the involvement in the pathogenesis of CRC were described: CR1, CD48, TTLL3, ABCC2 and ZNF420. Expression signatures associated with the activity of the RIG-I-like receptor signaling cascade were identified in CMS1–3 CRC samples, which may indicate the possible implementation of viral mimicry against the background of HML-2 activation. Conclusions: Analysis of the expression of HML-2 and its association with CpG methylation contributes to a comprehensive interpretation of the CRC pathogenesis mechanisms. Full article

(This article belongs to the Special Issue Epigenetic Signatures in Metabolic Health and Cancer)

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33 pages, 1104 KB

Open AccessReview

Genetic–Epigenetic Interplay in Epilepsy: Pathways, Biomarkers, and Epigenome-Targeted Therapies

by Andra-Giorgiana Zaruha, Patricia Codreanu, Mădălin-Codruț Coman, Monica Andreea Novac II, Simona Gabriela Duță-Ion, Ioana Ruxandra Jugănaru, Iulian Andrei Hotinceanu, Andra Dan, Livia Mălina Burtavel, Anca-Elena Eftenoiu, Diana Bârcă, Andreea Ionescu, Cerasela Paraschiv and Viorica-Elena Rădoi

Epigenomes 2026, 10(1), 10; https://doi.org/10.3390/epigenomes10010010 - 10 Feb 2026

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Abstract

Epilepsy is a heterogeneous neurological disorder with a strong genetic basis, yet recent evidence underscores the critical role of epigenetic mechanisms in its pathogenesis. This review synthesizes current knowledge on how chromatin remodeling, histone modifications, DNA methylation, and transcriptional regulation intersect with classical [...] Read more.

Epilepsy is a heterogeneous neurological disorder with a strong genetic basis, yet recent evidence underscores the critical role of epigenetic mechanisms in its pathogenesis. This review synthesizes current knowledge on how chromatin remodeling, histone modifications, DNA methylation, and transcriptional regulation intersect with classical channelopathies and signaling pathways. We emphasize how epigenetic dysregulation contributes to neuronal excitability and network plasticity, particularly through interactions with mTOR, PI3K-AKT, and GABAergic signaling cascades. The convergence of genetic mutations and epigenetic modifications creates a dynamic landscape in which environmental factors can modify gene expression and contribute to the development of epilepsy. Emerging therapeutic strategies—including epigenetic drugs (HDAC inhibitors, DNMT inhibitors), CRISPR/dCas9-based epigenome editing, and multi-omics approaches—offer promising avenues for precision medicine. This review provides a comprehensive synthesis of genetic and epigenetic mechanisms in epilepsy, examining how these layers interact to produce disease phenotypes and discussing the therapeutic implications of this multilayered regulation. Full article

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11 pages, 1116 KB

Open AccessArticle

Epigenetic Liquid Biopsy Marks Atrial Fibrillation: Evidence from the AF Big Picture Study

by Riccardo Proietti, Nicola Tidbury, Joshua Preston, Maanya Vittal, Philippa McCabe, Garry McDowell, Gregory Y. H. Lip and Manlio Vinciguerra

Epigenomes 2026, 10(1), 9; https://doi.org/10.3390/epigenomes10010009 - 5 Feb 2026

Viewed by 700

Abstract

Background/Objectives: Atrial fibrillation (AF) is currently the most common arrhythmia worldwide, and it is linked to increased mortality and morbidity, hence the need for a better clinical stratification of AF patients. Histone complexes or nucleosomes, released into the blood circulation, are found [...] Read more.

Background/Objectives: Atrial fibrillation (AF) is currently the most common arrhythmia worldwide, and it is linked to increased mortality and morbidity, hence the need for a better clinical stratification of AF patients. Histone complexes or nucleosomes, released into the blood circulation, are found elevated in acute conditions such as stroke, trauma, and sepsis. The aim of this pilot single-centre study was to assess whether circulating histone levels could be used for diagnostic purposes in patients with AF. Methods: A total of 40 patients, well characterised for their biochemical and clinical characteristics, were recruited from outpatient clinics. Patients were randomly recruited into two groups (n = 20 per group), i.e., persistent AF and hypertensive controls. A multi-channel flow imaging methodology based on ImageStreamX was used with a well-optimised protocol to image and quantify five individual histones (H2A, H2B, H3, H4, and macroH2A1.1) together with the dimers (H2A/H2B, and H3/H4). Results: In the AF groups, plasma levels of histone dimers H2A/H2B and H3/H4 were elevated compared to hypertensive controls, 1.8% vs. 1.06% (p-value = 0.03). H2A/H2B dimer levels were increased in AF patients irrespective of gender, smoking status, diabetes, and pharmacological therapy. In the overall population, an inverse correlation between H2A and BMI was detected. Conclusions: Our pilot study, although limited in sample size, suggests that circulating histone complexes may be epigenetic sentinels for AF, offering mechanistic insights while addressing unmet needs in risk stratification. Full article

