Epigenomes

15 pages, 1237 KB

Open AccessArticle

Epigenome-Wide Search for Distinctive Methylation Biomarkers of Endothelial and Leukocyte DNA

by Valeria A. Korolenya, Maxim L. Filipenko and Mariya A. Smetanina

Epigenomes 2025, 9(4), 53; https://doi.org/10.3390/epigenomes9040053 (registering DOI) - 17 Dec 2025

The endothelium, as the inner layer of the vascular wall, is in constant contact with blood components, so that leukocytes have the ability to adhere to endotheliocytes and penetrate to the subendothelial space. When studying heterogenic vascular samples containing endothelial cells or pathological [...] Read more.

The endothelium, as the inner layer of the vascular wall, is in constant contact with blood components, so that leukocytes have the ability to adhere to endotheliocytes and penetrate to the subendothelial space. When studying heterogenic vascular samples containing endothelial cells or pathological processes related to inflammation within the endothelium, it may be necessary to distinguish DNA by endothelial and leukocyte origin, which is possible due to its specific epigenetic modifications. To identify CpG loci that could serve as markers for endothelial cells, we searched for their distinctive stable methylated or demethylated states by applying marginal filtering (selecting CpG loci with methylation Beta values closer to 0 and 1) to the microarray data and identified 47 CpG loci with relatively stable methylation/demethylation status that differentiate endothelial (HUVEC, HCMEC, HPAEC, HPMEC, and LSEC) DNA from leukocyte (granulocytes, monocytes, and lymphocytes) DNA. In addition, we compared CpG loci with high and low levels of DNA methylation between different types of endothelial cells and leukocytes. We believe that the obtained data will hopefully facilitate further studies on endothelial dysfunction. Full article

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35 pages, 7521 KB

Open AccessArticle

The Exosome-Mediated Epigenome: Non-Coding RNA and mRNA-Coding Networks in Microbiome–Cellular Communication, Inflammation, and Tumorigenesis Along the Oral–Gut–Lung Axis

by Beatriz Andrea Otálora-Otálora, César Payán-Gómez, Juan Javier López-Rivera, Luisa Fernanda Patiño-Unibio, Sally Lorena Arboleda-Mojica, Claudia Aristizábal-Guzmán, Mario Arturo Isaza-Ruget and Carlos Arturo Álvarez-Moreno

Epigenomes 2025, 9(4), 52; https://doi.org/10.3390/epigenomes9040052 - 16 Dec 2025

Abstract

Background/Objectives: The oral–gut–lung axis represents a dynamic system where exosomes carrying mRNAs and non-coding RNAs might help to regulate microbiota and human cell crosstalk to establish transcriptional regulatory networks controlling cellular biological processes and signaling pathways. Methods: We conducted a comprehensive [...] Read more.

Background/Objectives: The oral–gut–lung axis represents a dynamic system where exosomes carrying mRNAs and non-coding RNAs might help to regulate microbiota and human cell crosstalk to establish transcriptional regulatory networks controlling cellular biological processes and signaling pathways. Methods: We conducted a comprehensive transcriptomic analysis to characterize the molecular cargo of extracellular exosomes in the context of gut and lung cancer. Results: By analyzing gut and lung exosomes cargo with our previous transcriptomic studies from tumoral and inflammatory tissues, we found that exosomes can transport key RNAs that codify specific receptors that facilitate pathogenic interaction with microorganisms and RNAs that are part of interacting gene and transcriptional regulatory networks that control the function of differentially expresses genes, all involved in biological processes like cell cycle, plasticity and growth regulation, invasion, metastasis, microenvironmental remodeling, epigenetic, and microbial and immunological modulation, during the unlocking of phenotypic plasticity for the acquisition of the hallmarks of cancer in the oral–gut–lung axis. Conclusions: Exosomal RNA regulation of transcriptional networks represents a pivotal axis in the interplay between inflammation and cancer, offering opportunities for innovative diagnostic and therapeutic approaches. Full article

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

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18 pages, 1787 KB

Open AccessReview

The Evolutionary Misfit: Evolution, Epigenetics, and the Rise of Non-Communicable Diseases

by Stefano Amatori

Epigenomes 2025, 9(4), 51; https://doi.org/10.3390/epigenomes9040051 - 13 Dec 2025

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Abstract

Human life expectancy has risen dramatically in the last century, but this demographic triumph has come at the cost of an explosion of non-communicable diseases (NCDs), threatening the sustainability of healthcare systems in aging, low-fertility societies. Evolutionary medicine provides a framework to understand, [...] Read more.

