Epigenomes

22 pages, 2660 KiB

Open AccessArticle

Arabidopsis thaliana Roots Exposed to Extracellular Self-DNA: Evidence of Epigenetic Effects

by Alessia Ronchi, Guido Incerti, Emanuele De Paoli, Speranza Claudia Panico, Giovanni Luca Sciabbarrasi, Pasquale Termolino, Fabrizio Cartenì, Mariachiara Langella, Maria Luisa Chiusano and Stefano Mazzoleni

Epigenomes 2025, 9(2), 13; https://doi.org/10.3390/epigenomes9020013 - 30 Apr 2025

Abstract

Background: Previous evidence demonstrated DNA methylation changes in response to stress in plants, showing rapid changes within a limited time frame. Exposure to self-DNA inhibits seedling root elongation, and it was shown that it causes changes in CG DNA methylation in Lactuca sativa [...] Read more.

Background: Previous evidence demonstrated DNA methylation changes in response to stress in plants, showing rapid changes within a limited time frame. Exposure to self-DNA inhibits seedling root elongation, and it was shown that it causes changes in CG DNA methylation in Lactuca sativa. We assessed cytosine methylation changes and associated gene expression patterns in roots of Arabidopsis thaliana Col-0 seedlings exposed to self-DNA for 6 and 24 h. Methods: We used whole genome bisulfite sequencing (WGBS) and RNA-seq analyses to assess genomic cytosine methylation and corresponding gene expression, respectively, on DNA and RNA extracted with commercial kits from roots exposed to self-DNA by an original setup. Fifteen hundred roots replicates, including the control in distilled water, were collected after exposure. Sequencing was performed on a NovaSeq 6000 platform and Ultralow Methyl-Seq System for RNA and DNA WGBS, respectively. Results: Gene expression in roots exposed to self-DNA differed from that of untreated controls, with a total of 305 genes differentially expressed and 87 ontologies enriched in at least one treatment vs. control comparison, and particularly after 24 h of exposure. DNA methylation, particularly in CHG and CHH contexts, was also different, with hyper- and hypomethylation prevailing in treatments vs. controls at 6 h and 24 h, respectively. Differentially expressed genes (DEGs) analysis, Gene Ontology (GO) enrichment analysis, and differentially methylated regions (DMRs) analysis, provided an integrated understanding of the changes associated with self-DNA exposure. Our results suggest differential gene expression associated with DNA methylation in response to self-DNA exposure in A. thaliana roots, enhanced after prolonged exposure. Conclusions: Main functional indications of association between DNA methylation and gene expression involved hypomethylation and downregulation of genes related to nucleotide/nucleoside metabolism (ATP synthase subunit) and cell wall structure (XyG synthase), consistent with previous observations from metabolomics and physiological studies. Further confirmation of these findings will contribute to improving our understanding of the plant molecular response to self-DNA and its implications in stress responses. Full article

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

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11 pages, 474 KiB

Open AccessArticle

The Effect of Clinical Factors on the Reversion of Cg05575921 Methylation in Smoking Cessation

by Robert Philibert, Steven R. H. Beach, Michelle R. vanDellen, James A. Mills and Jeffrey D. Long

Epigenomes 2025, 9(2), 12; https://doi.org/10.3390/epigenomes9020012 - 28 Apr 2025

Abstract

Background: Financial Incentive Treatments (FIT) can be effective in the treatment of smoking. However, weaknesses in current biochemical approaches for assessing smoking cessation may hinder its implementation, particularly for management of long-term smoking cessation. The use of cg05575921 methylation assessments could address some [...] Read more.

Background: Financial Incentive Treatments (FIT) can be effective in the treatment of smoking. However, weaknesses in current biochemical approaches for assessing smoking cessation may hinder its implementation, particularly for management of long-term smoking cessation. The use of cg05575921 methylation assessments could address some of the shortcomings of current self-report and non-self-report methods, but additional information is needed about the speed of methylation reversion as a function of key clinical and demographic variables. Methods: To better understand those relationships, we analyzed data from 3040 subjects from the National Lung Screening Trial (NLST), including 1552 self-reported quitters. Results: Plotting of the data as a function of time since quitting shows that methylation increases approximately 14%, on average, after at least one full year of cessation with a subsequent slow non-linear increase in methylation over the next 14 years. Least Squares Regression modeling shows strong effects of quit time and a modest, yet significant, effect of body mass index (BMI) on the rate of reversion. Prior cigarette consumption characteristics and sex made modest contributions as well, with the latter largely offset by pre-cessation methylation levels. Race and age were not significant factors in the models. Conclusions: When combined with data from prior studies, these analyses of the long-term reversion of cg05575921 methylation will be informative to those considering FIT approaches to incentivizing reversion of cg05575921 as an index of short- and long-term smoking cessation. Full article

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

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13 pages, 514 KiB

Open AccessReview

Induction of DNA Demethylation: Strategies and Consequences

by Pietro Salvatore Carollo and Viviana Barra

Epigenomes 2025, 9(2), 11; https://doi.org/10.3390/epigenomes9020011 - 12 Apr 2025

Abstract

DNA methylation is an important epigenetic modification with a plethora of effects on cells, ranging from the regulation of gene transcription to shaping chromatin structure. Notably, DNA methylation occurs thanks to the activity of DNA methyltransferases (DNMTs), which covalently add a methyl group [...] Read more.