(This article belongs to the Special Issue Epigenetic Signatures in Metabolic Health and Cancer)

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13 pages, 510 KB

Open AccessArticle

Differences in MicroRNA Expression in Firefighters Responding to a Train Derailment and Fire in East Palestine, Ohio

by Jaclyn M. Goodrich, Yaodong Xin, Shawn C. Beitel, John Gulotta, Lu Wang, Bhavya Thotakura, Judith M. Graber, Derek Urwin, Alexander C. Mayer, Sara Jahnke, Derrick L. Edwards, Casey Grant, Sreenivasan Ranganathan and Jefferey L. Burgess

Epigenomes 2026, 10(1), 8; https://doi.org/10.3390/epigenomes10010008 - 3 Feb 2026

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Abstract

Background/Objectives: High-risk, low-frequency incidents such as building collapses and large chemical fires can result in acute, high-dose exposures to toxic agents for first responders and the surrounding community. While these exposures may last for hours to days, their contribution to firefighters’ risks [...] Read more.

Background/Objectives: High-risk, low-frequency incidents such as building collapses and large chemical fires can result in acute, high-dose exposures to toxic agents for first responders and the surrounding community. While these exposures may last for hours to days, their contribution to firefighters’ risks for cancer and other diseases is relatively unknown. In February 2023, a freight train transporting chemicals derailed and caught fire in East Palestine, Ohio, US. More than 350 firefighters, primarily volunteer, responded to the incident. In this cross-sectional study, we evaluated epigenetic markers of toxicity in responding firefighters. We hypothesized that exposures from responding to the train derailment would alter the expression of microRNAs (miRNAs) linked to carcinogenesis. Methods: We enrolled 62 responding firefighters and a comparison group of 26 firefighters from the same region who did not respond to the incident. We measured the relative expression of 800 miRNAs in blood samples using the nCounter Human v3 miRNA expression panel. We compared the expression of miRNA between exposure groups in negative binomial regression models, adjusting for potential confounders. Results: At a false discover rate cut-off of 5% (q-value < 0.05), 16 miRNAs had significantly higher expression and one significantly lower among firefighters that responded to the incident. Top disease-related pathways in which these miRNAs were enriched included those relevant to neurodegenerative diseases, vascular disease, and multiple cancer sites. Conclusions: Overall, results suggest responding to one large incident can have non-transient impacts on miRNA expression. Whether this translates into longer-term health risks or adaptive responses to exposures is unclear. Full article

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12 pages, 4978 KB

Open AccessArticle

An Hsp70 Chaperone Is Involved in Meiotic Silencing by Unpaired DNA

by Victor T. Sy, Sterling S. Trawick, Hagen M. Tatarsky and Patrick K. T. Shiu

Epigenomes 2026, 10(1), 7; https://doi.org/10.3390/epigenomes10010007 - 26 Jan 2026

Viewed by 742

Abstract

In the filamentous fungus Neurospora crassa, a gene not having a pairing partner during meiosis is seen as a potential intruder and is targeted by a mechanism called meiotic silencing by unpaired DNA (MSUD). MSUD employs core RNA interference (RNAi) components such [...] Read more.

In the filamentous fungus Neurospora crassa, a gene not having a pairing partner during meiosis is seen as a potential intruder and is targeted by a mechanism called meiotic silencing by unpaired DNA (MSUD). MSUD employs core RNA interference (RNAi) components such as the SMS-2 Argonaute, which uses small interfering RNAs (siRNAs) as guides to seek out mRNAs from unpaired genes for silencing. In Drosophila melanogaster, the heat shock protein 70 (Hsp70) chaperone system facilitates the conformational activation of an Argonaute and allows it to load siRNAs. Here, our results demonstrate that an Hsp70 protein in Neurospora interacts with SMS-2 and mediates the silencing of unpaired genes. Full article

(This article belongs to the Collection Feature Papers in Epigenomes)

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11 pages, 1968 KB

Open AccessArticle

ARS2, a Cofactor of CBC, Promotes Meiotic Silencing by Unpaired DNA

by Michael M. Vierling, Victor T. Sy, Logan M. Decker, Hua Xiao, Justine N. Hemaya and Patrick K. T. Shiu

Epigenomes 2026, 10(1), 6; https://doi.org/10.3390/epigenomes10010006 - 21 Jan 2026

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Abstract

The presence of an extra DNA segment in a genome could indicate a transposon or another repetitive element on the move. In Neurospora crassa, a surveillance mechanism called meiotic silencing by unpaired DNA (MSUD) is maintained to monitor these selfish elements. MSUD [...] Read more.