Human life expectancy has risen dramatically in the last century, but this demographic triumph has come at the cost of an explosion of non-communicable diseases (NCDs), threatening the sustainability of healthcare systems in aging, low-fertility societies. Evolutionary medicine provides a framework to understand, at least in part, this paradox. Many vulnerabilities to disease are not failures of design but the predictable outcomes of evolutionary trade-offs, constraints, and mismatches. Evolutionary mismatch theory explains how traits once advantageous in ancestral environments become maladaptive in modern contexts of abundance, sedentarism, and urbanization. The developmental origins of health and disease (DOHaD) concept describes how epigenetic plasticity in early life can buffer or amplify these mismatches, depending on whether adult environments align with developmental forecasts. Transgenerational epigenetic inheritance, even if still debated in humans, may further influence phenotypic plasticity, increasing or mitigating the mismatch. In evolutionary terms, the theories of mutation accumulation, antagonistic pleiotropy, and the disposable soma explain why longer lifespans, and ecological and social conditions profoundly different from those in which we developed, increase the likelihood that these costs are expressed clinically. Because most NCDs can be prevented and effectively controlled but not cured, efforts should prioritize quality of life for people, families, and communities. At the individual level, aligning lifestyles with evolved biology can mitigate risk, but the greatest leverage lies in population-level interventions. Urban health strategies represent a forward-looking attempt to realign modern environments with human biology. In this way, the concept of the evolutionary misfit becomes not just a diagnosis of maladaptation, but a guide for building healthier, more sustainable societies. Full article

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

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19 pages, 4619 KB

Open AccessReview

The Epigenomic Impact of Quantum Dots: Emerging Biosensors and Potential Disruptors

by Abhishu Chand and Kyoungtae Kim

Epigenomes 2025, 9(4), 50; https://doi.org/10.3390/epigenomes9040050 - 8 Dec 2025

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Abstract

Quantum dots (QDs) have emerged as powerful tools in biomedical applications due to their unique optical and fluorescent properties which enable highly sensitive and multiplexed detection of biomolecules. Particularly in the field of epigenetic research, QDs are utilized as biosensors for monitoring changes [...] Read more.

Quantum dots (QDs) have emerged as powerful tools in biomedical applications due to their unique optical and fluorescent properties which enable highly sensitive and multiplexed detection of biomolecules. Particularly in the field of epigenetic research, QDs are utilized as biosensors for monitoring changes in DNA methylation, microRNA (miRNA) expression, and histone modifications, providing a viable alternative to conventional assays. However, increasing evidence also suggests that QDs act as an epigenetic disruptor, altering epigenetic mechanisms and downstream cellular processes. This dual role raises important questions about the safety, reliability, and translational potential of QDs in clinical usage. Therefore, in this commentary we critically evaluate the advances of QD-based epigenetic sensing platforms while also providing insights into QD-based epigenetic dysregulation. We further discuss the current limitations and provide future directions to gain a better understanding of how QDs function to bridge the gap between their diagnostic potential and clinical integration. Full article

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

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14 pages, 1226 KB

Open AccessArticle

Introducing the EpG² System: Epigenomic Processes and the Emergent Genome

by Edward A. Ruiz-Narváez

Epigenomes 2025, 9(4), 49; https://doi.org/10.3390/epigenomes9040049 - 5 Dec 2025

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Abstract

Background/Objectives: Current genomics research equates the genome with DNA sequence and treats the epigenome as a regulatory layer. This DNA-centric view obscures the fact that genomic identity arises through epigenomic processes. The objective of this article is to reinterpret published findings into a [...] Read more.

