Search Results (244)

RNA N⁶-methyladenosine (m⁶A) is a prevalent epitranscriptomic modification that governs plant growth, development, and environmental adaptation. This review synthesizes recent advances in understanding the molecular mechanisms and biological functions of m⁶A in plants. The m⁶A landscape is dynamically regulated by methyltransferases (writers), demethylases (erasers), and m⁶A-binding proteins (readers), which collectively influence mRNA stability, translation efficiency, alternative polyadenylation (APA), and chromatin crosstalk. Functionally, m⁶A integrates diverse developmental processes—including embryogenesis, organogenesis, flowering, fruit ripening, and leaf senescence—with abiotic stress responses such as salt, drought, cold, and heat. Notably, m⁶A modification exhibits remarkable species-, cultivar-, and tissue-specific plasticity, enabling precise spatiotemporal gene regulation. Recent breakthroughs have revealed bidirectional crosstalk between m⁶A and histone modifications, forming a multi-layered regulatory network, while emerging concepts including phase separation, RNA structure dynamics, and stress memory further expand the functional repertoire of m⁶A. Despite significant progress, plant epitranscriptomics remains mechanistically underexplored, with critical gaps persisting in our understanding of translation initiation mechanisms, upstream regulatory signals controlling writers/erasers activities, and the functional significance of individual m⁶A sites. This review provided systematic insights into the complexity and specificity of m⁶A regulation in plants, offering a theoretical foundation for future efforts to decipher and ultimately manipulate this epitranscriptional layer for crop improvement. Full article

The ubiquitously transcribed tetratricopeptide repeat Y-linked gene (UTY/KDM6C), a catalytically impaired histone demethylase encoded on the Y chromosome, has garnered increasing attention for its emerging roles in tumorigenesis and cancer progression. Despite high sequence homology with its X-linked paralog UTX/KDM6A, UTY exhibits markedly reduced or absent H3K27me3 demethylase activity due to critical amino acid substitutions in its Jumonji C domain. Consequently, UTY primarily functions through non-enzymatic mechanisms, acting as a scaffold in chromatin-remodelling complexes like COMPASS and SWI/SNF, or mediating protein–protein interactions that regulate transcriptional programs independent of demethylation. This aligns with epigenetic dysregulation in cancers, where imbalances in repressive H3K27me3 and active H3K4me either drive tumour suppressor silencing or oncogene activation. Unlike frequently mutated UTX in cancers such as breast, renal cell carcinoma, and acute myeloid leukaemia, UTY’s contributions in cancer are less defined, constrained by male-specific expression. Emerging evidence suggests UTY as a context-dependent tumour suppressor in AML and squamous-like pancreatic ductal adenocarcinoma. While direct functional validation remains limited in several cancer types, UTY is increasingly implicated as a potential tumour suppressor in haematological malignancies and prostate cancer. Therapeutically targeting UTY’s scaffold functions shows promise for male-specific cancers and merits future investigation. Full article

Histone demethylases regulate epigenetic modifications and DNA damage repair in fungal pathogens, yet their specific functions in Magnaporthe oryzae remain poorly understood. This study identifies MoRph1, a JmjC domain-containing histone demethylase that interacts with the COMPASS complex. Targeted deletion of MoRph1 resulted in significantly reduced vegetative growth, impaired conidiation, and defective appressorium formation. The mutant displayed compromised appressorial turgor pressure due to delayed degradation of glycogen and lipid reserves, leading to inefficient host penetration and attenuated virulence on rice and barley. MoRph1 localized to the nucleus, and its absence caused increased nuclear abnormalities under DNA damage stress, suggesting impaired genome stability maintenance. Biochemical analysis confirmed that MoRph1 specifically demethylates histone H3 lysine 36 trimethylation. Transcriptome analysis revealed altered expression of genes associated with DNA replication, mismatch repair, and oxidative stress response. These results establish MoRph1 as a crucial epigenetic regulator coordinating fungal development, infection structure function, energy mobilization, and DNA damage repair. This study underscores the importance of chromatin-level regulation in fungal pathogenicity and provides a foundation for future evaluation of MoRph1 as a potential antifungal target. Full article