The presence of an extra DNA segment in a genome could indicate a transposon or another repetitive element on the move. In Neurospora crassa, a surveillance mechanism called meiotic silencing by unpaired DNA (MSUD) is maintained to monitor these selfish elements. MSUD utilizes common RNA interference (RNAi) factors, including the SMS-2 Argonaute, to target mRNAs from genes lacking a pairing partner during meiosis. In eukaryotes, an mRNA transcript is typically bound at the 5′ cap by the cap-binding complex (CBC), which assists in its nuclear export. Previously, we discovered that CBC and its interactor NCBP3 mediate MSUD, possibly by guiding the perinuclear SMS-2 to effectively recognize exported mRNAs. Here, we report that ARS2, a CBC cofactor, is involved in MSUD. ARS2 interacts with both CBC and NCBP3, and it may help bring them together. In addition to its role in silencing, ARS2 also contributes to vegetative growth and sexual sporulation. Full article

(This article belongs to the Collection Feature Papers in Epigenomes)

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18 pages, 2156 KB

Open AccessReview

Something Old, Something New, Something Borrowed… About the Placenta

by Nadezhda Milova, Maria Nikolova, Angel Yordanov, Antoan Milov and Stoilka Mandadzhieva

Epigenomes 2026, 10(1), 5; https://doi.org/10.3390/epigenomes10010005 - 19 Jan 2026

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Abstract

The connection between the mother and the child has been considered one of the strongest bonds in nature. Though there are numerous factors that can influence the establishment of pregnancy, in its essence, three are considered major: a good quality embryo, a receptive [...] Read more.

The connection between the mother and the child has been considered one of the strongest bonds in nature. Though there are numerous factors that can influence the establishment of pregnancy, in its essence, three are considered major: a good quality embryo, a receptive endometrium, and successful cross-talk between them. The placenta, which derives from the trophoblast of the embryo, develops when a successful implantation occurs. It is an ephemeral organ through which the turnover of nutrients, gases, and waste molecules is realized. It serves as a barrier and can provide the embryo with immune factors. Placental disorders are observed in some rare but life-threatening obstetric conditions like preeclampsia (PE), fetal growth restriction (FGR), gestational trophoblastic diseases (GTDs), and gestational diabetes mellitus (GDM). The etiology and pathogenesis of some are still partially enigmatic. Our attention in this review was driven by the participation of small RNA molecules—miRNAs and piRNAs—as potential epigenetic modulators of genes that play a pivotal role in placental functioning. In this study, we analyze the influence of these epigenetic factors on the mechanisms of the development of preeclampsia. The molecular approach for understanding placental disorders may help new diagnostic and therapeutic solutions to be found. Full article

(This article belongs to the Collection Feature Papers in Epigenomes)

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12 pages, 257 KB

Open AccessReview

Epigenetic Alterations in Colitis-Associated Colorectal Cancer

by Nisha Ganesh, William M. Grady and Andrew M. Kaz

Epigenomes 2026, 10(1), 4; https://doi.org/10.3390/epigenomes10010004 - 16 Jan 2026

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Abstract

Colitis-associated colorectal cancer (CAC) represents a distinct subtype of colorectal malignancy that arises in the setting of chronic inflammatory bowel disease (IBD). Unlike sporadic colorectal cancer, CAC develops through inflammation-driven molecular pathways, in which epigenetic alterations play a pivotal role in tumor initiation [...] Read more.