Background/Objectives: Current genomics research equates the genome with DNA sequence and treats the epigenome as a regulatory layer. This DNA-centric view obscures the fact that genomic identity arises through epigenomic processes. The objective of this article is to reinterpret published findings into a new theoretical framework: the EpG² (Epigenome–Genome) system. Methods: This work develops a new conceptual framework by integrating published evidence from diverse domains—including enhancer biology, overlapping genomic functions, alternative coding frames, zygotic genome activation, and disease-associated loci—and reinterpreting these findings through the lens of epigenomic processes. Results: Evidence shows that enhancers emerge only through the interplay of sequence, transcription factors, and chromatin environment. At fertilization, paternal and maternal genomes remain separate, and a new genome emerges through coordinated epigenomic reprogramming or zygote genome emergence (ZGE). DNA sequence risk variants illustrate the concept of contextual risk alleles, whose effects shift across tissues and developmental stages as epigenomic contexts change. Conclusions: The EpG² system reframes the genome as a processual, emergent entity generated and regulated by epigenomic processes, offering a paradigm for understanding genomic variation beyond DNA sequence. Full article

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

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13 pages, 659 KB

Open AccessArticle

Adverse Childhood Experiences, DNA Methylation, and Depressive Symptoms in Black Pregnant Women

by Alexandra L. Nowak, Marvin A. Schilt-Solberg, Xiaoyu Liang, Fabiola Magaña, Dawn P. Misra and Carmen Giurgescu

Epigenomes 2025, 9(4), 48; https://doi.org/10.3390/epigenomes9040048 - 27 Nov 2025

Viewed by 414

Abstract

Background: Prenatal depression, affecting up to a quarter of all pregnancies in the United States, contributes to morbidity and mortality and is associated with increased risk of adverse birth and long-term mental health outcomes. Adverse childhood experiences (ACEs, or experiences of abuse, neglect, [...] Read more.

Background: Prenatal depression, affecting up to a quarter of all pregnancies in the United States, contributes to morbidity and mortality and is associated with increased risk of adverse birth and long-term mental health outcomes. Adverse childhood experiences (ACEs, or experiences of abuse, neglect, or family dysfunction experienced prior to age 18) are a strong predictor of adult depression and adverse health outcomes. The present study investigated whether epigenetic modification in the form of DNA methylation (DNAm) of four stress-related, glucocorticoid pathway genes (CRH, CRHR1, FKBP5, NR3C1) mediates associations between ACEs and depressive symptoms among Black pregnant women. Methods: Using a cross-sectional design, we examined the mediating role of DNAm on the relationship between depressive symptoms (Center for Epidemiologic Studies Depression Scale (CES-D)) and ACEs (Centers for Disease Control and Prevention 10-item questionnaire), in a subsample (n = 61) of Black pregnant women who were participants of the Biosocial Impacts of Black Births (BIBB) study. Results: A significant association was found between ACEs and depressive symptoms scores (TE α_X = 2.29 with p_TE = 6.60 × 10⁵). DNAm on five CpG sites within two genes significantly mediated the relationship between ACEs and depressive symptoms (cg03238273 on CRHR1, and cg08845721, cg16594263, cg19820298, and cg23430507 on NR3C1). Conclusions: This study provides evidence that DNAm partially mediated the association of ACEs and depressive symptoms during pregnancy among Black pregnant women. Understanding the molecular pathways underlying the mediating effect of ACEs on depressive symptoms among Black pregnant women can illuminate biological markers that help identify and treat pregnant women who are at an increased risk for depression following childhood trauma. Full article

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

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21 pages, 1907 KB

Open AccessReview

CircRNAs—Potential Diagnostic Biomarkers and Therapeutic Targets for Receptive and Cancerous Endometrium

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

Epigenomes 2025, 9(4), 47; https://doi.org/10.3390/epigenomes9040047 - 17 Nov 2025

Viewed by 479

Abstract

Circular RNAs (circRNAs) are small, non-coding RNAs in which the 5′ and 3′ ends are linked covalently by back-splicing of exons from a single pre-mRNA. More and more scientific evidence is gathered for their wide distribution in the animal world, playing the role [...] Read more.

