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PubMed2026

Epigenetic Regulation of the BDNF Gene by Molybdenum in 9 to 11-Year-Old Children: A Targeted Gene DNA Methylation Study.

While essential trace minerals are known to influence DNA methylation (DNAm), molybdenum's (Mo) role in epigenetic regulation remains largely unexplored. This study examined associations between Mo status and DNAm of the brain-derived neurotrophic factor (BDNF) gene, a critical regulator of neurogenesis, in children aged 9-11 years, focusing on 107 CpG sites across BDNF and its antisense transcript (BDNF-AS).BDNF and BDNF-AS methylation was analyzed in blood samples from 72 children randomly selected from a cohort of 292 participants. Dietary Mo intake was estimated from food records, and creatinine-adjusted urinary Mo levels were quantified. Higher urinary molybdenum was significantly associated with decreased methylation at five BDNF 5'UTR sites (p<.05) and increased methylation of BDNF-AS (p =  .0001), consistent with enhanced BDNF transcriptional activity. African American children exhibited lower urinary Mo excretion than European American children, suggesting greater retention, and showed cortisol-associated increases in BDNF methylation not observed in European American children.These findings demonstrate associations between molybdenum status and DNA methylation patterns at the BDNF locus in children. While functional validation through BDNF protein measurement is needed, results suggest molybdenum may influence neurotrophin gene regulation through epigenetic mechanisms, highlighting the importance of trace mineral nutrition during neurodevelopment.

Humans↗

PubMed2026

Epigenetic regulation of transgenes.

Gene therapy holds significant potential for treating genetic disorders, but the use of viral vectors is limited by factors such as immunogenicity, payload capacity, and high manufacturing costs. Nonviral gene delivery (NVGD) using plasmid DNA presents an attractive alternative; however, it typically provides a limited magnitude or duration of transgene expression. One potential reason for these shortcomings is the host cell's epigenetic regulation mechanisms, which can silence both viral and nonviral transgenes. Specifically, when foreign DNA enters the nucleus, it is detected by nuclear DNA sensors, such as IFI16, which initiate the assembly of a "restrictosome" or nuclear domain 10 (ND10) body. This multiprotein complex contains several components, such as PML, Speckled Proteins (e.g., SP100), DAXX, and ATRX that act as a scaffold for recruiting various epigenetic modifiers that subsequently deposit repressive histone modifications like H3K9me3 and H3K27me3 on the transgene chromatin. These marks induce DNA methylation and the subsequent condensation of plasmids or episomes into heterochromatin, which represses transgene expression. Alternatively, unmethylated CpG motifs in bacterial plasmid DNA can trigger innate immune responses in the cytosol, but this review will specifically focus on the detailed mechanisms of epigenetic regulation responsible for silencing plasmid DNA within the host cell nucleus. Addressing these nuclear defense mechanisms, potentially through strategies that manipulate DNA methylation or inhibit restrictosome activity, is crucial for advancing the development of safe, effective, and long-lasting plasmid viral and non-viral gene therapies.

Epigenesis, Genetic↗

PubMed2025

Design of optimized epigenetic regulators for durable gene silencing with application to PCSK9 in nonhuman primates.

Epigenetic editing is a promising strategy for modifying gene expression while avoiding the permanent alterations and potential genotoxicity of genome-editing technologies. Here we designed optimized epigenetic regulators (EpiRegs) by testing combinations of transcription activator-like effector (TALE)-based and catalytically deactivated Cas9 (dCas9)-based epigenetic modification effectors and fusion protein structures. TALE-based EpiReg (EpiReg-T) achieved a final efficiency of 98% in mice, surpassing the initial dCas9-based efficiency of 64%. We demonstrated the approach in macaques by introducing DNA methylation and histone modifications to inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9) expression, thereby lowering low-density lipoprotein cholesterol levels. A single dose of EpiReg-T delivered with lipid nanoparticles achieved efficient (>90%) and long-lasting (343 days) silencing of PCSK9 in the liver. Integrative multiomic analyses revealed minimal off-target effects in EpiReg-T-treated monkeys, mice and human-derived cells. EpiReg can be redirected to other genes by reengineering the DNA-binding domain. Our findings represent a step toward the clinical application of epigenetic editing for the treatment of human diseases.