Colitis-associated colorectal cancer (CAC) represents a distinct subtype of colorectal malignancy that arises in the setting of chronic inflammatory bowel disease (IBD). Unlike sporadic colorectal cancer, CAC develops through inflammation-driven molecular pathways, in which epigenetic alterations play a pivotal role in tumor initiation and progression. This review highlights the major epigenetic mechanisms implicated in CAC, including DNA methylation, histone modifications, and microRNA (miRNA) dysregulation. Aberrant DNA methylation patterns, such as promoter hypermethylation of tumor suppressor genes and global hypomethylation, contribute to genomic instability and altered gene expression. In parallel, inflammation-induced changes in histone configuration modulate chromatin accessibility and transcriptional activity of key oncogenic and tumor-suppressive pathways. Furthermore, deregulated miRNAs influence multiple aspects of CAC pathogenesis by targeting genes involved in inflammation and tumor progression. Understanding these epigenetic processes provides valuable insights into the development of colorectal malignancy and identifies potential biomarkers for early detection and intervention in colitis-associated colorectal cancer. Full article

(This article belongs to the Special Issue Epigenetic Signatures in Metabolic Health and Cancer)

17 pages, 2282 KB

Open AccessArticle

Fisetin Suppresses the Proliferative and Migratory Behavior of HeLa Cells by Modulating Aberrant Epigenetic Marks (Writers and Erasers)

by Nazia Afroze, Reham I. Alagal, Lujain A. Almousa, Ritu Raina, Prathap Bava, Lizna Mohamed Ali, Tarique Noorul Hasan and Arif Hussain

Epigenomes 2026, 10(1), 3; https://doi.org/10.3390/epigenomes10010003 - 12 Jan 2026

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Abstract

Purpose: The reversible deviant in epigenomic modulations is the highlight of developing new anti-cancer drugs, necessitating the use of fisetin as an epigenetic modifier in the study. Methods: In silico and molecular studies were performed to analyze the modulatory effect of fisetin on [...] Read more.

Purpose: The reversible deviant in epigenomic modulations is the highlight of developing new anti-cancer drugs, necessitating the use of fisetin as an epigenetic modifier in the study. Methods: In silico and molecular studies were performed to analyze the modulatory effect of fisetin on various writers and erasers. Further, whole genome DNA methylation sequencing and expression studies were performed. Global DNA methylation-LINE 1 kit was used to check global DNA methylation. Additionally, the effect of fisetin on migration was evaluated by colony, scratch, and invasion assays and qPCR and protein expression studies of migration-related genes were carried out on HeLa cells. Results: In silico studies have supported that fisetin interacts with writers and erasers in their catalytic site and the simulation studies showed minimum fluctuations in energy and temperature over a 10 ns timescale indicating that these complexes are likely to remain stable. Fisetin (20–50 µM) dose-dependently inhibited DNA methyltransferases (DNMT), histone deacetyl transferases (HDAC), histone acetyl transferases (HAT), and histone methyltransferases (HMT) activities at 48 h, with inhibition ranging from 24 to 72% compared to the control. The expression and enzymatic activity of these proteins, along with various H4 and H3 modification marks, were observed to be altered following fisetin treatment at 48 h. Fisetin treatment reduced promoter methylation in various tumor suppressor genes ranging from 15.29% to 76.23% and leading to the corresponding reactivation of important tumor suppressor genes; however, it did not lead to any alteration in the global DNA methylation compared to untreated controls linked with the anti-migratory properties of fisetin as the percentage of migrated cells dropped from ~40% to ~8%. Conclusions: This study gives a mechanistic insight of fisetin as a potential epigenetic modifier in HeLa cells. Full article

(This article belongs to the Collection Epigenetic Regulation of Cellular Differentiation)

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16 pages, 1732 KB

Open AccessArticle

Epigenetic Regulation and Gene Expression Profiles in Cervical Swabs: Toward Non-Invasive Biomarkers of Cervical Lesion Progression

by Ivana Kašubová, Andrea Hornáková, Lucia Kotúľová, Tomáš Rokos, Zuzana Kolková, Andrea Kapinová, Terézia Pribulová, Erik Kozubík, Michal Kalman, Kamil Biringer, Erik Kúdela and Veronika Holubeková

Epigenomes 2026, 10(1), 2; https://doi.org/10.3390/epigenomes10010002 - 7 Jan 2026

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Abstract

Background/Objectives: Cervical cancer is a common malignancy in women worldwide, closely associated with persistent human papillomavirus (HPV) infection. Epigenetic mechanisms, particularly promoter methylation, may contribute to tumour progression. This pilot study aimed to analyse the promoter methylation patterns and gene expression of [...] Read more.