Circular RNAs (circRNAs) are small, non-coding RNAs in which the 5′ and 3′ ends are linked covalently by back-splicing of exons from a single pre-mRNA. More and more scientific evidence is gathered for their wide distribution in the animal world, playing the role of regulators for biological processes, being cell- and tissue-specific. They can influence cellular physiology by various molecular mechanisms, finally modulating gene expression. CircRNAs are believed nowadays to be expressed in both receptive and cancerous endometrium. Due to their abundant expression in the endometrial tissue and their small size and stability, they have been considered potential diagnostic markers and treatment targets for endometrial-related diseases. The regulation of proliferation and differentiation is essential for the formation of receptive endometrium and for endometrial cancer emergence and progression. The receptive endometrium can be regarded as the most highly differentiated state of the endometrium. In contrast, the cancerous endometrium is characterized by a high level of proliferation and the lowest degree of differentiation. These endometria could be conditionally considered opposites. We are investigating the circRNA–miRNA–mRNA regulatory networks that can promote or suppress the proliferation and differentiation of endometrial cells by activating specific signaling pathways in both receptive and cancerous endometria. It could be worth knowing whether there are universal endometrial switches responsible for proliferation and differentiation processes that can alter the balance between them. We are interested in their clinical application as biomarkers and therapeutic targets for both endometrial receptivity issues and EC cases, particularly in diagnosis, progression assessment, and outcome prediction. Full article

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

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40 pages, 3182 KB

Open AccessReview

Epigenetic Regulation of Salt Stress Responses in Rice: Mechanisms and Prospects for Enhancing Tolerance

by Emanuela Talarico, Eleonora Greco, Francesco Guarasci, Fabrizio Araniti, Adriana Chiappetta and Leonardo Bruno

Epigenomes 2025, 9(4), 46; https://doi.org/10.3390/epigenomes9040046 - 16 Nov 2025

Viewed by 554

Abstract

Rice (Oryza sativa L.) is a staple food for over half the global population and a model organism for monocot plant research. However, it is susceptible to salinity, with most cultivated varieties showing reduced growth at salt levels above 3 dS/m. Despite [...] Read more.

Rice (Oryza sativa L.) is a staple food for over half the global population and a model organism for monocot plant research. However, it is susceptible to salinity, with most cultivated varieties showing reduced growth at salt levels above 3 dS/m. Despite numerous efforts to improve its salt tolerance, little progress has been made. A promising area of research lies in the study of epigenetic regulation, which encompasses DNA methylation, histone modifications, and chromatin remodelling. These processes play a crucial role in mediating how plants respond to salt stress by modulating gene expression. This often results in heritable changes that can be used as molecular markers. Studies in rice and other cereals have demonstrated a clear association between histone alterations, shifts in DNA methylation patterns, and the expression of salt-responsive genes. Furthermore, epigenetic mechanisms contribute to the development of stress memory, enabling plants to respond more effectively to recurring stressful conditions. Understanding these regulatory pathways offers new opportunities for breeding or engineering salt-tolerant rice varieties, potentially leading to improved crop resilience and productivity under saline conditions. Full article

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17 pages, 999 KB

Open AccessReview

Convergent Evolution and the Epigenome

by Sebastian Gaston Alvarado, Annaliese Chang and Maral Tajerian

Epigenomes 2025, 9(4), 45; https://doi.org/10.3390/epigenomes9040045 - 11 Nov 2025

Viewed by 1030

Abstract

Background: Trait convergence or parallelism is widely seen across the animal and plant kingdoms. For example, the evolution of eyes in cephalopods and vertebrate lineages, wings in bats and insects, or shark and dolphin body shapes are examples of convergent evolution. Such traits [...] Read more.

Background: Trait convergence or parallelism is widely seen across the animal and plant kingdoms. For example, the evolution of eyes in cephalopods and vertebrate lineages, wings in bats and insects, or shark and dolphin body shapes are examples of convergent evolution. Such traits develop as a function of environmental pressures or opportunities that lead to similar outcomes despite the independent origins of underlying tissues, cells, and gene transcriptional patterns. Our current understanding of the molecular processes underlying these phenomena is gene-centric and focuses on how convergence involves the recruitment of novel genes, the recombination of gene products, and the duplication and divergence of genetic substrates. Scope: Despite the independent origins of a given trait, these model organisms still possess some form of epigenetic processes conserved in eukaryotes that mediate gene-by-environment interactions. These traits evolve under similar environmental pressures, so attention should be given to plastic molecular processes that shape gene function along these evolutionary paths. Key Mechanisms: Here, we propose that epigenetic processes such as histone-modifying machinery are essential in mediating the dialog between environment and gene function, leading to trait convergence across disparate lineages. We propose that epigenetic modifications not only mediate gene-by-environment interactions but also bias the distribution of de novo mutations and recombination, thereby channeling evolutionary trajectories toward convergence. An inclusive view of the epigenetic landscape may provide a parsimonious understanding of trait evolution. Full article

