Journal Description
Epigenomes
Epigenomes
is an international, peer-reviewed, open access journal on epigenetics and epigenomics, published quarterly online by MDPI. The Epigenetics Society is affiliated with Epigenomes and its members receive discounts on the article processing charges.
- Open Access— free for readers, with article processing charges (APC) paid by authors or their institutions.
- High Visibility: indexed within Scopus, ESCI (Web of Science), PMC, PubMed, Embase, PubAg, CAPlus / SciFinder, and other databases.
- Journal Rank: JCR - Q2 (Genetics and Heredity) / CiteScore - Q2 (Biochemistry, Genetics and Molecular Biology (miscellaneous))
- Rapid Publication: manuscripts are peer-reviewed and a first decision is provided to authors approximately 20.3 days after submission; acceptance to publication is undertaken in 2.8 days (median values for papers published in this journal in the first half of 2025).
- Recognition of Reviewers: reviewers who provide timely, thorough peer-review reports receive vouchers entitling them to a discount on the APC of their next publication in any MDPI journal, in appreciation of the work done.
Impact Factor:
3.5 (2024);
5-Year Impact Factor:
3.1 (2024)
Latest Articles
Deciphering the Heterogeneity of Pancreatic Cancer: DNA Methylation-Based Cell Type Deconvolution Unveils Distinct Subgroups and Immune Landscapes
Epigenomes 2025, 9(3), 34; https://doi.org/10.3390/epigenomes9030034 - 5 Sep 2025
Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly heterogeneous malignancy, characterized by low tumor cellularity, a dense stromal response, and intricate cellular and molecular interactions within the tumor microenvironment (TME). Although bulk omics technologies have enhanced our understanding of the molecular landscape of
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Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly heterogeneous malignancy, characterized by low tumor cellularity, a dense stromal response, and intricate cellular and molecular interactions within the tumor microenvironment (TME). Although bulk omics technologies have enhanced our understanding of the molecular landscape of PDAC, the specific contributions of non-malignant immune and stromal components to tumor progression and therapeutic response remain poorly understood. Methods: We explored genome-wide DNA methylation and transcriptomic data from the Cancer Genome Atlas Pancreatic Adenocarcinoma cohort (TCGA-PAAD) to profile the immune composition of the TME and uncover gene co-expression networks. Bioinformatic analyses included DNA methylation profiling followed by hierarchical deconvolution, epigenetic age estimation, and a weighted gene co-expression network analysis (WGCNA). Results: The unsupervised clustering of methylation profiles identified two major tumor groups, with Group 2 (n = 98) exhibiting higher tumor purity and a greater frequency of KRAS mutations compared to Group 1 (n = 87) (p < 0.0001). The hierarchical deconvolution of DNA methylation data revealed three distinct TME subtypes, termed hypo-inflamed (immune-deserted), myeloid-enriched, and lymphoid-enriched (notably T-cell predominant). These immune clusters were further supported by co-expression modules identified via WGCNA, which were enriched in immune regulatory and signaling pathways. Conclusions: This integrative epigenomic–transcriptomic analysis offers a robust framework for stratifying PDAC patients based on the tumor immune microenvironment (TIME), providing valuable insights for biomarker discovery and the development of precision immunotherapies.
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(This article belongs to the Collection Feature Papers in Epigenomes)
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Innate Immune Surveillance and Recognition of Epigenetic Marks
by
Yalong Wang
Epigenomes 2025, 9(3), 33; https://doi.org/10.3390/epigenomes9030033 - 5 Sep 2025
Abstract
The innate immune system protects against infection and cellular damage by recognizing conserved pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Emerging evidence suggests that aberrant epigenetic modifications—such as altered DNA methylation and histone marks—can serve as immunogenic signals that activate pattern
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The innate immune system protects against infection and cellular damage by recognizing conserved pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Emerging evidence suggests that aberrant epigenetic modifications—such as altered DNA methylation and histone marks—can serve as immunogenic signals that activate pattern recognition receptor (PRR)-mediated immune surveillance. This review explores the concept that epigenetic marks may function as DAMPs or even mimic PAMPs. I highlight how unmethylated CpG motifs, which are typically suppressed using host methylation, are recognized as foreign via Toll-like receptor 9 (TLR9). I also examine how cytosolic DNA sensors, including cGAS, detect mislocalized or hypomethylated self-DNA resulting from genomic instability. In addition, I discuss how extracellular histones and nucleosomes released during cell death or stress can act as DAMPs that engage TLRs and activate inflammasomes. In the context of cancer, I review how epigenetic dysregulation can induce a “viral mimicry” state, where reactivation of endogenous retroelements produces double-stranded RNA sensed by RIG-I and MDA5, triggering type I interferon responses. Finally, I address open questions and future directions, including how immune recognition of epigenetic alterations might be leveraged for cancer immunotherapy or regulated to prevent autoimmunity. By integrating recent findings, this review underscores the emerging concept of the epigenome as a target of innate immune recognition, bridging the fields of immunology, epigenetics, and cancer biology.
