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Epigenomes, Volume 9, Issue 4 (December 2025) – 6 articles

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26 pages, 2023 KB  
Review
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 496
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  
Article
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  
Article
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  
Article
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
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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  
Review
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 689
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
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15 pages, 1343 KB  
Article
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 450
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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