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

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24 pages, 7415 KB

Open AccessSystematic Review

Exploring the Impact of Nanotherapeutics on Histone H3 and H4 Acetylation Enrichment in Cancer Epigenome: A Systematic Scoping Synthesis

by Milad Shirvaliloo, Sepideh Khoee, Samideh Khoei, Roghayeh Sheervalilou, Parisa Mohammad Hosseini, Reza Afzalipour and Sakine Shirvalilou

Epigenomes 2025, 9(4), 44; https://doi.org/10.3390/epigenomes9040044 - 7 Nov 2025

Viewed by 813

Abstract

Background/Objectives: Histone acetylation regulates gene expression and plays a key role in cancer pathophysiology. Nanotherapeutics are known to modulate histone acetylation and influence cancer progression. This systematic scoping review examines the effects of nanotherapeutics on histone acetylation enrichment across multiple cancers. Methods [...] Read more.

Background/Objectives: Histone acetylation regulates gene expression and plays a key role in cancer pathophysiology. Nanotherapeutics are known to modulate histone acetylation and influence cancer progression. This systematic scoping review examines the effects of nanotherapeutics on histone acetylation enrichment across multiple cancers. Methods: A systematic search of Embase, PubMed/MEDLINE, Scopus, and Web of Science was conducted in accordance with the PRISMA 2020 statement. A total of 13 studies were included. Data were analyzed and visualized in R, and risk of bias was assessed with ToxRTool (OSF Registration: 10.17605/OSF.IO/E643S). Results: Nanotherapeutics were most commonly evaluated against breast (21.4%), prostate (21.4%), pancreatic (14.3%), and bladder (14.3%) cancers. Primary nanomaterials used in the synthesis of nanotherapeutics included poly(lactic-co-glycolic acid) (25.0%), gold (21.4%) and arsenic oxide (21.4%) nanoparticles. Studied histone acetylation marks included H3K9ac, H3K14ac, H3K27ac and H4K16ac. Treatment with nanotherapeutics increased histone H3 and H4 acetylation enrichment, particularly H3K14ac in colorectal and prostate cancers and H4K16ac in ovarian cancer. Conversely, gold-based nanotherapeutics decreased H3K9ac and H3K14ac enrichment in breast cancer. The optimal concentration for most nanotherapeutics was ≤25 µM, with PpIX-FFYSV showing the strongest anticancer effect (viability <25%). Across four preclinical studies (n = 58), treatment with the nanotherapeutics reduced tumor size to less than 50% of control in 64% of animals (95% CI: 21–92%, I² = 63.8%). Altered histone acetylation was associated with differential expression of CDKN1A, HSPA1, SREBF2 and TGFB. Conclusions: The evidence demonstrates that nanotherapeutics can alter histone acetylation patterns by modulating EP300/CBP, GCN5 and HDAC, preventing cancer progression and invasion. Full article

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

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27 pages, 1141 KB

Open AccessReview

Epigenetic Mechanisms of Plant Adaptation to Cadmium and Heavy Metal Stress

by Eleonora Greco, Emanuela Talarico, Francesco Guarasci, Marina Camoli, Anna Maria Palermo, Alice Zambelli, Adriana Chiappetta, Fabrizio Araniti and Leonardo Bruno

Epigenomes 2025, 9(4), 43; https://doi.org/10.3390/epigenomes9040043 - 2 Nov 2025

Viewed by 895

Abstract

Heavy metal and metalloid stress, particularly from toxic elements like cadmium (Cd), poses a growing threat to plant ecosystems, crop productivity, and global food security. Elevated concentrations of these contaminants can trigger cytotoxic and genotoxic effects in plants, severely impairing growth, development, and [...] Read more.