DNA methylation is an important epigenetic modification with a plethora of effects on cells, ranging from the regulation of gene transcription to shaping chromatin structure. Notably, DNA methylation occurs thanks to the activity of DNA methyltransferases (DNMTs), which covalently add a methyl group to the cytosine in position 5′ in CpG dinucleotides. Different strategies have been developed to study the effects of DNA methylation in cells, involving either DNMTs inhibition (passive DNA demethylation) or the use of Ten-eleven translocation protein (TET) family enzymes, which directly demethylate DNA (active DNA demethylation). In this manuscript, we will briefly cover the most commonly used strategies in the last two decades to achieve DNA demethylation, along with their effects on cells. We will also discuss some of the newest inducible ways to inhibit DNMTs without remarkable side effects, as well as the effect of non-coding RNAs on DNA methylation. Lastly, we will briefly examine the use of DNA methylation inhibition in biomedical research. Full article

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

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Graphical abstract

27 pages, 3184 KiB

Open AccessReview

The Good, the Bad, and the Epigenetic: Stress-Induced Metabolite Regulation and Transgenerational Effects

by Saida Ibragić, Sabina Dahija and Erna Karalija

Epigenomes 2025, 9(2), 10; https://doi.org/10.3390/epigenomes9020010 - 29 Mar 2025

Cited by 1

Abstract

Background: Plants face a wide range of environmental stresses that disrupt growth and productivity. To survive and adapt, they undergo complex metabolic reprogramming by redirecting carbon and nitrogen fluxes toward the biosynthesis of protective secondary metabolites such as phenylpropanoids, flavonoids, and lignin. Recent [...] Read more.

Background: Plants face a wide range of environmental stresses that disrupt growth and productivity. To survive and adapt, they undergo complex metabolic reprogramming by redirecting carbon and nitrogen fluxes toward the biosynthesis of protective secondary metabolites such as phenylpropanoids, flavonoids, and lignin. Recent research has revealed that these stress-induced metabolic processes are tightly regulated by epigenetic mechanisms, including DNA methylation, histone modifications, chromatin remodeling, and non-coding RNAs. Methods: This review synthesizes current findings from studies on both model and crop plants, examining the roles of key epigenetic regulators in controlling secondary metabolism under stress. Special focus is placed on dynamic changes in DNA methylation, histone acetylation, and the action of small RNAs such as siRNAs and miRNAs in transcriptional and post-transcriptional regulation. Results: Evidence indicates that stress triggers rapid and reversible epigenetic modifications that modulate gene expression linked to secondary metabolic pathways. These modifications not only facilitate immediate metabolic responses but can also contribute to stress memory. In some cases, this memory is retained and transmitted to the next generation, influencing progeny stress responses. However, critical knowledge gaps remain, particularly concerning the temporal dynamics, tissue specificity, and long-term stability of these epigenetic marks in crops. Conclusions: Understanding how epigenetic regulation governs secondary metabolite production offers promising avenues to enhance crop resilience and productivity in the context of climate change. Future research should prioritize dissecting the stability and heritability of these modifications to support the development of epigenetically informed breeding strategies. Full article

(This article belongs to the Collection Epigenetic Control in Plants)

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14 pages, 1099 KiB

Open AccessArticle

The Association of Childhood Allergic Diseases with Prenatal Exposure to Pollen Grains Through At-Birth DNA Methylation

by Rajesh Melaram, Hongmei Zhang, James Adefisoye and Hasan Arshad

Epigenomes 2025, 9(1), 9; https://doi.org/10.3390/epigenomes9010009 - 11 Mar 2025

Abstract

Background: Pollen exposure in early life is shown to be associated with allergy and asthma. DNA methylation (DNAm), an epigenetic marker, potentially reacts to pollen. However, the role of at-birth DNAm between prenatal pollen grain (PPG) exposure and childhood asthma and allergic rhinitis [...] Read more.