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(This article belongs to the Special Issue Epigenetics Meets Immunology: Mechanisms, Crosstalk, and Therapeutic Implications)
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Open AccessSystematic Review
An Epigenomic Meta-Analysis of Differentially Methylated Sites in Pre- and Post-Metabolic/Bariatric Surgery Adult Female Patients
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Agnieszka Lovett, Graham A. Hitman, Georgios K. Dimitriadis, Alice M. Murphy, Gyanendra Tripathi and Aparna Duggirala
Epigenomes 2025, 9(3), 32; https://doi.org/10.3390/epigenomes9030032 - 29 Aug 2025
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Background/Objectives: Metabolic/bariatric surgery is currently the most successful treatment for patients with obesity; however, a fifth of patients undergoing surgery may not lose enough weight to be considered successful. Recent studies have shown that bariatric/metabolic surgery alters the epigenome and may explain postoperative
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Background/Objectives: Metabolic/bariatric surgery is currently the most successful treatment for patients with obesity; however, a fifth of patients undergoing surgery may not lose enough weight to be considered successful. Recent studies have shown that bariatric/metabolic surgery alters the epigenome and may explain postoperative improvements in metabolic health. The primary objective is to consolidate published differentially methylated CpG sites in pre- and post-metabolic/bariatric surgery female patients and associate them with the respective genes and pathways. Methods: This systematic review adhered to the PRISMA-P guidelines and was registered with the PROSPERO (CRD42023421852). Following an initial screening of 541 studies using COVIDENCE, six studies were selected, comprising three epigenome-wide association studies (EWAS) and three candidate gene methylation studies. The published studies collected DNA samples from female patients with obesity before and after surgery (3 months, 6 months, 9–31 months, and 2 years). KEGG pathway analysis was performed on genes where the extracted CpG sites were located. Results: The meta-analysis showed that 11,456 CpG sites are differentially methylated after a successful weight loss surgery, with 109 sites mapped to genes involved in key metabolic pathways, including FoxO, mTOR, insulin, cAMP, adipocytokine, Toll-like receptor, and PI3K-Akt. Conclusion: The highlighted differentially methylated CpG sites can be further used to predict the molecular signature associated with successful metabolic/bariatric surgery.
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Open AccessReview
Dynamics and Malleability of Plant DNA Methylation During Abiotic Stresses
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Niraj Lodhi and Rakesh Srivastava
Epigenomes 2025, 9(3), 31; https://doi.org/10.3390/epigenomes9030031 - 29 Aug 2025
Abstract
Epigenetic regulation, particularly DNA methylation, plays a crucial role in plant adaptation to environmental stresses by modulating gene expression without altering the underlying DNA sequence. In response to major abiotic stresses such as salinity, drought, heat, cold, and heavy metal toxicity, plants undergo
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Epigenetic regulation, particularly DNA methylation, plays a crucial role in plant adaptation to environmental stresses by modulating gene expression without altering the underlying DNA sequence. In response to major abiotic stresses such as salinity, drought, heat, cold, and heavy metal toxicity, plants undergo dynamic changes in DNA methylation patterns. These modifications are orchestrated by DNA methyltransferases and demethylases with variations depending on plant species, genetic background, and ontogenic phase. DNA methylation affects the expression of key genes involved in cellular, physiological, and metabolic processes essential for stress tolerance. Furthermore, it contributes to the establishment of stress memory, which can be transmitted across generations, thereby enhancing long-term plant resilience. The interaction of DNA methylation with other epigenetic mechanisms, including histone modifications, small RNAs, and chromatin remodeling, adds layers of regulatory complexity. Recent discoveries concerning N6-methyladenine have opened new avenues for understanding the epigenetic landscape in plant responses to abiotic stress. Overall, this review addresses the central role of DNA methylation in regulating plant stress responses and emphasizes its potential for application in crop improvement through epigenetic and advanced biotechnological approaches.
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(This article belongs to the Collection Epigenetic Control in Plants)
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Epigenetic Mechanisms in Neurofibromatosis Types 1 and 2
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Christina Stylianides, Gavriel Hadjigavriel, Paschalis Theotokis, Efstratios Vakirlis, Soultana Meditskou, Maria Eleni Manthou and Iasonas Dermitzakis
Epigenomes 2025, 9(3), 30; https://doi.org/10.3390/epigenomes9030030 - 14 Aug 2025
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Neurocutaneous syndromes, known as phakomatoses, encompass a diverse group of congenital conditions affecting the nervous system and skin, with neurofibromatosis type 1 (NF1) and neurofibromatosis type 2 (NF2) among the most clinically significant. Both disorders are inherited in an autosomal dominant manner. NF1
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Neurocutaneous syndromes, known as phakomatoses, encompass a diverse group of congenital conditions affecting the nervous system and skin, with neurofibromatosis type 1 (NF1) and neurofibromatosis type 2 (NF2) among the most clinically significant. Both disorders are inherited in an autosomal dominant manner. NF1 presents with café-au-lait macules; cutaneous, subcutaneous, and plexiform neurofibromas; skeletal abnormalities; learning disabilities; and optic pathway gliomas, while NF2 is characterised by bilateral vestibular schwannomas, multiple meningiomas, ependymomas, and peripheral nerve schwannomas. Although germline mutations in the NF1 and NF2 tumour suppressor genes are well established, they do not fully explain the broad clinical variability observed, even among individuals carrying identical mutations. As increasingly recognised in other genetic diseases, epigenetic mechanisms, including DNA methylation, histone modifications, chromatin remodelling, and non-coding RNA (ncRNA) regulation, play a critical role in modulating gene expression and influencing disease severity. Despite important findings, the research remains fragmented, and a unified model is lacking. This review organises the current knowledge, emphasising how epigenetic alterations impact disease behaviour and outlining their potential as prognostic biomarkers and therapeutic targets. A deeper understanding of these mechanisms could lead to improved personalised management and the development of targeted epigenetic therapies for individuals with NF1 and NF2.