Heavy metal and metalloid stress, particularly from toxic elements like cadmium (Cd), poses a growing threat to plant ecosystems, crop productivity, and global food security. Elevated concentrations of these contaminants can trigger cytotoxic and genotoxic effects in plants, severely impairing growth, development, and reproduction. In recent years, epigenetic mechanisms have emerged as crucial regulators of plant responses to heavy metal stress, offering novel insights and strategies for enhancing plant resilience in contaminated environments. This review synthesises current advances in the field of plant epigenetics, focusing on key modifications such as DNA methylation, histone acetylation and remodelling, chromatin dynamics, and small RNA-mediated regulation. These processes not only influence gene expression under metal-induced stress but also hold promise for long-term adaptation through transgenerational epigenetic memory. Recent developments in high-throughput sequencing and functional genomics have accelerated the identification of epigenetic markers associated with stress tolerance, enabling the integration of these markers into breeding programs and targeted epigenome editing strategies. Special attention is given to cadmium stress responses, where specific epigenetic traits have been linked to enhanced tolerance. As plant epigenomic research progresses, its application in sustainable agriculture becomes increasingly evident offering environmentally friendly solutions to mitigate the impact of heavy metal pollution. This review provides a foundation for future research aimed at leveraging epigenetic tools to engineer crops capable of thriving under metal stress, thereby contributing to resilient agricultural systems and sustainable food production. Full article

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26 pages, 2023 KB

Open AccessReview

Role of m⁶A mRNA Methylation in Plant Defense

by Rakesh Srivastava and Niraj Lodhi

Epigenomes 2025, 9(4), 42; https://doi.org/10.3390/epigenomes9040042 - 15 Oct 2025

Viewed by 1150

Abstract

N6-methyladenosine (m⁶A) is the most abundant and dynamic RNA modification in eukaryotic messenger and non-coding RNAs, playing a pivotal role in the post-transcriptional regulation of gene expression. The coordinated actions of m⁶A writers, erasers, and readers influence transcript stability, [...] Read more.

N6-methyladenosine (m⁶A) is the most abundant and dynamic RNA modification in eukaryotic messenger and non-coding RNAs, playing a pivotal role in the post-transcriptional regulation of gene expression. The coordinated actions of m⁶A writers, erasers, and readers influence transcript stability, immune activation, and pathogen suppression. Growing evidence indicates that m⁶A fine-tunes the expression of defense-related genes, modulates RNA processing events, and is frequently hijacked by pathogens and pests to promote virulence. Notably, the dual role of m⁶A in enhancing plant defense and facilitating pathogen adaptation highlights its significance in the host–pathogen arms race. This review emphasizes recent advances in our understanding of m⁶A-mediated epitranscriptomic regulation in plants, with a focus on its role in responses to biotic stresses, including fungi, bacteria, virus infections, insects, and nematode attacks. This regulatory layer offers novel opportunities for crop protection through targeted manipulation of the epitranscriptomic mechanism. Full article

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

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14 pages, 2057 KB

Open AccessArticle

Exploration into the MLL4/WRAD Enzyme-Substrate Network: Systematic In Vitro Identification of CFP1 as a Potential Non-Histone Substrate of the MLL4 Lysine Methyltransferase

by Mullen Boulter, Ryan Collins and Kyle K. Biggar

Epigenomes 2025, 9(4), 41; https://doi.org/10.3390/epigenomes9040041 - 15 Oct 2025

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Abstract

Lysine methylation is a critical post-translational modification catalyzed by lysine methyltransferases (KMTs), originally characterized in the regulation of histones. However, the breadth of non-histone targets remains largely unexplored. Here, we used a systematic peptide array-based approach to define a substrate preference motif for [...] Read more.

Lysine methylation is a critical post-translational modification catalyzed by lysine methyltransferases (KMTs), originally characterized in the regulation of histones. However, the breadth of non-histone targets remains largely unexplored. Here, we used a systematic peptide array-based approach to define a substrate preference motif for the SET-domain-containing KMT MLL4 (KMT2D), a member of the COMPASS complex and a known H3K4 methyltransferase. Using this motif, we identified CXXC finger protein 1 (CFP1), a core component of Setd1A/B complexes, as a putative MLL4 substrate. In vitro methyltransferase assays confirmed robust methylation of CFP1 by an MLL4-WRAD complex. Surprisingly, while initial predictions implicated K328, array-based methylation profiling revealed multiple lysine residues within CFP1’s lysine-rich basic domain as methylation targets, including K331, K335, K339, and K340. We further demonstrated that CFP1 methylation likely modulates its interaction with MLL4’s PHD cassettes and facilitates binding to Setd1A. Binding preferences of MLL4’s PHD1–3 and PHD4–6 domains varied with methylation state and site, suggesting non-histone methyl mark recognition by these cassettes. Pulldown assays confirmed that methylated, but not unmethylated, CFP1 binds Setd1A, supporting a potential methyl-switch mechanism. Together, our findings propose CFP1 as a potential non-histone substrate of MLL4 and suggest that MLL4 may regulate Setd1A/B function indirectly via CFP1 methylation. This study expands the substrate landscape of MLL4 and lays the groundwork for future investigations into non-histone methylation signaling in chromatin regulation. Full article