Background: Pollen exposure in early life is shown to be associated with allergy and asthma. DNA methylation (DNAm), an epigenetic marker, potentially reacts to pollen. However, the role of at-birth DNAm between prenatal pollen grain (PPG) exposure and childhood asthma and allergic rhinitis is unknown. Methods: Data in a birth cohort study on the Isle of Wight, UK, were analyzed (n = 236). Newborn DNAm was measured in cord blood or blood spots on Guthrie cards and screened for potential association with PPG exposure using the R package ttScreening. CpGs that passed screening were further assessed for such associations via linear regressions with adjusting covariates included. Finally, DNAm at PPG-associated CpGs were evaluated for their association with asthma and allergic rhinitis using logistic regressions, adjusting for covariates. The impact of cell heterogeneity on the findings was assessed. Statistical significance was set at p < 0.05. Results: In total, 42 CpGs passed screening, with 41 remaining statistically significant after adjusting for covariates and cell types (p < 0.05). High PPG exposure was associated with lower DNAm at cg12318501 (ZNF99, β = −0.029, p = 0.032) and cg00929606 (ADM2, β = −0.023, p = 0.008), which subsequently was associated with decreased odds of asthma (OR = 0.11, 95% CI 0.02–0.53, p = 0.006; OR = 0.14, 95% CI 0.02–1.00, p = 0.049). For rhinitis, cg15790214 (HCG11) was shown to play such a role as a mediator (β = −0.027, p ≤ 0.0001; OR = 0.22, 95% CI 0.07–0.72, p = 0.01). Conclusions: The association of PPG exposure with childhood asthma and allergic rhinitis incidence is potentially mediated by DNAm at birth. Full article

(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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23 pages, 5026 KiB

Open AccessArticle

Investigating Single-Molecule Molecular Inversion Probes for Medium-Scale Targeted DNA Methylation Analysis

by Roy B. Simons, Hieab H. H. Adams, Manfred Kayser and Athina Vidaki

Epigenomes 2025, 9(1), 8; https://doi.org/10.3390/epigenomes9010008 - 2 Mar 2025

Abstract

Background: Epigenetic biomarkers, particularly CpG methylation, are increasingly employed in clinical and forensic settings. However, we still lack a cost-effective, sensitive, medium-scale method for the analysis of hundreds to thousands of user-defined CpGs suitable for minute DNA input amounts (<10 ng). In this [...] Read more.

Background: Epigenetic biomarkers, particularly CpG methylation, are increasingly employed in clinical and forensic settings. However, we still lack a cost-effective, sensitive, medium-scale method for the analysis of hundreds to thousands of user-defined CpGs suitable for minute DNA input amounts (<10 ng). In this study, motivated by promising results in the genetics field, we investigated single-molecule molecular inversion probes (smMIPs) for simultaneous analysis of hundreds of CpGs by using an example set of 514 age-associated CpGs (Zhang model). Methods: First, we developed a novel smMIP design tool to suit bisulfite-converted DNA (Locksmith). Then, to optimize the capture process, we performed single-probe capture for ten selected, representative smMIPs. Based on this pilot, the full smMIP panel was tested under varying capture conditions, including hybridization and elongation temperature, smMIP and template DNA amounts, dNTP concentration and elongation time. Results: Overall, we found that the capture efficiency was highly probe-(and hence, sequence-) dependent, with a heterogeneous coverage distribution across CpGs higher than the 1000-fold range. Considering CpGs with at least 20X coverage, we yielded robust methylation detection with levels comparable to those obtained from the gold standard EPIC microarray analysis (Pearsons’s r: 0.96). Conclusions: The observed low specificity and uniformity indicate that smMIPs in their current form are not compatible with the lowered complexity of bisulfite-converted DNA. Full article

(This article belongs to the Special Issue A Commemorative Issue in Honor of the 30th Anniversary of the Epigenetics Society)

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21 pages, 3570 KiB

Open AccessArticle

Isothiocyanates Enhance the Anti-Melanoma Effect of Zebularine Through Modulation of Apoptosis and Regulation of DNMTs’ Expression, Chromatin Configuration and Histone Posttranslational Modifications Associated with Altered Gene Expression Patterns

by Ioannis Anestopoulos, Ioannis Paraskevaidis, Sotiris Kyriakou, Louiza Potamiti, Dimitrios T. Trafalis, Sotiris Botaitis, Rodrigo Franco, Aglaia Pappa and Mihalis I. Panayiotidis

Epigenomes 2025, 9(1), 7; https://doi.org/10.3390/epigenomes9010007 - 25 Feb 2025

Abstract

Background: In the present study, we aimed to characterize the cytotoxic efficacy of Zebularine either as a single agent or in combination with various isothiocyanates in an in vitro model consisting of human melanoma (A375, Colo-679) as well as non-tumorigenic immortalized keratinocyte (HaCaT) [...] Read more.