Background/Objectives: Cervical cancer is a common malignancy in women worldwide, closely associated with persistent human papillomavirus (HPV) infection. Epigenetic mechanisms, particularly promoter methylation, may contribute to tumour progression. This pilot study aimed to analyse the promoter methylation patterns and gene expression of selected genes (DNMT, BCL2, CDH1, CD8A, MUC1, ALCAM). The goal was to identify associations between promoter hypermethylation, gene expression, and HPV infection in cervical swab specimens obtained from patients with low-grade squamous intraepithelial lesions (SILs), high-grade SILs, or squamous cell carcinomas. Methods: A total of 81 cervical swab samples from Slovak participants were included in the study. DNA methylation and gene expression profiling was performed using real-time PCR (qPCR) and pyrosequencing. Results: BCL2 expression was significantly reduced across all lesion grades. CD8A expression was slightly elevated in low- and high-grade SILs, particularly in HPV-positive samples. MUC1 showed variability with lesion grade. No statistically significant differences in DNA methylation were observed across groups stratified by HPV status, community state type, and lesion grade. Conclusions: Our findings suggest that BCL2 downregulation and gene activity variability influenced by the vaginal microbiome may play a role in cervical lesion progression. These results highlight potential non-invasive biomarkers for monitoring cervical lesions. Full article

(This article belongs to the Special Issue Epigenetic Signatures in Metabolic Health and Cancer)

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19 pages, 1291 KB

Open AccessArticle

Upregulation of a MicroRNA Signature Involving miR-17-5p, miR-26b-5p, miR-106a-5p, and miR-146a-5p During Cervical Epithelial Transformation

by Andrea Hornakova, Zuzana Kolkova, Lucia Kotulova, Tomas Rokos, Ivana Kasubova, Terezia Pribulova, Erik Kozubik, Kamil Biringer, Erik Kudela and Veronika Holubekova

Epigenomes 2026, 10(1), 1; https://doi.org/10.3390/epigenomes10010001 - 26 Dec 2025

Viewed by 653

Abstract

Background: Cervical cancer remains the fourth most common malignancy among women worldwide. Despite vaccination and regular screening, new molecular biomarkers are needed for improved early detection and risk assessment. MicroRNAs (miRNAs) play crucial roles in post-transcriptional regulation, and their dysregulation may contribute [...] Read more.

Background: Cervical cancer remains the fourth most common malignancy among women worldwide. Despite vaccination and regular screening, new molecular biomarkers are needed for improved early detection and risk assessment. MicroRNAs (miRNAs) play crucial roles in post-transcriptional regulation, and their dysregulation may contribute to cervical carcinogenesis. This study evaluated the expression of selected miRNAs in cervical swab samples and corresponding biopsies from women with various grades of cervical lesions and assessed their relationship with human papillomavirus (HPV) infection. Methods: A total of 72 cervical swab samples were included in this study, divided according to cytological severity: negative for intraepithelial lesion or malignancy (NILM, n = 15), atypical squamous cells of undetermined significance (ASC-US, n = 12), low-grade squamous intraepithelial lesion (LSIL, n = 19), and high-grade squamous intraepithelial lesion (HSIL, n = 26). In a subset of patients, corresponding biopsy specimens were analysed for comparison. The association of miRNA expression with HPV infection status was also examined. miRNA expression was quantified by real-time PCR using commercially available assays. Results: To assess the relationship between miRNA expression, lesion severity, and HPV infection, fold change values were compared to the control group (NILM). No significant differences were observed in the ASC-US group (p > 0.05). In contrast, several miRNAs were significantly upregulated in the LSIL and/or HSIL groups, as well as in HPV-positive samples, indicating their association with both lesion progression and viral infection. Specifically, miR-17-5p, miR-26b-5p, miR-29a-3p, miR-103a-3p, miR-106a-5p, miR-146a-5p, miR-155-5p, and miR-191-5p showed increased expression (p < 0.05) compared with controls. The observed upregulation of miR-26b-5p, miR-106a-5p, and miR-146a-5p highlights their potential role in HPV-associated cervical carcinogenesis. Dysregulated miRNAs were enriched in pathways related to infectious diseases, various types of cancer, and cell adhesion processes. Conclusions: The gradual increase in specific miRNAs with lesion severity and HPV infection suggests their role in cervical carcinogenesis. The identified miRNAs may serve as promising non-invasive biomarkers for early detection and monitoring of HPV-associated cervical lesions. Full article

(This article belongs to the Special Issue Epigenetic Signatures in Metabolic Health and Cancer)

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Epigenomes, Volume 10, Issue 1 (March 2026) – 21 articles

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