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Open AccessReview
Role of Ionizing Radiation in Shaping the Complex Multi-Layered Epigenome
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Claudia E. Rübe, Mutaz A. Abd Al-razaq, Carola Meier, Markus Hecht and Christian Rübe
Epigenomes 2025, 9(3), 29; https://doi.org/10.3390/epigenomes9030029 - 8 Aug 2025
Abstract
The impact of ionizing radiation (IR) with induction of various DNA damage is based not only on genetic but also on epigenetic effects. Epigenetic modifications determine the chromatin structure and DNA accessibility, thereby regulating cellular functions through the expression of individual genes or
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The impact of ionizing radiation (IR) with induction of various DNA damage is based not only on genetic but also on epigenetic effects. Epigenetic modifications determine the chromatin structure and DNA accessibility, thereby regulating cellular functions through the expression of individual genes or entire groups of genes. However, the influence of DNA repair processes on the restoration of local chromatin structures and global nuclear architectures is still insufficiently understood. In multicellular organisms, epigenetic mechanisms control diverse cellular functions of specific cell types through precise temporal and spatial regulation of gene expression and silencing. How altered epigenetic mechanisms regulate the pathophysiological function of cells, tissues, and ultimately entire organs following IR exposure remains to be investigated in detail. Radiation-induced epigenetic processes are particularly critical for immature cell populations such as tissue-specific stem and progenitor cells during development and differentiation of organ tissues. Genome-wide patterns of DNA and histone modifications are established cell types—specifically during the development and differentiation of organ tissues but can also be fundamentally altered in adult organism by stress responses, such as radiation-induced DNA damage. Following IR exposure, epigenetic factors are not always fully restored to their original state, resulting in epigenetic dysfunction that causes cells to lose their original identity and function. Moreover, severe radiation-induced DNA damage can induce premature senescence of cells in complex tissues, which ultimately leads to signs of aging and age-related diseases such as cancer. In this work, we provide an overview of the most important epigenetic changes following IR exposure and their pathophysiological significance for the development of acute and chronic radiation reactions.
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(This article belongs to the Special Issue Features Papers in Epigenomes 2025)
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DNA Methylation Status of Regulatory Regions of Apoptosis-Associated Genes in Dystropy «Huntington’s Disease—Non-Small Cell Lung Cancer»
by
Nadezhda P. Babushkina, Elena Yu. Bragina, Densema E. Gomboeva, Iuliia A. Koroleva, Sergey N. Illarioshkin, Sergey A. Klyushnikov, Nataliya Yu. Abramycheva, Maria A. Nikitina, Valentina M. Alifirova, Nikolai V. Litviakov, Marina K. Ibragimova, Matvey M. Tsyganov, Irina A. Tsydenova, Aleksei A. Zarubin, Irina A. Goncharova, Maria V. Golubenko, Ramil R. Salakhov, Aleksei A. Sleptcov, Aksana N. Kucher, Maria S. Nazarenko and Valery P. Puzyrevadd
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Epigenomes 2025, 9(3), 28; https://doi.org/10.3390/epigenomes9030028 - 7 Aug 2025
Abstract
Background. Studies of comorbid (syntropic) and inversely comorbid (rarely occurring together, i.e., dystropic) diseases have focused on the search for molecular causes of this phenomenon. Materials. We investigated DNA methylation levels in regulatory regions of 23 apoptosis-associated genes as candidate loci associated with
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Background. Studies of comorbid (syntropic) and inversely comorbid (rarely occurring together, i.e., dystropic) diseases have focused on the search for molecular causes of this phenomenon. Materials. We investigated DNA methylation levels in regulatory regions of 23 apoptosis-associated genes as candidate loci associated with the “cancer–neurodegeneration” dystropy in patients with Huntington’s disease (HD) and patients with non–small cell lung cancer (LC). Results. Statistically significant differences in methylation levels between the HD and LC groups were found for 41 CpG sites in 16 genes. The results show that five genes (SETDB1, TWIST1, HDAC1, SP1, and GRIA2) are probably involved in the phenomenon of inverse comorbidity of these diseases. For these genes, the methylation levels of the studied CpG sites were altered in opposite directions in the two groups of patients, compared to the control group. Conclusions. For the SP1 gene, the above hypothesis is supported by our analysis of open-access data on gene expression in patients with the aforementioned diagnoses and fits a probable mechanism of the “HD–LC” dystropy.