Background: In the present study, we aimed to characterize the cytotoxic efficacy of Zebularine either as a single agent or in combination with various isothiocyanates in an in vitro model consisting of human melanoma (A375, Colo-679) as well as non-tumorigenic immortalized keratinocyte (HaCaT) cells. Methods: In this model, we have evaluated the anti-melanoma effect of Zebularine (in single and combinatorial protocols) in terms of cell viability, apoptotic induction and alterations in ultrastructural chromatin configuration, protein expression levels of DNA methyltransferases (DNMTs) and associated histone epigenetic marks capable of mediating gene expression. Results: Exposure to Zebularine resulted in dose- and time-dependent cytotoxicity through apoptotic induction in malignant melanoma cells, while neighboring non-tumorigenic keratinocytes remained unaffected. A more profound response was observed in combinational protocols, as evidenced by a further decline in cell viability leading to an even more robust apoptotic induction followed by a differential response (i.e., activation/de-activation) of various apoptotic genes. Furthermore, combined exposure protocols caused a significant decrease of DNMT1, DNMT3A and DNMT3B protein expression levels together with alterations in ultrastructural chromatin configuration and protein expression levels of specific histone modification marks capable of modulating gene expression. Conclusions: Overall, we have developed a novel experimental approach capable of potentiating the cytotoxic efficacy of Zebularine against human malignant melanoma cells while at the same time maintaining a non-cytotoxic profile against neighboring non-tumorigenic keratinocyte (HaCaT) cells. Full article

(This article belongs to the Collection Epigenetics of Melanoma)

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14 pages, 5219 KiB

Open AccessArticle

Novel Epigenetics Control (EpC) Nanocarrier for Cancer Therapy Through Dual-Targeting Approach to DNA Methyltransferase and Ten-Eleven Translocation Enzymes

by Risa Mitsuhashi, Kiyoshi Sato and Hiroyoshi Kawakami

Epigenomes 2025, 9(1), 6; https://doi.org/10.3390/epigenomes9010006 - 11 Feb 2025

Abstract

Background/Objectives: Aberrant hypermethylation in the promoter regions of tumor suppressor genes facilitates the pathogenesis and progression of cancer. Therefore, inhibitors targeting DNA methyltransferase (DNMT) have been tested in clinical studies. However, the current monotherapy of DNMT inhibitors shows limited efficacy. Furthermore, the mechanism [...] Read more.

Background/Objectives: Aberrant hypermethylation in the promoter regions of tumor suppressor genes facilitates the pathogenesis and progression of cancer. Therefore, inhibitors targeting DNA methyltransferase (DNMT) have been tested in clinical studies. However, the current monotherapy of DNMT inhibitors shows limited efficacy. Furthermore, the mechanism of action of DNMT inhibitors is DNA replication-dependent. To address these limitations, we developed a novel core–shell-type “epigenetics control (EpC) nanocarrier” that encapsulated decitabine (5-aza-dC) in the PLGA core nanoparticle and hybridized TET1 gene-encoding pDNA on the lipid shell surface. This study aimed to evaluate whether the dual delivery of DNMT inhibitors and pDNA of TET1 could synergistically enhance tumor suppressor gene expression and induce cell cycle arrest and/or apoptosis in cancer cells. Herein, we demonstrate the potential of the EpC carrier in HCT116 human colon cancer cells to upregulate tumor suppressor gene expression and rapidly achieve cell cycle arrest. Methods: PLGA core nanoparticles were prepared by the W/O/W double emulsion method. The formation of core–shell nanoparticles and complexation with pDNA were investigated and optimized by dynamic light scattering, zeta potential measurement, and agarose gel electrophoresis. The cellular uptake and transfection efficiency were measured by confocal laser scanning microscopy and a luciferase assay, respectively. The expression of p53 protein was detected by Western blotting. The anti-tumor effects of the EpC nanocarrier were evaluated by cell cycle analysis and an apoptosis assay. Results: The EpC nanocarrier delivered the DNMT inhibitor and TET gene-encoding pDNA into HCT116 cells. It promoted the expression of the tumor suppressor protein p53 and induced rapid cell cycle arrest in the G2/M phase in HCT116 cells. Conclusions: Our findings suggest that the dual-targeting of DNMT and TET enzymes effectively repairs aberrant DNA methylation and induces growth arrest in cancer cells, and the dual-targeting strategy may contribute to the advancement of epigenetic cancer therapy. Full article

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

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25 pages, 5961 KiB

Open AccessReview

Epigenomic Echoes—Decoding Genomic and Epigenetic Instability to Distinguish Lung Cancer Types and Predict Relapse

by Alexandra A. Baumann, Zholdas Buribayev, Olaf Wolkenhauer, Amankeldi A. Salybekov and Markus Wolfien

Epigenomes 2025, 9(1), 5; https://doi.org/10.3390/epigenomes9010005 - 5 Feb 2025

Abstract

Genomic and epigenomic instability are defining features of cancer, driving tumor progression, heterogeneity, and therapeutic resistance. Central to this process are epigenetic echoes, persistent and dynamic modifications in DNA methylation, histone modifications, non-coding RNA regulation, and chromatin remodeling that mirror underlying genomic chaos [...] Read more.