Animals↗

PubMed2026

Epigenetic regulation of kidney development.

The methylation or demethylation of genomic DNA at specific locations and the diverse array of post-translational modifications of histones associated with genomic DNA are collectively known as epigenetic modifications, so-called because they affect chromatin structure but do not affect the actual DNA sequence of the genome. Nevertheless, post-translational modifications of histones, including methylation, acetylation, phosphorylation and ubiquitination, as well as the methylation and subsequent de-methylation of genomic DNA, can profoundly affect gene expression. Nowhere has the study of epigenetically regulated gene expression had such impact as on our understanding of organism development. In the developing kidney, epigenetic-based regulation affects the cell fate decisions of stem-like nephron progenitor cells (NPCs). Changes in chromatin accessibility at the loci of genes associated with NPC self-renewal and nephron differentiation - in part driven by transcription factors known to regulate kidney development - affect the differentiation of NPCs into precursors of the nephron such as the pretubular aggregate and renal vesicle, and the subsequent differentiation of various segments of the mature nephron. Epigenetic mechanisms also contribute to the process of NPC ageing and the cessation of nephrogenesis, with consequences for nephron endowment and kidney function.

Epigenesis, Genetic↗

PubMed2026

Molecular mechanisms of plant thermal response: from signal transduction and epigenetic regulation to signaling integration.

Global warming intensification elevates heat stress to one of the major threats to crop productivity. This review synthesizes recent advances in understanding the mechanisms governing plant responses to both moderate and acute heat stress, with a focus on the integration of epigenetic regulation and signaling networks that underpin thermal adaptation. This review highlights how transcription factors PHYTOCHROME-INTERACTING FACTOR 4 (PIF4, during thermomorphogenesis) and HEAT SHOCK FACTOR A1s (HSFA1s, in heat shock responses) orchestrate plant adaptive growth through crosstalk among light, circadian, and hormone signaling pathways. Importantly, epigenetic mechanisms, including histone variant H2A.Z dynamics and histone modification reprogramming, function as central regulators of thermal plasticity. Key among these processes are HSFA2-mediated chromatin remodeling and small interfering RNA (siRNA)-dependent control of transgenerational thermomemory. Despite this progress, fundamental questions persist regarding temperature sensing, HSFA1s activation dynamics, and stress signal integration. Multi-omics and synthetic biology approaches are proposed to be pivotal in deciphering conserved principles of plant thermal resilience, ultimately providing a theoretical foundation and molecular breeding strategies for climate-smart crops.

Epigenesis, Genetic↗

PubMed2026

The Jumonji C domain-containing proteins GmJMJ19 and GmJMJ20 link florigen signaling with epigenetic regulation of photoperiodic flowering and post-flowering plant height in soybean.

Soybean (Glycine max) is a photoperiod-sensitive legume whose latitudinal adaptation depends on the precise control of flowering time and plant height. Histone demethylases of the JmjC domain-containing (JMJ) protein family have been implicated in these processes across plant species, but their specific roles in soybean remain largely unexplored. Here, we identify soybean GmJMJ19 and GmJMJ20, two closely related JMJD5/KDM8 orthologs, as master epigenetic regulators that coordinately control both photoperiodic flowering and post-flowering plant height. Both genes exhibit intrinsic, rhythmic expression peaking at ZT12, and their encoded proteins physically interact with the florigen proteins FT2a and FT5a. Loss-of-function mutants display delayed flowering under long days (LDs) and increased plant height under both LDs and short days (SDs), whereas overexpression phenocopies the mutant flowering phenotype, indicating revealing a critical dosage requirement for proper function. Mechanistically, GmJMJ19 and GmJMJ20 are recruited by the FT/FD transcriptional complex to directly activate AP1a and AP1c expression through chromatin modulation. Population genomic analyses reveal distinct selection signatures: GmJMJ19 underwent sustained directional selection during cultivation, whereas GmJMJ20 experienced an early domestication sweep with limited subsequent change. Haplotype analysis identifies coordinated latitudinal clines, with the JMJ19H1/JMJ20H1 combination predominating at high latitudes to promote early flowering and limit height, while JMJ19H2/JMJ20H2 and wild JMJ19H3/JMJ20H3 alleles prevail at low latitudes, conferring later flowering and increased height. Collectively, our findings establish GmJMJ19 and GmJMJ20 as central chromatin regulators linking florigen signaling to downstream target expression and provide valuable allelic resources for breeding regionally adapted soybean varieties across a wide range of latitudinal environments.