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(This article belongs to the Special Issue DNA Methylation Markers in Health and Disease)
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Targeting the Kynureninase–HDAC6–Complement Axis as a Novel Therapeutic Strategy in Glioblastoma
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Arif Ul Hasan, Sachiko Sato, Mami Obara, Yukiko Kondo and Eiichi Taira
Epigenomes 2025, 9(3), 27; https://doi.org/10.3390/epigenomes9030027 - 28 Jul 2025
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Background/Objectives: Glioblastoma (GBM) is an aggressive brain tumor known for its profound heterogeneity and treatment resistance. Dysregulated complement signaling and epigenetic alterations have been implicated in GBM progression. This study identifies kynureninase (KYNU), a key enzyme in the kynurenine pathway, as a novel
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Background/Objectives: Glioblastoma (GBM) is an aggressive brain tumor known for its profound heterogeneity and treatment resistance. Dysregulated complement signaling and epigenetic alterations have been implicated in GBM progression. This study identifies kynureninase (KYNU), a key enzyme in the kynurenine pathway, as a novel regulator of complement components and investigates its interaction with histone deacetylase 6 (HDAC6) in the context of therapeutic targeting. Methods: KYNU expression, and its association with complement signaling in GBM, were analyzed using publicly available datasets (TCGA, GTEx, HPA). Pathway enrichment was performed via LinkedOmics. In vitro studies in GBM cell lines (U87, U251, T98G) assessed the effects of KYNU silencing and treatment with an HDAC6 inhibitor (tubastatin) and a BET inhibitor (apabetalone) on gene expression and cell viability. Results: Bioinformatic analyses revealed significant overexpression of KYNU in GBM tissues compared to normal brain tissue. KYNU expression was positively associated with genes involved in complement and coagulation cascades. In vitro experiments demonstrated that KYNU silencing reduced the expression of C3, C3AR1, and C5AR1 and suppressed GBM cell viability. Treatment with tubastatin, while reducing viability, paradoxically upregulated complement genes, suggesting potential limitations in therapeutic efficacy. However, this effect was mitigated by KYNU knockdown. Combined treatment with apabetalone and tubastatin effectively suppressed KYNU expression and enhanced cytotoxicity, particularly in cells with high complement expression. Conclusions: Our findings establish the KYNU–HDAC6–complement axis as a critical regulatory pathway in GBM. Targeting KYNU-mediated complement activation through combined epigenetic approaches—such as HDAC6 and BET inhibition—represents a promising strategy to overcome complement-driven resistance in GBM therapy.
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Epigenomic Interactions Between Chronic Pain and Recurrent Pressure Injuries After Spinal Cord Injury
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Letitia Y. Graves, Melissa R. Alcorn, E. Ricky Chan, Katelyn Schwartz, M. Kristi Henzel, Marinella Galea, Anna M. Toth, Christine M. Olney and Kath M. Bogie
Epigenomes 2025, 9(3), 26; https://doi.org/10.3390/epigenomes9030026 - 23 Jul 2025
Abstract
Background/Objectives: This study investigated variations in DNA methylation patterns associated with chronic pain and propensity for recurrent pressure injuries (PrI) in persons with spinal cord injury (SCI). Methods: Whole blood was collected from 81 individuals with SCI. DNA methylation was quantified using Illumina
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Background/Objectives: This study investigated variations in DNA methylation patterns associated with chronic pain and propensity for recurrent pressure injuries (PrI) in persons with spinal cord injury (SCI). Methods: Whole blood was collected from 81 individuals with SCI. DNA methylation was quantified using Illumina genome-wide arrays (EPIC and EPICv2). Comprehensive clinical profiles collected included secondary health complications, in particular current PrI and chronic pain. Relationships between recurrent PrI and chronic pain and whether the co-occurrence of both traits was mediated by changes in DNA methylation were investigated using R packages limma, DMRcate and mCSEA. Results: Three differentially methylated positions (DMPs) (cg09867095, cg26559694, cg24890286) and one region in the micro-imprinted locus for BLCAP/NNAT are associated with chronic pain in persons with SCI. The study cohort was stratified by PrI status to identify any sites associated with chronic pain and while the same three sites and region were replicated in the group with no recurrent PrI, two novel, hypermethylated (cg21756558, cg26217441) sites and one region in the protein-coding gene FDFT1 were identified in the group with recurrent PrI. Gene enrichment and genes associated with specific promoters using MetaScape identified several shared disorders and ontology terms between independent phenotypes of pain and recurrent PrI and interactive sub-groups. Conclusions: DMR analysis using mCSEA identified several shared genes, promoter-associated regions and CGI associated with overall pain and PrI history, as well as sub-groups based on recurrent PrI history. These findings suggest that a much larger gene regulatory network is associated with each phenotype. These findings require further validation.