Genomic and epigenomic instability are defining features of cancer, driving tumor progression, heterogeneity, and therapeutic resistance. Central to this process are epigenetic echoes, persistent and dynamic modifications in DNA methylation, histone modifications, non-coding RNA regulation, and chromatin remodeling that mirror underlying genomic chaos and actively influence cancer cell behavior. This review delves into the complex relationship between genomic instability and these epigenetic echoes, illustrating how they collectively shape the cancer genome, affect DNA repair mechanisms, and contribute to tumor evolution. However, the dynamic, context-dependent nature of epigenetic changes presents scientific and ethical challenges, particularly concerning privacy and clinical applicability. Focusing on lung cancer, we examine how specific epigenetic patterns function as biomarkers for distinguishing cancer subtypes and monitoring disease progression and relapse. Full article

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

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19 pages, 2372 KiB

Open AccessArticle

Single-Molecule Nanopore Sequencing of the CpG Island from the Promoter of O6-Methylguanine-DNA Methyltransferase Provides Insights into the Mechanism of De Novo Methylation of G/C-Rich Regions

by Alexander V. Sergeev, Daniil P. Malyshev, Adelya I. Genatullina, Galina V. Pavlova, Elizaveta S. Gromova and Maria I. Zvereva

Epigenomes 2025, 9(1), 4; https://doi.org/10.3390/epigenomes9010004 - 26 Jan 2025

Cited by 1

Abstract

Background: The methylation of cytosine residues at CpG sites within the O6-methylguanine-DNA methyltransferase (MGMT) promoter is a key biomarker in glioblastoma therapy. The MGMT promoter (MGMTp) contains multiple guanine-rich sequences capable of folding into G-quadruplexes (G4s), but their relevance for MGMTp [...] Read more.

Background: The methylation of cytosine residues at CpG sites within the O6-methylguanine-DNA methyltransferase (MGMT) promoter is a key biomarker in glioblastoma therapy. The MGMT promoter (MGMTp) contains multiple guanine-rich sequences capable of folding into G-quadruplexes (G4s), but their relevance for MGMTp methylation is poorly understood. Objectives: Our study explores the impact of potential G-quadruplex-forming sequences (PQS) in the MGMT promoter CpG island on the activity of de novo DNA methyltransferase Dnmt3a. Additionally, we investigate their influence on the accuracy of methylation pattern detection using nanopore sequencing. Methods: Nanopore sequencing was employed to analyze the methylation of 94 clinically significant CpG sites in the human MGMTp using an in vitro de novo methylation system. Circular dichroism spectroscopy was used to identify G4 structures within the MGMTp CpG island. Interactions between the catalytic domain of Dnmt3a and the PQS from the MGMTp were examined by biolayer interferometry. Results: Guanine-rich DNA strands of the PQSs in the MGMTp were hypomethylated, while the complementary cytosine-rich strands were methylated by DNA methyltransferase Dnmt3a with higher efficiency. The accuracy of detecting modified bases in the PQS was significantly lower compared to surrounding sequences. Single-stranded guanine-rich DNA sequences from the MGMTp exhibited strong binding to Dnmt3a-CD, with an affinity approximately 10 times higher than their cytosine-rich complements (K_d = 3 × 10⁻⁸ M and 3 × 10⁻⁷ M, respectively). By binding to Dnmt3a, G4-forming oligonucleotides from MGMTp effectively inhibited the methylation reaction (IC₅₀ 6 × 10⁻⁷ M). Conclusions: The obtained data indicate the role of PQSs in establishing de novo methylation of the MGMT promoter. They also highlight the challenges of sequencing guanine-rich regions and the impact of specific de novo methylation patterns on clinical data interpretation. Full article

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24 pages, 1725 KiB

Open AccessReview

Epigenetics in Skin Homeostasis and Ageing

by Iasonas Dermitzakis, Stella Aikaterini Kyriakoudi, Sofia Chatzianagnosti, Despoina Chatzi, Efstratios Vakirlis, Soultana Meditskou, Maria Eleni Manthou and Paschalis Theotokis

Epigenomes 2025, 9(1), 3; https://doi.org/10.3390/epigenomes9010003 - 9 Jan 2025

Abstract

The skin, the largest organ of the human body, plays numerous essential roles, including protection against environmental hazards and the regulation of body temperature. The processes of skin homeostasis and ageing are complex and influenced by many factors, with epigenetic mechanisms being particularly [...] Read more.

The skin, the largest organ of the human body, plays numerous essential roles, including protection against environmental hazards and the regulation of body temperature. The processes of skin homeostasis and ageing are complex and influenced by many factors, with epigenetic mechanisms being particularly significant. Epigenetics refers to the regulation of gene expression without altering the underlying DNA sequence. The dynamic nature of the skin, characterized by constant cellular turnover and responsiveness to environmental stimuli, requires precise gene activity control. This control is largely mediated by epigenetic modifications such as DNA methylation, histone modification, and regulation by non-coding RNAs. The present review endeavours to provide a comprehensive exploration and elucidation of the role of epigenetic mechanisms in regulating skin homeostasis and ageing. By integrating our current knowledge of epigenetic modifications with the latest advancements in dermatological research, we can gain a deeper comprehension of the complex regulatory networks that govern skin biology. Understanding these mechanisms also presents promising avenues for therapeutic interventions aimed at improving skin health and mitigating age-related skin conditions. Full article