Histone modulation↗

PubMed2026

Transcriptomic and network analyses identify epigenetic regulators of drug-tolerant persister (DTP) subsets in EGFR-mutant HCC827 non-small cell lung cancer.

BACKGROUND: The clinical efficacy of osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), in EGFR-mutant non-small cell lung cancer (NSCLC) is limited by the inevitable acquired resistance. Drug-tolerant persister (DTP) cells, which survive initial therapy, are considered a key reservoir for this resistance. Understanding the molecular characteristics of DTPs is essential for developing strategies to prevent relapse. OBJECTIVE: This study aimed to characterize the transcriptomic landscape of osimertinib-tolerant DTP cells and identify key epigenetic regulators associated with the DTP phenotype in EGFR-mutant HCC827 NSCLC cells through integrated transcriptomic and network analyses. METHODS: We established an in vitro model of osimertinib tolerance using an EGFR-mutant (exon 19 deletion) HCC827 NSCLC cell line. Parental HCC827 cells and DTP subsets were subjected to transcriptomic analysis by RNA sequencing (RNA-seq). Differentially expressed genes were identified, followed by bioinformatics analyses, including Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and protein-protein interaction (PPI) network analyses to identify key biological processes driving the DTP phenotype. Key findings were validated using quantitative real-time PCR (qPCR). RESULTS: Osimertinib treatment induced a morphologically distinct DTP population. Transcriptomic profiling revealed a marked shift in gene expression compared to parental cells. Functional enrichment analysis showed significant upregulation of epigenetic pathways. PPI network analysis identified a core module of eight hub genes, including histone deacetylases (HDAC5, HDAC9), sirtuins (SIRT1, SIRT2), and histone acetyltransferase (KAT2B). qPCR confirmed increased expression of HDAC5, HDAC9, and SIRT1. CONCLUSION: Epigenetic reprogramming accompanies the transition to an osimertinib-tolerant state in EGFR-mutant HCC827 cells. Targeting HDACs and sirtuins may represent a promising strategy to eliminate DTP subpopulations and delay or prevent acquired resistance.

Drug-tolerant persister↗

PubMed2025

A comprehensive atlas of full-length Arabidopsis eccDNA populations identifies their genomic origins and epigenetic regulation.

Extrachromosomal circular DNA (eccDNA) has been described in several eukaryotic species and has been shown to impact phenomena as diverse as cancer and herbicide tolerance. EccDNA is thought to arise mainly through transposable element (TE) mobilization. Because studies based on short-read sequencing cannot efficiently identify full-length eccDNA forms generated from TEs, we employed the CIDER-Seq pipeline based on long-read sequencing, to obtain full-length eccDNAs from Arabidopsis. The generated eccDNA datasets identified centromeric/pericentromeric regions as hotspots of eccDNAs with several eccDNA molecules originating from Helitron and LTR TEs. To investigate the role of epigenetic marks on TE-derived eccDNA biogenesis, we studied Arabidopsis methylation mutants dcl3, rdr6, ros1, and ddm1. Contrasting the TE-suppression previously reported in the hypermethylated ros1 mutants, we identified activation of TEs in ros1, specifically of LTR/Gypsy TEs. An enrichment of LTR/Copia elements was identified in actively dividing calli and the shoot apical meristem (SAM). Uncharacterized "variable TEs" with high eccDNA and expression were identified in the SAM, including ATCOPIA58. Together, our study reveals the genomic origins of eccDNAs and delineates the link between epigenetic regulation, transposon mobilization, and eccDNA biogenesis.

Arabidopsis↗

PubMed2026

Engineering chromatin loops to control cell fate: LoopID reveals catalytic-independent functions of epigenetic regulators.