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(This article belongs to the Special Issue Features Papers in Epigenomes 2025)
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Exploring Epigenetic Ageing Using Direct Methylome Sequencing
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Elena-Cristina Găitănaru, Roua Gabriela Popescu, Andreea-Angelica Stroe, Sergiu Emil Georgescu and George Cătălin Marinescu
Epigenomes 2025, 9(3), 25; https://doi.org/10.3390/epigenomes9030025 - 14 Jul 2025
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Background/Objectives: Advances in nanopore sequencing have opened new avenues for studying DNA methylation at single-base resolution, yet their application in epigenetic ageing research remains underdeveloped. Methods: We present a novel framework that leverages the unique capabilities of nanopore sequencing to profile
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Background/Objectives: Advances in nanopore sequencing have opened new avenues for studying DNA methylation at single-base resolution, yet their application in epigenetic ageing research remains underdeveloped. Methods: We present a novel framework that leverages the unique capabilities of nanopore sequencing to profile and interpret age-associated methylation patterns in native DNA. Results: Unlike conventional array-based approaches, long reads sequencing captures full CpG context, accommodates diverse and repetitive genomic regions, removes bisulfite conversion steps, and is compatible to the latest reference genome. Conclusions: This work establishes nanopore sequencing as a powerful tool for next-generation epigenetic ageing studies, offering a scalable and biologically rich platform for anti-ageing interventions monitoring and longitudinal ageing studies.
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Trends in DNA Methylation over Time Between Parous and Nulliparous Young Women
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Su Chen, John W. Holloway, Wilfried Karmaus, Hongmei Zhang, S. Hasan Arshad and Susan Ewart
Epigenomes 2025, 9(3), 24; https://doi.org/10.3390/epigenomes9030024 - 10 Jul 2025
Abstract
Background/Objectives: The experience of pregnancy and parturition has been associated with long-term health effects in mothers, imparting protective effects against some diseases while the risk of other diseases is increased. The mechanisms that drive these altered disease risks are unknown. This study examined
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Background/Objectives: The experience of pregnancy and parturition has been associated with long-term health effects in mothers, imparting protective effects against some diseases while the risk of other diseases is increased. The mechanisms that drive these altered disease risks are unknown. This study examined DNA methylation (DNAm) changes from pre-pregnancy to several years after giving birth in parous women compared to nulliparous controls over the same time interval. Methods: Using 180 parous-associated CpGs, three analyses were carried out to test DNAm changes from pre-pregnancy at age 18 years to gestation; from gestation to post-pregnancy at age 26 years in parous women; and from 18 to 26 years in nulliparous women using linear mixed models with repeated measures. Results: The directions of DNAm changes were the same between the parous and nulliparous groups. Most CpG dinucleotides (67%, 121 of 180) had a decreasing trend while a small number (7%, 13 of 180) had an increasing trend. Of the CpGs showing increasing or decreasing DNAm, approximately half had DNAm change to a smaller extent in parous women and the other half changed more in parous women than nulliparous controls. 9% (17 of 180) changed significantly in nulliparous women only, leading to a significant difference in DNAm levels in parous women at the post-pregnancy 26 years time point. Conclusions: Pregnancy and parturition may accelerate methylation changes in some CpGs, but slow down or halt methylation changes over time in other CpGs.
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(This article belongs to the Special Issue Longitudinal Studies on Prenatal or Early Life Exposures, Their Associated Epigenetics, and Population Health)
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The Fundamental Role of Nutrients for Metabolic Balance and Epigenome Integrity Maintenance
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Ana Paula de Souza, Vitor Marinho and Marcelo Rocha Marques
Epigenomes 2025, 9(3), 23; https://doi.org/10.3390/epigenomes9030023 - 9 Jul 2025
Abstract
Epigenetic modifications act as crucial regulators of gene activity and are influenced by both internal and external environmental factors, with diet being the most impactful external factor. On the other hand, cellular metabolism encompasses a complex network of biochemical reactions essential for maintaining
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Epigenetic modifications act as crucial regulators of gene activity and are influenced by both internal and external environmental factors, with diet being the most impactful external factor. On the other hand, cellular metabolism encompasses a complex network of biochemical reactions essential for maintaining cellular function, and it impacts every cellular process. Many metabolic cofactors are critical for the activity of chromatin-modifying enzymes, influencing methylation and the global acetylation status of the epigenome. For instance, dietary nutrients, particularly those involved in one-carbon metabolism (e.g., folate, vitamins B12 and B6, riboflavin, methionine, choline, and betaine), take part in the generation of S-adenosylmethionine (SAM), which represents the main methyl donor for DNA and histone methylation; α-ketoglutarate and ascorbic acid (vitamin C) act, respectively, as a co-substrate and cofactor for Ten-eleven Translocation (TET), which is responsible for DNA demethylation; and metabolites such as Acetyl-CoA directly impact histone acetylation, linking metabolism of the TCA cycle to epigenetic regulation. Further, bioactive compounds, such as polyphenols, modulate epigenetic patterns by affecting methylation processes or targeting epigenetic enzymes. Since diet and nutrition play a critical role in shaping epigenome functions and supporting human health, this review offers a comprehensive update on recent advancements in metabolism, epigenetics, and nutrition, providing insights into how nutrients contribute to metabolic balance, epigenome integrity maintenance and, consequently, disease prevention.