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17 pages, 1510 KiB

Open AccessReview

DNA and RNA Methylation in Rheumatoid Arthritis—A Narrative Review

by Kajetan Kiełbowski, Estera Bakinowska, Anna Gorący-Rosik, Karolina Figiel, Roksana Judek, Jakub Rosik, Paweł Dec, Andrzej Modrzejewski and Andrzej Pawlik

Epigenomes 2025, 9(1), 2; https://doi.org/10.3390/epigenomes9010002 - 8 Jan 2025

Abstract

Rheumatoid arthritis (RA) is a progressive autoimmune disease leading to structural and functional joint damage and, eventually, to physical disability. The pathogenesis of the disease is highly complex and involves interactions between fibroblast-like synoviocytes (FLSs) and immune cells, which stimulate the secretion of [...] Read more.

Rheumatoid arthritis (RA) is a progressive autoimmune disease leading to structural and functional joint damage and, eventually, to physical disability. The pathogenesis of the disease is highly complex and involves interactions between fibroblast-like synoviocytes (FLSs) and immune cells, which stimulate the secretion of pro-inflammatory factors, leading to chronic inflammation. In recent years, studies have demonstrated the importance of epigenetics in RA. Specifically, epigenetic alterations have been suggested to serve as diagnostic and treatment biomarkers, while epigenetic mechanisms are thought to be involved in the pathogenesis of RA. Epigenetic regulators coordinate gene expression, and in the case of inflammatory diseases, they regulate the expression of a broad range of inflammatory molecules. In this review, we discuss current evidence on the involvement of DNA and RNA methylation in RA. Full article

(This article belongs to the Special Issue The Interplay Between Epigenetics and Inflammation in Chronic Diseases)

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20 pages, 2480 KiB

Open AccessReview

Two Clinically Implementable Digital PCR Assessments of DNA Methylation for Diagnosing Heavy Alcohol Consumption

by Robert Philibert, Steven R. H. Beach and Allan M. Andersen

Epigenomes 2025, 9(1), 1; https://doi.org/10.3390/epigenomes9010001 - 24 Dec 2024

Abstract

Background: Heavy alcohol consumption (HAC) has a profound adverse effect on human health. Unfortunately, there is a relative lack of tools that are easily implementable in clinical settings and that can be used to supplement self-reporting in the diagnosis and management of HAC. [...] Read more.

Background: Heavy alcohol consumption (HAC) has a profound adverse effect on human health. Unfortunately, there is a relative lack of tools that are easily implementable in clinical settings and that can be used to supplement self-reporting in the diagnosis and management of HAC. In part, this paucity is due to limitations of currently available biological measures and a mismatch between available biological measures and the needs of clinicians managing HAC. Objectives: We first review the pros and cons of existing biological measures. Next, we review the underlying theory and the performance characteristics of two recently developed methylation-sensitive digital PCR (MSdPCR) assays, referred to as the Alcohol T Score (ATS) and ZSCAN25, for the assessment of chronic and recent HAC, respectively. Finally, we outline a paradigm for improving the clinical diagnosis and management of alcohol use disorders by utilizing these new markers of alcohol consumption. Conclusions: We conclude that further studies to understand the test performance characteristics of each of these epigenetic tools in larger, diverse populations are in order. Full article

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

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16 pages, 2789 KiB

Open AccessArticle

Epigenome-Wide and Methylation Risk Score Analysis of Body Mass Index Among People with HIV

by Nanzha Abi, Alexandra Young, Pradeep Tiwari, Junyu Chen, Chang Liu, Qin Hui, Kaku So-Armah, Matthew S. Freiberg, Amy C. Justice, Ke Xu, Marta Gwinn, Vincent C. Marconi and Yan V. Sun

Epigenomes 2024, 8(4), 46; https://doi.org/10.3390/epigenomes8040046 - 12 Dec 2024

Abstract

Background/Objectives: People with HIV (PWH) on antiretroviral therapy (ART) often gain weight, which increases their risk of type 2 diabetes and cardiovascular disease. The role of DNA methylation (DNAm) markers in obesity among PWH is understudied. This research explores the relationship between body [...] Read more.