Background: Intracerebral hemorrhage (ICH) is a devastating subtype of stroke, in which neuroinflammation and blood–brain barrier (BBB) disruption are secondary pathophysiological events that drive progressive brain injury. Histone lysine demethylase JMJD3 (Jumonji C domain-containing protein 3) is a master epigenetic switch governing inflammatory signaling; however, its participation in ICH-induced vascular disruption and its possible mechanism remain elusive. Objective: To examine the expression patterns of JMJD3 in the context of ICH and to evaluate the therapeutic potential of its specific inhibitor, GSK-J4, in attenuating neuroinflammation and BBB disruption in a murine ICH model. Methods: Hemin treatment of a mouse C8-D1A astrocytic cell line was used to develop an in vitro ICH model. The transcript level of the Jmjd3 gene and its correlation with pro-inflammatory signaling were analyzed with or without GSK-J4 pretreatment. ICH in vivo was created experimentally in adult male C57BL/6 mice through stereotactic striatal injection of collagenase IV, and the mice were randomly assigned to sham, ICH + vehicle, and ICH + GSK-J4 (30 mg/kg intraperitoneally (i.p.), every other day starting three days before ICH) groups. At three days post-ICH, ipsilateral brain tissues were collected to detect JMJD3 cellular localization, pro-inflammatory mediator levels, tight junction protein expression, BBB ultrastructure, and hematoma volume. White matter integrity and neuronal recovery were assessed on day 7, and sensorimotor function was assessed longitudinally on days 1, 3, 5, 7, and 14. Results: Jmjd3 gene transcription was upregulated in hemin-treated astrocytes and correlated positively with IL-6 pro-inflammatory signaling activation. In vivo, the co-localization of JMJD3 with the astrocytic identifier glial fibrillary acidic protein (GFAP) was markedly increased in the area adjacent to the hematoma at three days post-ICH. GSK-J4 administration significantly suppressed the pro-inflammatory signaling cascade by decreasing the levels of inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α), and matrix metalloproteinase-9 (MMP-9), enhanced brain vascular structural and functional integrity by upregulating tight junction proteins zonula occludens protein-1 (ZO-1) and claudin-5, improved BBB ultrastructural integrity, and decreased hematoma volume at three days post-ICH. Furthermore, GSK-J4 administration promoted white matter integrity (increased myelin basic protein [MBP] expression) and neuronal recovery (increased neuron-specific nuclear protein [NeuN] expression) at seven days post-ICH and significantly improved the performance of ICH mice in sensorimotor behavioral tests. Conclusions: Astrocytic JMJD3 is upregulated following ICH and promotes neuroinflammation, which in turn mediates BBB disruption. Pharmacological inhibition of JMJD3 by GSK-J4 attenuates neuroinflammation and subsequent BBB damage, accelerates hematoma resolution, and promotes histological and functional recovery after ICH, likely by downregulating MMP-9 expression. These findings identify astrocytic JMJD3 as a novel epigenetic therapeutic target for acute ICH. Full article

The efficacy of the host antiviral response against Influenza A virus (IAV), a leading cause of global pandemics, hinges upon the rapid recognition of the pathogen and the prompt activation of immune mechanisms. Nevertheless, the epigenetic landscape that orchestrates this antiviral response remains largely elusive. Here, we identify histone demethylase JMJD2D as a critical regulator in defense against IAV infection. A significant upregulation of JMJD2D expression was observed clinically in response to IAV infection, indicating that JMJD2D may play a role in regulating IAV infection. Indeed, JMJD2D-deficient mice exhibit increased susceptibility to IAV, characterized by elevated viral loads, severe lung tissue damage, and reduced survival rates, suggesting that JMJD2D plays an essential role in defense against IAV infection. Consistently, knockdown or pharmacological inhibition of JMJD2D in lung cells suppressed IAV replication and the IAV-triggered innate immune response. Mechanistically, JMJD2D suppressed IAV infection by removing H3K9me3 at the promoter region of retinoic acid inducible gene-I (RIG-I) and cooperating with NF-κB to enhance the expression of RIG-I, a critical sensor for IAV RNA. This study identifies JMJD2D as an epigenetic rheostat that governs RIG-I-mediated antiviral signaling, highlighting its potential as a therapeutic target for mitigating severe IAV infection. Full article

Drought stress is a major abiotic factor limiting maize yield and stability. Although Jumonji C (JMJ) histone demethylases are known to regulate plant growth, development, and stress responses, their systematic characterization in maize has remained limited. Here, 27 ZmJMJ genes were identified in the maize genome through BLAST and conserved-domain analyses and classified into five subfamilies: JMJD6, KDM3/JHDM2, KDM4/JHDM3, KDM5/JARID1, and JmjC domain-only. Members within the same subfamily showed similar physicochemical properties, domain composition, and motif distribution, whereas clear divergence was observed among subfamilies. Chromosomal mapping revealed that ZmJMJ genes were unevenly distributed across nine chromosomes, with two interchromosomal homologous gene pairs, suggesting roles for segmental and/or whole-genome duplication in family expansion. Promoter analysis indicated widespread enrichment of elements related to light responsiveness, growth and development, and hormone and stress responses. Expression profiling showed that most ZmJMJ genes were highly expressed in leaves, while several displayed tissue specificity. Under drought stress, ZmJMJ17a, ZmJMJ17b, ZmJMJ28, and ZmJMJ32 were significantly induced, highlighting them as promising candidates for functional studies and molecular breeding for drought tolerance in maize. This study provides a foundation for elucidating the evolution and functions of the ZmJMJ family and identifies candidate genes for drought-related functional validation and molecular breeding. Full article