Enhancer-promoter (E-P) interactions are central to cell-type-specific transcriptional programs, yet the molecular machinery that establishes and maintains these loops has remained poorly defined. A recent study by Jiang et al, published in Nature Genetics, presents a series of transformative discoveries that redefine our understanding of E-P interactions and their role in gene regulation and cell fate determination. The research introduces LoopID, a chromatin-interaction-based proteomic platform that, for the first time, enables systematic identification of protein components, termed the "looposome," localized specifically at chromatin looping anchors. Using LoopID, they profile the "looposome" in mouse embryonic stem cells (ESCs) and uncover an unexpected, catalytic-independent role for the histone demethylase JMJD2 (KDM4) in organizing chromatin architecture through phase-separated condensates. Beyond mechanism, the study demonstrates that targeted assembly of JMJD2 condensates at defined genomic loci can engineer E-P interactions driving cellular reprogramming toward pluripotent and two-cell-like states. Together, these findings represent not only a major technical advance but also a conceptual leap-establish LoopID as a foundational technology for dissecting chromatin structure, introduce a new conceptual framework for epigenetic regulators as structural organizers, and provide a powerful strategy to manipulate cell fate by rewiring three-dimensional (3D) genome architecture.

Animals↗

PubMed2021

Epigenetically regulated digital signaling defines epithelial innate immunity at the tissue level.

To prevent damage to the host or its commensal microbiota, epithelial tissues must match the intensity of the immune response to the severity of a biological threat. Toll-like receptors allow epithelial cells to identify microbe associated molecular patterns. However, the mechanisms that mitigate biological noise in single cells to ensure quantitatively appropriate responses remain unclear. Here we address this question using single cell and single molecule approaches in mammary epithelial cells and primary organoids. We find that epithelial tissues respond to bacterial microbe associated molecular patterns by activating a subset of cells in an all-or-nothing (i.e. digital) manner. The maximum fraction of responsive cells is regulated by a bimodal epigenetic switch that licenses the TLR2 promoter for transcription across multiple generations. This mechanism confers a flexible memory of inflammatory events as well as unique spatio-temporal control of epithelial tissue-level immune responses. We propose that epigenetic licensing in individual cells allows for long-term, quantitative fine-tuning of population-level responses.

Animals↗

PubMed2025

FTDC1/2, oocyte-specific cofactors of DNMT1 required for epigenetic regulation and embryonic development.

The unique epigenetic patterns during gametogenesis and embryonic development indicate the existence of specialized methylation machinery. In the present study, we describe the discovery of two oocyte-specific cofactors of DNA methyltransferase 1 (DNMT1), encoded by uncharacterized genes, ferritin domain containing 1 and 2 (Ftdc1 and Ftdc2). Genetic ablation of Ftdc1 or Ftdc2 causes midgestation defects and female infertility. FTDC1 or FTDC2 depletion induces the progressive loss of DNA methylation including imprinted regions in early embryos. This loss correlates with a marked reduction in DNMT1 protein due to increased degradation, likely via the ubiquitin-proteasome pathway. Mechanistically, we find that FTDC1, FTDC2 and DNMT1 form a complex by direct interactions, thereby stabilizing each other. Surprisingly, knockout of Ftdc1 or Ftdc2 displayed stronger DNA demethylation phenotypes and earlier embryonic lethality than the Dnmt1-null mutant, implying their unique functions. These data suggest that FTDC1/2 are crucial players specifically involved in maintaining genomic methylation during embryogenesis, offering new insights into the epigenetic control of mammalian development.

DNA (Cytosine-5-)-Methyltransferase 1↗

PubMed2025

EBV Latency Programs: Molecular and Epigenetic Regulation and Its Role in Disease Pathogenesis.