Background/Objectives: People with HIV (PWH) on antiretroviral therapy (ART) often gain weight, which increases their risk of type 2 diabetes and cardiovascular disease. The role of DNA methylation (DNAm) markers in obesity among PWH is understudied. This research explores the relationship between body mass index (BMI) and epigenetic patterns to better understand and manage obesity-related risks in PWH. Methods: We conducted an epigenome-wide association study (EWAS) on 892 African American male PWH from the Veterans Aging Cohort Study, examining BMI associations with DNAm using linear mixed models, adjusting for covariates, including soluble CD14. We compared our results with BMI-associated DNAm markers from non-HIV individuals and developed a methylation risk score (MRS) for BMI using machine learning and a cross-validation approach. Results: We identified four epigenome-wide significant CpG sites, including one in the RAP1B gene, indicating shared and unique BMI-related epigenetic markers between PWH and non-HIV individuals. The constructed BMI MRS explained approximately 19% of the BMI variance in PWH. Conclusions: DNAm markers and MRS are significantly linked to BMI in PWH, suggesting shared and distinct molecular mechanisms with non-HIV populations. These insights could lead to targeted interventions to reduce cardiometabolic disease risks in PWH under ART. Full article

(This article belongs to the Collection Epigenetic Mechanisms in Diabetes Research)

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16 pages, 1855 KiB

Open AccessArticle

DNA Imprinting and Differentially Expressed Genes in Longissimus thoracis Muscle of Bos indicus Submitted to Early Weaning Management

by Gustavo Tinoco, Gustavo Russo, Rogério Curi, Marcelo Vicari, Paloma Melo, Isabella Souza, Juliana Torrecilhas, Philipe Moriel, Welder Baldassini, Luis Chardulo, Otávio Neto and Guilherme Pereira

Epigenomes 2024, 8(4), 45; https://doi.org/10.3390/epigenomes8040045 - 4 Dec 2024

Cited by 1

Abstract

Background/Objectives: Early weaning management followed by energy supplementation can lead to metabolic alterations in the calf that exert long-term effects on the animal’s health and performance. It is believed that the main molecular basis underlying these metabolic adaptations are epigenetic mechanisms that regulate, [...] Read more.

Background/Objectives: Early weaning management followed by energy supplementation can lead to metabolic alterations in the calf that exert long-term effects on the animal’s health and performance. It is believed that the main molecular basis underlying these metabolic adaptations are epigenetic mechanisms that regulate, activate, or silence genes at different stages of development and/or in response to different environmental stimuli. However, little is known about postnatal metabolic programming in Bos indicus. Therefore, this study aimed to compare the DNA methylation profile of Nellore animals submitted to conventional and early weaning and to correlate the findings with genes differentially expressed in the Longissimus thoracis skeletal muscle of Bos indicus cattle. Methods: For this, we used Reduced Representation Bisulfite Sequencing (RRBS) and RNA-Sequencing techniques to prospect differentially methylated genes (DMGs). Results: A total of 481 differentially methylated regions were identified, with 52% (250) being hypermethylated and 48% (231) hypomethylated. Functional enrichment analysis of 53 differentially methylated and differentially expressed genes was performed. The main enriched terms and pathways were associated with 3′-5′-cyclic adenosine monophosphate (cAMP) signaling, which presents the upregulated adenylate cyclase 3 (ADCY3) gene and significatively hypomethylated in the promoter region. Alterations in cAMP signaling are involved in numerous processes, many of them related to lipid metabolism. The relative differential expression of key genes of this pathway demonstrates the relationship between cAMP signaling and de novo lipogenesis. Conclusions: These findings suggest an important role of postnatal metabolic programming through DNA methylation mechanisms in determining fat deposition in beef. Full article

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

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18 pages, 1760 KiB

Open AccessArticle

Environmental Factor Index (EFI): A Novel Approach to Measure the Strength of Environmental Influence on DNA Methylation in Identical Twins

by Yoichi Takenaka, Osaka Twin Research Group and Mikio Watanabe

Epigenomes 2024, 8(4), 44; https://doi.org/10.3390/epigenomes8040044 - 21 Nov 2024

Cited by 1

Abstract

Background/Objectives: The dynamic interaction between genomic DNA, epigenetic modifications, and phenotypic traits was examined in identical twins. Environmental perturbations can induce epigenetic changes in DNA methylation, influencing gene expression and phenotypes. Although DNA methylation mediates gene-environment correlations, the quantitative effects of external factors [...] Read more.

Background/Objectives: The dynamic interaction between genomic DNA, epigenetic modifications, and phenotypic traits was examined in identical twins. Environmental perturbations can induce epigenetic changes in DNA methylation, influencing gene expression and phenotypes. Although DNA methylation mediates gene-environment correlations, the quantitative effects of external factors on DNA methylation remain underexplored. This study aimed to quantify these effects using a novel approach. Methods: A cohort study was conducted on healthy monozygotic twins to evaluate the influence of environmental stimuli on DNA methylation. We developed the Environmental Factor Index (EFI) to identify methylation sites showing statistically significant changes in response to environmental stimuli. We analyzed the identified sites for associations with disorders, DNA methylation markers, and CpG islands. Results: The EFI identified methylation sites that exhibited significant associations with genes linked to various disorders, particularly cancer. These sites were overrepresented on CpG islands compared to other genomic features, highlighting their regulatory importance. Conclusions: The EFI is a valuable tool for understanding the molecular mechanisms underlying disease pathogenesis. It provides insights into the development of preventive and therapeutic strategies and offers a new perspective on the role of environmental factors in epigenetic regulation. Full article