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(This article belongs to the Collection Feature Papers in Epigenomes)
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Methylation of the Glucocorticoid Receptor Gene in Children with Somatic Symptom Disorder: A Case-Control Study
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Kyoko Hatta, Masato Kantake, Kyoko Tanaka, Hirofumi Nakaoka, Toshiaki Shimizu and Hiromichi Shoji
Epigenomes 2025, 9(2), 22; https://doi.org/10.3390/epigenomes9020022 - 13 Jun 2025
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Background: Somatic symptom disorder (SSD) in children may be influenced by stress reactivity and psychosocial factors. The glucocorticoid receptor (GR), encoded by NR3C1, is a key mediator of stress responses. However, the relationship between NR3C1 methylation and SSD remains unclear. Methods: We analyzed
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Background: Somatic symptom disorder (SSD) in children may be influenced by stress reactivity and psychosocial factors. The glucocorticoid receptor (GR), encoded by NR3C1, is a key mediator of stress responses. However, the relationship between NR3C1 methylation and SSD remains unclear. Methods: We analyzed NR3C1 exon 1F methylation in cell-free DNA from saliva in 34 children with SSD and 29 age- and sex-matched controls using bisulfite amplicon sequencing. Psychological assessments included the Beck Depression Inventory-II (BDI-II) and KINDL questionnaires to evaluate associations with methylation patterns. Results: Methylation levels showed age-related differences. In children under 13, CpG sites displayed mixed methylation, and specific sites correlated with KINDL and BDI-II scores. KINDL physical and total well-being scores negatively correlated with CpG30 and positively with CpG35; BDI-II scores negatively correlated with CpG32 and CpG35. In children aged 13 or older, CpG sites showed uniformly high methylation with no correlation to psychological measures. The SSD group showed significantly higher average methylation across the exon 1F region than controls in the older age group. These children also had more cases of orthostatic dysregulation and longer illness duration. Conclusions: This study suggests age-dependent epigenetic regulation of NR3C1 in SSD. While younger children showed CpG-specific correlations with psychological symptoms, older children demonstrated uniformly high methylation and potentially reduced gene expression, potentially reflecting cumulative stress, autonomic dysfunction, and internalizing disorders such as anxiety and depression.
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Open AccessReview
The Dynamic Interactions of m6A Modification and R-Loops: Implications for Genome Stability
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Nicholas Kim and Hong Sun
Epigenomes 2025, 9(2), 21; https://doi.org/10.3390/epigenomes9020021 - 11 Jun 2025
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R-loops, three-stranded RNA-DNA hybrid nucleic acid structures, are recognized for their roles in both physiological and pathological processes. Regulation of R-loops is critical for genome stability as disruption of R-loop homeostasis can lead to aberrant gene expression, replication stress, and DNA damage. Recent
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R-loops, three-stranded RNA-DNA hybrid nucleic acid structures, are recognized for their roles in both physiological and pathological processes. Regulation of R-loops is critical for genome stability as disruption of R-loop homeostasis can lead to aberrant gene expression, replication stress, and DNA damage. Recent studies suggest that the RNA modification, N6-methyladenosine (m6A), can modify R-loops and the writers, erasers, and readers of m6A are involved in the dynamic regulation of R-loops. Here, we discuss the reported functions of various m6A regulatory proteins in relation to R-loops, highlighting their distinct roles in recognizing and modulating the formation, stability, and resolution of these structures. We further examine the functional implications of m6A and R-loop interaction in human diseases, with a particular emphasis on their roles in cancer.
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Open AccessReview
Epigenetic Insights into Tuberous Sclerosis Complex, Von Hippel–Lindau Syndrome, and Ataxia–Telangiectasia
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Gavriel Hadjigavriel, Christina Stylianides, Evangelos Axarloglou, Maria Eleni Manthou, Efstratios Vakirlis, Paschalis Theotokis, Soultana Meditskou and Iasonas Dermitzakis
Epigenomes 2025, 9(2), 20; https://doi.org/10.3390/epigenomes9020020 - 9 Jun 2025
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Abstract
Neurocutaneous syndromes represent a clinically and genetically heterogeneous group of disorders, with tuberous sclerosis complex (TSC), von Hippel–Lindau syndrome (VHL), and ataxia–telangiectasia (A-T) exemplifying some of the most complex entities within this category. These syndromes have traditionally been considered monogenic disorders, caused by
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Neurocutaneous syndromes represent a clinically and genetically heterogeneous group of disorders, with tuberous sclerosis complex (TSC), von Hippel–Lindau syndrome (VHL), and ataxia–telangiectasia (A-T) exemplifying some of the most complex entities within this category. These syndromes have traditionally been considered monogenic disorders, caused by germline mutations in tumor suppressor or regulatory genes. However, they exhibit a striking degree of phenotypic variability and divergent clinical trajectories that cannot be fully explained by their underlying genetic alterations alone. Increasingly, epigenetic regulatory mechanisms, such as DNA methylation, histone modifications, chromatin remodeling, and non-coding RNA (ncRNA) activity, are recognized as key modulators of gene expression, cellular differentiation, and tissue-specific function. Disruption of these mechanisms has been implicated in disease pathogenesis, tumorigenesis, and neurodegeneration associated with TSC, VHL, and A-T. Aberrant epigenetic profiles may underlie the observed variability in clinical outcomes, even among individuals with identical mutations. This review consolidates current evidence on the epigenetic landscape of these syndromes, elucidating how these modifications may influence disease behavior and contribute to incomplete genotype–phenotype correlations. By integrating epigenetic insights with known molecular pathways, a more nuanced understanding of disease biology emerges, with potential implications for diagnostic stratification, prognostic assessment, and therapeutic innovation.