Epstein-Barr virus (EBV) asymptomatically infects over 95% of the global population, and poses a great threat to human health. This review summarizes the complex mechanisms underlying EBV latency programs and their roles in both viral persistence and disease development. We comprehensively analyze the four distinct latency programs (0, I, II, and III) and their associated gene expression patterns, with particular emphasis on the key viral proteins, the Epstein-Barr virus nuclear antigen EBNA1, EBNA2, EBNA3A/B/C, LMP1, and LMP2A/B. The review explores how these latency programs contribute to various EBV-associated malignancies and autoimmune conditions, including Burkitt lymphoma, Hodgkin lymphoma, nasopharyngeal carcinoma, and multiple sclerosis. We detail the multilayered regulation of EBV latency, encompassing epigenetic modifications, chromatin organization, and long-range genomic interactions. Recent advances in understanding the molecular mechanisms of EBV latency maintenance and the virus's interaction with host cellular machinery provide new insights into potential therapeutic approaches for EBV-associated diseases.

Humans↗

PubMed1979

Epigenetic regulation of the shape and position of the auricle in the rat.

We hypothesized that epigenetic (non-genomic) factors, related to muscular function, significantly regulate the shape and position of the auricular cartilage. We tested this experimentally by doing unilateral partial and total facial neurectomies, auricular myectomies, and ear rotations with skin excisions in rats. The neurectomies produced muscle atrophy, abolished the horizontal scaphoid ridging, and produced characteristic changes in the auricular shape. The myectomies of extrinsic auricular musculature alone were followed routinely by complete muscle regeneration and no changes in shape. The auricular rotations, with skin excision, produced an antihelix-like complex analogous to the human ear--a configuration that was permanent and was accompanied by muscle relocation. The findings are believed to support our hypothesis.

Animals↗

PubMed2026

Activity-dependent DNA methylation and demethylation: epigenetic regulators of learning and memory.

Learning and memory are fundamental cognitive processes that rely on activity-dependent epigenetic mechanisms to shape synaptic and neuronal plasticity. Among these, DNA methylation and demethylation have emerged as pivotal regulators that convert transient neural activity into enduring transcriptional programs. In mammals, DNA methylation marks include 5-methylcytosine (5mC) as well as the less well-established N6-methyladenine (6mA) and the more enigmatic N4-methylcytosine (4mC). Compared with 5mC, the abundance, genomic distribution, and regulatory role of 6mA and 4mC remain incompletely defined, partly due to low abundance and technical challenges, yet these non-canonical marks may provide an additional regulatory layer in specific biological contexts. Accordingly, this review focuses on the best-characterized pathway in the nervous system, 5mC and its activity-regulated oxidative turnover. This system comprises a dynamic spectrum of cytosine modifications, including 5mC, 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC), orchestrated by distinct enzyme families such as DNMTs, TETs, and TDG. We review current insights about how these regulators shape activity-induced gene expression programs underlying learning and memory, and we discuss how dysregulated DNA (de) methylation contributes to impaired transcriptional control and cognitive decline in neurodegenerative diseases, particularly Alzheimer's disease. Finally, we highlight recent advances in high-resolution mapping technologies for DNA modifications, which are expanding our ability to resolve cell type- and locus-specific epigenetic dynamics in the brain. A deeper understanding of these pathways may inform targeted strategies to preserve or restore cognitive function in neurological disorders.

Alzheimer’s disease↗

PubMed2025

Epigenetic regulation of HOXA2 expression affects tumor progression and predicts breast cancer patient survival.

Accumulating evidence suggests that genetic and epigenetic biomarkers hold potential for enhancing the early detection and monitoring of breast cancer (BC). Epigenetic alterations of the Homeobox A2 (HOXA2) gene have recently garnered significant attention in the clinical management of various malignancies. However, the precise role of HOXA2 in breast tumorigenesis has remained elusive. To address this point, we conducted high-throughput RNA sequencing and DNA methylation array studies on laser-microdissected human BC samples, paired with normal tissue samples. Additionally, we performed comprehensive in silico analyses using large public datasets: TCGA and METABRIC. The diagnostic performance of HOXA2 was calculated by means of receiver operator characteristic curves. Its prognostic significance was assessed through immunohistochemical studies and Kaplan-Meier Plotter database interrogation. Moreover, we explored the function of HOXA2 and its role in breast carcinogenesis through in silico, in vitro, and in vivo investigations. Our work revealed significant hypermethylation and downregulation of HOXA2 in human BC tissues. Low HOXA2 expression correlated with increased BC aggressiveness and unfavorable patient survival outcomes. Suppression of HOXA2 expression significantly heightened cell proliferation, migration, and invasion in BC cells, and promoted tumor growth in mice. Conversely, transgenic HOXA2 overexpression suppressed these cellular processes and promoted apoptosis of cancer cells. Interestingly, a strategy of pharmacological demethylation successfully restored HOXA2 expression in malignant cells, reducing their neoplastic characteristics. Bioinformatics analyses, corroborated by in vitro experimentations, unveiled a novel implication of HOXA2 in the lipid metabolism of BC. Specifically, depletion of HOXA2 leaded to a concomitantly decreased expression of PPARγ and its target CIDEC, a master regulator of lipid droplet (LD) accumulation, thereby resulting in reduced LD abundance in BC cells. In summary, our study identifies HOXA2 as a novel prognosis-relevant tumor suppressor in the mammary gland.