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

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10 pages, 1876 KiB

Open AccessArticle

Age-Dependent DNA Methylation Variability on the X-Chromosome in Male and Female Twins

by Qihua Tan, Hikmat Alo, Marianne Nygaard, Mette Sørensen, Alisa Saleh, Jonas Mengel-From and Kaare Christensen

Epigenomes 2024, 8(4), 43; https://doi.org/10.3390/epigenomes8040043 - 18 Nov 2024

Abstract

We aimed to explore the age-dependent epigenetic variability on the X-chromosome with consideration of X-chromosome inactivation by applying a sex-stratified regression analysis to DNA methylation array data on X-linked CpGs in aging identical twins. We found 13 X-linked CpGs showing age-related significant increase [...] Read more.

We aimed to explore the age-dependent epigenetic variability on the X-chromosome with consideration of X-chromosome inactivation by applying a sex-stratified regression analysis to DNA methylation array data on X-linked CpGs in aging identical twins. We found 13 X-linked CpGs showing age-related significant increase in variability in males (FDR < 0.05) but none in females. In females, we found a significantly higher proportion of CpGs showing increased variability with age among nominally significant (p < 0.05) CpGs under inactivation, but not among CpGs escaping inactivation. Survival analysis showed a slight trend of correlation by directional change in the variable CpGs with mortality in males. Compared with females, the male X-chromosome can be more vulnerable to epigenetic instability during aging. Full article

(This article belongs to the Special Issue X-Chromosome Inactivation)

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8 pages, 694 KiB

Open AccessOpinion

Histone Modification Pathways Suppressing Cryptic Transcription

by Hong-Yeoul Ryu

Epigenomes 2024, 8(4), 42; https://doi.org/10.3390/epigenomes8040042 - 12 Nov 2024

Abstract

Cryptic transcription refers to the unintended expression of non-canonical sites within the genome, producing aberrant RNA and proteins that may disrupt cellular functions. In this opinion piece, I will explore the role of histone modifications in modulating cryptic transcription and its implications for [...] Read more.

Cryptic transcription refers to the unintended expression of non-canonical sites within the genome, producing aberrant RNA and proteins that may disrupt cellular functions. In this opinion piece, I will explore the role of histone modifications in modulating cryptic transcription and its implications for gene expression and cellular integrity, particularly with a focus on H3K36 and H3K4 methylation marks. H3K36 tri-methylation plays a crucial role in maintaining chromatin integrity by facilitating the recruitment of the Rpd3S histone deacetylase (HDAC) complex, which helps restore closed chromatin states following transcription and prevents cryptic initiation within gene bodies. In parallel, crosstalk between H3K4 di-methylation and histone ubiquitylation and sumoylation is critical for recruiting the Set3 HDAC complex, which maintains low histone acetylation levels in gene bodies and further suppresses cryptic transcription. Therefore, by elucidating these regulatory mechanisms, this opinion highlights the intricate interplay of histone modifications in preserving transcriptional fidelity and suggests potential pathways for future research to develop novel therapies for age-related disorders and other diseases associated with dysregulated gene expression. Full article

(This article belongs to the Special Issue Histone Variants)

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12 pages, 883 KiB

Open AccessReview

Epigenetic Landscape of DNA Methylation in Pancreatic Ductal Adenocarcinoma

by Peiyi Liu, Juliette Jacques and Chang-Il Hwang

Epigenomes 2024, 8(4), 41; https://doi.org/10.3390/epigenomes8040041 - 3 Nov 2024

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, characterized by its aggressive progression and dismal prognosis. Advances in epigenetic profiling, specifically DNA methylation analysis, have significantly deepened our understanding of PDAC pathogenesis. This review synthesizes findings from recent genome-wide DNA [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, characterized by its aggressive progression and dismal prognosis. Advances in epigenetic profiling, specifically DNA methylation analysis, have significantly deepened our understanding of PDAC pathogenesis. This review synthesizes findings from recent genome-wide DNA methylation studies, which have delineated a complex DNA methylation landscape differentiating between normal and cancerous pancreatic tissues, as well as across various stages and molecular subtypes of PDAC. These studies identified specific differentially methylated regions (DMRs) that not only enhance our grasp of the epigenetic drivers of PDAC but also offer potential biomarkers for early diagnosis and prognosis, enabling the customization of therapeutic approaches. The review further explores how DNA methylation profiling could facilitate the development of subtype-tailored therapies, potentially improving treatment outcomes based on precise molecular characterizations. Overall, leveraging DNA methylation alterations as functional biomarkers holds promise for advancing our understanding of disease progression and refining PDAC management strategies, which could lead to improved patient outcomes and a deeper comprehension of the disease’s underlying biological mechanisms. Full article

(This article belongs to the Special Issue New Insights into Epigenetic Regulation in Cancer)

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