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(This article belongs to the Collection Feature Papers in Epigenomes)
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Association of Model-Predicted Epigenetic Age and Female Infertility
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Elena Pozdysheva, Vitaly Korchagin, Tatiana Rumyantseva, Daria Ogneva, Vera Zhivotova, Irina Gaponova, Konstantin Mironov and Vasily Akimkin
Epigenomes 2025, 9(2), 19; https://doi.org/10.3390/epigenomes9020019 - 5 Jun 2025
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Background: To date, there are no precise clinical and laboratory methods to accurately predict the onset of fertility decline in women, with chronological age being the ultimate predictor. This has led to increased interest in developing methods to determine biological age, as it
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Background: To date, there are no precise clinical and laboratory methods to accurately predict the onset of fertility decline in women, with chronological age being the ultimate predictor. This has led to increased interest in developing methods to determine biological age, as it provides a more accurate understanding of individual age-related physiological changes. Methods: In this study, we developed a model for estimating biological age based on DNA methylation levels in the ELOVL2, TRIM59, C1orf132, FHL2, and KLF14 genes using pyrosequencing. The model was tested in 64 Russian women, aged 25–39 years, to find an association between epigenetic age, infertility, low anti-Müllerian hormone (AMH) levels, and assisted reproductive technology (ART) failure. Results: The predictive performance of the model was evaluated. The mean absolute deviation of the model was 2.8 years; the mean absolute error was 2.6 years (R2 = 0.95). In the studied cohort, 33% of women exhibited epigenetic age acceleration (EAA), while 45% showed epigenetic age deceleration (EAD). All women with an EAA of ≥3 years (n = 6) had a history of infertility. Conclusions: In this study, no statistically significant associations were observed between EAA/EAD and AMH, body mass index, infertility, or ART failure in women.
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Open AccessReview
DNA Methylation, Aging, and Cancer
by
Himani Vaidya, Jaroslav Jelinek and Jean-Pierre J. Issa
Epigenomes 2025, 9(2), 18; https://doi.org/10.3390/epigenomes9020018 - 3 Jun 2025
Cited by 1
Abstract
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Aging and cancer, though distinct biological processes, share overlapping molecular pathways, particularly in epigenetic regulation. Among these, DNA methylation is central to mediating gene expression, maintaining cellular identity, and regulating genome stability. This review explores how age-associated changes in DNA methylation, characterized by
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Aging and cancer, though distinct biological processes, share overlapping molecular pathways, particularly in epigenetic regulation. Among these, DNA methylation is central to mediating gene expression, maintaining cellular identity, and regulating genome stability. This review explores how age-associated changes in DNA methylation, characterized by both global hypomethylation and focal hypermethylation, contribute to the emergence of cancer. We discuss mechanisms of DNA methylation drift, the development of epigenetic clocks, and the role of entropy and epigenetic mosaicism, in aging and tumorigenesis. Emphasis is placed on how stochastic methylation errors accumulate in aging cells and lead to epiallelic shifts and gene silencing, predisposing tissues to malignant transformation, even despite recently increased cancer incidences at younger ages. We also highlight the translational potential of DNA methylation-based biomarkers, and therapeutic targets, in age-related diseases. By framing cancer as a disease of accelerated epigenetic aging, this review offers a unifying perspective and calls for age-aware approaches to both basic research and clinical oncology.
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Open AccessOpinion
Epigenetic DNA Methylation Under the Influence of Low-Dose Ionizing Radiation, and Supplementation with Vitamin B12 and Folic Acid: Harmful or Beneficial for Professionals?
by
Borivoje Savic, Bozidar Savic and Svetlana Stanojlovic
Epigenomes 2025, 9(2), 17; https://doi.org/10.3390/epigenomes9020017 - 31 May 2025
Abstract
This review paper highlights the importance of educating current and future professionals about epigenetic mechanisms and recognizing epigenetics as a crucial model for protection against ionizing radiation. Two basic models for radiation-induced DNA damage are currently in use. The association between mutations and
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This review paper highlights the importance of educating current and future professionals about epigenetic mechanisms and recognizing epigenetics as a crucial model for protection against ionizing radiation. Two basic models for radiation-induced DNA damage are currently in use. The association between mutations and chromosomal aberrations provides a framework for analyzing risks at low radiation doses and exposure to small doses. However, there is no monitoring of epigenetic changes in professionals exposed to low doses of ionizing radiation. Epigenetic events regulate gene activity and expression not only during cell development and differentiation but also in response to environmental stimuli, such as ionizing radiation. Furthermore, the potential occurrence of malignant and hereditary diseases at low doses of ionizing radiation is linearly correlated and is considered a scientifically accepted assumption, despite recognized scientific limitations associated with this assessment. The aim of this review is to integrate novel and intriguing radiobiological paradigms regarding the effects of ionizing radiation on DNA methylation and epigenetic regulation of the DNA molecule. Several hypothesized biological responses to ionizing radiation are examined, linking them to epigenetic mechanisms involved in health risk assessment for professionals. The second part of the review includes published research related to epigenetics, supplementation, and virus reactivation in the context of epigenetic modifications of the DNA molecule. We hypothesize that different cycles lead to changes in the epigenome, which may be associated with the reactivation of certain viruses and the deficiency of specific dietary elements. These findings are linked to minimal deficiencies in vitamin B12 and folic acid, which may contribute to epigenomic changes. This aspect is crucial for the immune status of individuals working in high-risk environments.