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15 pages, 467 KB

Open AccessArticle

Elevated Alcohol Consumption and Chronic Inflammation Predict Cardiovascular Risk Among Black Americans: Examination of a Dual-Risk Model Using Epigenetic Risk Markers

by Steven R. H. Beach, Robert A. Philibert, Mei-Ling Ong, Man-Kit Lei and Kaixiong Ye

Epigenomes 2025, 9(4), 40; https://doi.org/10.3390/epigenomes9040040 - 7 Oct 2025

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Abstract

Background: Heart disease may take a greater toll on Black Americans than White Americans despite similar levels of traditional risk factors. Elevated alcohol consumption (EAC) and chronic inflammation are two potentially important additional risk factors to consider. Both are relevant to understanding health [...] Read more.

Background: Heart disease may take a greater toll on Black Americans than White Americans despite similar levels of traditional risk factors. Elevated alcohol consumption (EAC) and chronic inflammation are two potentially important additional risk factors to consider. Both are relevant to understanding health disparities in cardiovascular health. Methods: Couples with a Black preadolescent or early adolescent child living in the home were recruited and followed. In waves 5 and 6 of data collection, biological samples were also collected allowing the characterization of elevated alcohol consumption, chronic inflammation, and cardiac risk using DNA methylation indices. 383 individual partners comprising 221 couples were examined across the two waves of data, yielding 661 person-wave observations from 383 individuals. Results: EAC at wave 5 forecast increased cardiac risk at W6 (R² change = 0.276), β = −0.193, p = 0.001. However, chronic inflammation at wave 5 did not add significantly to the baseline model, β = −0.042, p = 0.549. Conversely, the slope of change for chronic inflammation was associated with slope of change in cardiac risk (R² change = 0.111), b = −0.014, p = <0.001, but EAC change was not significantly associated with change in cardiac risk, b = −0.001, p = 0.185. Conclusions: Elevated alcohol consumption may be an important risk factor for increased cardiac risk over time in middle age. If so, it could be an important avenue for preventative intervention to decrease cardiac risk. Future research should examine whether similar associations are observed for other racial or minoritized groups and for non-minoritized groups. Full article

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

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18 pages, 772 KB

Open AccessArticle

A Pilot Epigenome-Wide Study of Posttraumatic Growth: Identifying Novel Candidates for Future Research

by Mackenzie Rubens, Paul Ruiz Pinto, Anita Sathyanarayanan, Olivia Miller, Amy B. Mullens, Dagmar Bruenig, Patricia Obst, Jane Shakespeare-Finch and Divya Mehta

Epigenomes 2025, 9(4), 39; https://doi.org/10.3390/epigenomes9040039 - 6 Oct 2025

Viewed by 1157

Abstract

Background: Posttraumatic growth (PTG) refers to positive psychological change following trauma. While its psychological aspects are well-documented, the biological mechanisms remain unclear. Epigenetic changes, such as DNA methylation (DNAm), may offer insight into PTG’s neurobiological basis. Aims: This study aimed to identify epigenetic [...] Read more.

Background: Posttraumatic growth (PTG) refers to positive psychological change following trauma. While its psychological aspects are well-documented, the biological mechanisms remain unclear. Epigenetic changes, such as DNA methylation (DNAm), may offer insight into PTG’s neurobiological basis. Aims: This study aimed to identify epigenetic markers associated with PTG using an epigenome-wide association study (EWAS), the first of its kind in a trauma-exposed population. Methods: A longitudinal EWAS design was used to assess DNAm before and after trauma exposure in first-year paramedicine students (n = 39). Genome-wide methylation data were analyzed for associations with PTG, applying epigenome-wide and gene-wise statistical thresholds. Pathway enrichment analysis was also conducted. Results: The study identified two CpGs (cg09559117 and cg05351447) within the PCDHA1/PCDHA2 and PDZD genes significantly associated with PTG at the epigenome-wide threshold (p < 9.42 × 10^–8); these were replicated in an independent sample. DNAm in 5 CpGs across known PTSD candidate genes ANK3, DICER1, SKA2, IL12B and TPH1 were significantly associated with PTG after gene-wise Bonferroni correction. Pathway analysis revealed that PTG-associated genes were overrepresented in the Adenosine triphosphate Binding Cassette (ABC) transporters pathway (p = 2.72 × 10⁻⁴). Conclusions: These results identify genes for PTG, improving our understanding of the neurobiological underpinnings of PTG. Full article