Humans↗

PubMed2025

Epigenetic Regulation in Dilated Cardiomyopathy.

Dilated cardiomyopathy (DCM) is a nonischemic heart muscle disease characterized by impaired contractility, cardiac dilation, and heart failure, with both genetic and nongenetic causes. Emerging evidence highlights epigenetic mechanisms, including deoxyribonucleic acid methylation, histone modifications, chromatin remodeling, and noncoding RNAs, as critical regulators of gene expression in DCM pathogenesis. This article explores familial DCM linked to pathogenic variants in genes like lamin A/C and titin, as well as nongenetic forms such as diabetic and autoimmune DCM. By summarizing recent discoveries, it highlights the epigenetic factors in bridging genetic and environmental influences, offering potential biomarkers and therapeutic targets for improved DCM management.

Humans↗

PubMed2025

Comprehensive analysis of DNA methylome and transcriptome reveals the epigenetic regulation of nitric oxide treatment in delaying apricot fruit senescence.

Apricot produces climacteric fruit, which are perishable after harvest. To elucidate the regulatory role of NO treatment through DNA methylation in post-harvest senescence, apricot fruits were treated with 0.2 mmol/L sodium nitroprusside (SNP) solution for 10 min, with distilled water treatment serving as the control. Treated fruits were then stored at 25°C and 80% relative humidity. Changes in appearance quality, physiological parameters, metabolome profiles, transcriptome dynamics, and DNA methylation patterns were analyzed before and after storage. Results showed that NO treatment delayed apricot softening, increased flavonoid metabolite accumulation, and reduced lipid and abscisic acid accumulation, with these effects correlated to the expression of specific genes and transcription factors. This work reveals the epigenetic regulatory mechanism underlying NO treatment delaying ripening and senescence. Further analysis revealed that the transcription levels of ACO, PAL, UFGT-like, NCED1, PP2C, MYB21, CCoAOMT-like, CYP707A, and ZNF7-like were all correlated with DNA methylation. This indicates that SNP treatment can lead to large changes in DNA methylation levels in apricot fruits, and that the differences in gene transcription levels are associated with the occurrence of hypomethylation and hypermethylation. Collectively, these findings establish an epigenetic framework for post-harvest regulation of apricot fruit, revealing DNA methylation-mediated freshness preservation mechanisms.

DNA Methylation↗

PubMed2026

Histone variant H2A.J is an epigenetic regulator of metastasis in lung adenocarcinoma.

Metastasis is a major contributor to poor patient survival in lung adenocarcinoma (LUAD); however, the underlying mechanisms remain incompletely understood. Unlike tumorigenesis-associated mutations, recurrent genetic alterations specifically linked to metastasis have not been identified, suggesting that epigenetic mechanisms may play a key role. In this study, we report that histone H2A variant H2A.J expression is significantly down-regulated in LUAD, and that low H2A.J levels are associated with unfavorable survival outcomes. Functional assays revealed that H2A.J overexpression suppresses cancer cell invasion and metastatic potential by modulating the expression of metastasis-associated genes, including TMEM158. Mechanistically, H2A.J is deposited in the promoter region of TMEM158, where it alters the local chromatin status to suppress transcriptional activity. Taken together, our findings suggest that H2A.J functions as an epigenetic suppressor of metastasis in LUAD and highlights its potential as both a prognostic biomarker and a therapeutic target to metastatic progression.

Humans↗