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(This article belongs to the Special Issue Features Papers in Epigenomes 2025)
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Open AccessReview
Genetics and Epigenetics of Chemoinduced Oral Mucositis in Paediatric Patients with Haematological Malignancies—A Review
by
Juliana Ramalho Guimarães, José Maria Chagas Viana Filho and Naila Francis Paulo de Oliveira
Epigenomes 2025, 9(2), 16; https://doi.org/10.3390/epigenomes9020016 - 30 May 2025
Abstract
Background: Oral mucositis (OM) is a painful inflammation resulting from chemotherapy. It is dependent on factors such as age, gender, chemotherapy regimen, oral health, immunological and nutritional status, and genetics. Objectives: The aim of the study was to conduct a narrative review to
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Background: Oral mucositis (OM) is a painful inflammation resulting from chemotherapy. It is dependent on factors such as age, gender, chemotherapy regimen, oral health, immunological and nutritional status, and genetics. Objectives: The aim of the study was to conduct a narrative review to compile studies on the contribution of genetic and epigenetic aspects to the pathogenesis of OM in children with haematological malignancies undergoing chemotherapy treatment. Methods: The literature search was performed in Pubmed, Scopus, Web of Science, Cochrane, Lilacs, and grey literature databases covering articles published since 2010. Results: Twenty-two studies investigating polymorphisms and four studies investigating DNA methylation were included. Polymorphisms in the MTHFR, ABCB1, ABCC2, ABCG2, SLCO1B, miR-1206, miR-3683, CAT, and VDR genes were associated as risk factors for OM and polymorphisms in the TYMS and miR-4268 genes were associated as protective factors. With regard to DNA methylation, associations such as protection or susceptibility to OM have not yet been proven. However, studies have shown that DNMT1 methylation and hypomethylation in total DNA and in the TNF-α gene are associated with recovery of the oral mucosa. Conclusions: Genetic variants are associated with OM in various biological pathways, such as folate metabolism, transport proteins, epigenetic machinery, oxidative stress, and vitamin D metabolism. The DNA methylation profile, which is still poorly understood in the pathogenesis of OM, is associated with mucosal recovery (inflammation and epigenetic machinery). Genetic and epigenetic markers may be tools to indicate a patient’s susceptibility to developing OM, and epigenetic markers may be a target for therapies.
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(This article belongs to the Special Issue Epigenetic Mechanisms of Hematologic Malignancies)
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Open AccessArticle
Histone H3 Lysine 9 Acetylation Plays a Role in Adipogenesis of Periodontal Ligament-Derived Stem Cells
by
Julio A. Montero-Del-Toro, Angelica A. Serralta-Interian, Geovanny I. Nic-Can, Mónica Lamas, Rodrigo A. Rivera-Solís and Beatriz A. Rodas-Junco
Epigenomes 2025, 9(2), 15; https://doi.org/10.3390/epigenomes9020015 - 24 May 2025
Abstract
Background: The epigenetic regulation of adipogenic differentiation in dental stem cells (DSCs) remains poorly understood, as research has prioritized osteogenic differentiation for dental applications. However, elucidating these mechanisms could enable novel regenerative strategies for soft tissue engineering. Periodontal ligament stem cells (PDLSCs) exhibit
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Background: The epigenetic regulation of adipogenic differentiation in dental stem cells (DSCs) remains poorly understood, as research has prioritized osteogenic differentiation for dental applications. However, elucidating these mechanisms could enable novel regenerative strategies for soft tissue engineering. Periodontal ligament stem cells (PDLSCs) exhibit notable adipogenic potential, possibly linked to histone 3 acetylation at lysine 9 (H3K9ac); however, the mechanistic role of this modification remains unclear. Methods: To address this gap, we investigated how histone deacetylase inhibitors (HDACis)—valproic acid (VPA, 8 mM) and trichostatin A (TSA, 100 nM)—modulate H3K9ac dynamics, adipogenic gene expression (C/EBPβ and PPARγ-2), and chromatin remodeling during PDLSCs differentiation. Techniques used included quantitative PCR (qPCR), lipid droplet analysis, and chromatin immunoprecipitation followed by qPCR (ChIP-qPCR). Results: TSA-treated cells exhibited increased lipid deposition with smaller lipid droplets compared to VPA-treated cells. Global H3K9ac levels correlated positively with adipogenic progression. VPA induced early upregulation of C/EBPβ and PPARγ-2 (day 7), whereas TSA triggered a delayed but stronger PPARγ-2 expression. ChIP-qPCR analysis revealed significant H3K9ac enrichment at the PPARγ-2 promoter in TSA-treated cells, indicating enhanced chromatin accessibility. Conclusions: These findings demonstrate that H3K9ac-mediated epigenetic remodeling plays a critical role in the adipogenic differentiation of PDLSCs and identifies TSA as a potential tool for modulating this process.
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(This article belongs to the Collection Epigenetic Regulation of Cellular Differentiation)
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