(This article belongs to the Special Issue DNA Methylation Markers in Health and Disease)

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25 pages, 1309 KB

Open AccessReview

Tripartite Interaction of Epigenetic Regulation, Brain Aging, and Neuroinflammation: Mechanistic Insights and Therapeutic Implications

by Shenghui Mi, Hideyuki Nakashima and Kinichi Nakashima

Epigenomes 2025, 9(4), 38; https://doi.org/10.3390/epigenomes9040038 - 5 Oct 2025

Viewed by 1473

Abstract

Aging of the central nervous system (CNS) involves widespread transcriptional and structural remodeling, prominently marked by synaptic loss, impaired neurogenesis, and glial dysfunction. While age-related gene expression changes have been documented for decades, recent genome-wide next-generation sequencing studies emphasize the importance of epigenetic [...] Read more.

Aging of the central nervous system (CNS) involves widespread transcriptional and structural remodeling, prominently marked by synaptic loss, impaired neurogenesis, and glial dysfunction. While age-related gene expression changes have been documented for decades, recent genome-wide next-generation sequencing studies emphasize the importance of epigenetic mechanisms—such as DNA methylation and histone modification—in shaping these profiles. Notably, these modifications are potentially reversible, making them promising targets for therapeutic intervention. However, the mechanisms by which age-associated factors, such as inflammation and oxidative stress, orchestrate these epigenetic alterations across distinct CNS cell types remain poorly understood. In this review, we propose a framework for understanding how aging and neuroinflammation are regulated by epigenetic mechanisms, contributing to brain dysfunction and disease vulnerability. Full article

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

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15 pages, 1343 KB

Open AccessArticle

Sustained Higher Levels of Plasma hsa-miR-17-5p Expression During Gestational Diabetes Mellitus and Postpartum

by Arathi Pillai, Sibin M Kandi, Nidhi Tripathy, Deeptika Agarwal, Indrani Mukhopadhyay, Bhasker Mukherjee and Y Vashum

Epigenomes 2025, 9(4), 37; https://doi.org/10.3390/epigenomes9040037 - 24 Sep 2025

Viewed by 690

Abstract

Background: The role of circulatory miRNAs in gestational diabetes mellitus (GDM) was explored extensively in previous studies. However, there was limited literature on longitudinal studies exploring the changes in miRNA expression during pregnancy and postpartum to understand the changes in their expression levels [...] Read more.

Background: The role of circulatory miRNAs in gestational diabetes mellitus (GDM) was explored extensively in previous studies. However, there was limited literature on longitudinal studies exploring the changes in miRNA expression during pregnancy and postpartum to understand the changes in their expression levels in GDM patients. Methods: Blood samples from thirty GDM subjects and twenty normoglycemic pregnant women (NGT) were collected between 24 and 28 weeks of their pregnancy, and follow-up samples from the same subjects were collected till 12 weeks postpartum (FGDM and FNGT, respectively). Three candidate miRNAs, hsa-miR-16-5p, hsa-miR-17-5p, and hsa-miR-20a-5p, were quantified from their plasma samples using RT-qPCR. Comparative analysis of these miRNA expression levels was made between different groups. Results: hsa-miR-16-5p, hsa-miR-17-5p, and hsa-miR-20a-5p expression were significantly higher in GDM patients when compared to NGT subjects. Interestingly, hsa-miR-17-5p has shown consistent upregulation in FGDM even after these patients turned normoglycemic. Additionally, hsa-miR-16-5p was found to be higher in FGDM patients compared to FNGT subjects. Conclusions: The present study corroborated the finding of differential expression of hsa-miR-16-5p, hsa-miR-17-5p, and hsa-miR-20a-5p in GDM. It also marked the importance of monitoring the levels of hsa-miR-17-5p and hsa-miR-16-5p during pregnancy and postpartum in GDM patients. Full article

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Epigenomes, Volume 9, Issue 4 (December 2025) – 17 articles

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