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, driven by aggressive tumor biology, extensive intratumoral heterogeneity, and profound resistance to standard therapies. While recurrent genetic alterations such as KRAS mutations are central to PDAC initiation, growing evidence demonstrates that epigenetic dysregulation is a critical determinant of disease progression, cellular plasticity, immune evasion, and therapeutic failure. Epigenetic mechanisms, including DNA methylation, histone modifications, chromatin remodeling, and non-coding RNA regulation, shape transcriptional programs without altering the underlying DNA sequence, rendering them dynamic and potentially reversible therapeutic targets. This review provides a comprehensive overview of key epigenetic proteins implicated in PDAC, encompassing writers, readers, and erasers of chromatin marks. Aberrant activity of histone methyltransferases and acetyltransferases, bromodomain-containing proteins, histone deacetylases, and demethylases orchestrates transcriptional reprogramming that promotes epithelial–mesenchymal transition, stem-like phenotypes, metabolic adaptation, and resistance to chemotherapy and radiotherapy. In parallel, epigenetic alterations within the tumor microenvironment contribute to stromal activation and immune suppression, further limiting therapeutic efficacy. We summarize recent advances in pharmacological targeting of epigenetic regulators and discuss the rationale for combination strategies integrating epigenetic inhibitors with cytotoxic agents, targeted therapies, and immunotherapies. Emphasis is placed on emerging experimental platforms—including patient-derived organoids, co-culture systems, and in vivo models—combined with multi-omic profiling and computational approaches to identify biomarkers of response and optimize therapeutic design. Collectively, this review highlights epigenetic regulation as a central and actionable vulnerability in PDAC and outlines future directions toward biomarker-guided, personalized epigenetic therapies aimed at overcoming resistance and improving clinical outcomes. Full article

Chromatin architecture is highly dynamic, undergoing nanoscale rearrangements throughout the cell cycle and in response to environmental cues. In this study, we employed high-resolution stochastic optical reconstruction microscopy (STORM) to visualize chromatin organization and cellular plasticity at the nanoscale in two osteosarcoma cell lines, U2OS and MG63. To promote a tumor-suppressive bone microenvironment, we applied three biophysical modalities, namely mechanical vibration, electrical stimulation, and optical pulses, each previously linked to altered tumor behavior by reprogramming cells and generating induced tumor-suppressing (iTS) cells. These stimuli enlarged nuclear size and disrupted nuclear envelope integrity, as revealed by increased surface roughness. Critically, all three modalities transiently scattered nucleosome clusters, indicating chromatin decondensation as a hallmark of iTS cell generation. iTS cells exhibited elevated expression of histone demethylases lysine demethylase 3A (KDM3A) and lysine demethylase 4 (KDM4), accompanied by reduced levels of trimethylated histone H3 lysine 9 (H3K9me3). Consistently, pharmacological agents—Trichostatin A as a histone deacetylase inhibitor and chaetocin as a histone methyltransferase inhibitor—induced nucleosome scattering and converted U2OS cells into iTS cells, whose conditioned media exerted tumor-suppressive effects. Our findings highlight nucleosome clustering as a key epigenetic feature responsive to both biophysical and chemical cues, underscoring its role in microscale chromatin remodeling and reprogramming of the tumor microenvironment. Full article

For decades, 8-oxoguanine (8-oxoG) has been recognized as a pervasive and pro-mutagenic oxidative DNA lesion. In human cells, 8-oxoG is removed from DNA via the base excision repair pathway initiated by 8-oxoguanine–DNA glycosylase (OGG1). However, emerging evidence over the past twenty years suggests a more complex, regulatory role for this DNA modification. Here, we discuss findings that 8-oxoG, particularly when present in gene promoters, can act as a signal to modulate transcription, establishing an 8-oxoG/OGG1 axis in the inflammatory response. Proposed mechanisms include the generation of 8-oxoG during chromatin remodeling processes involving histone demethylases, the recruitment of transcription factors (NF-κB, HIF1α, Myc, SMAD, etc.) by OGG1, and the lesion’s enrichment in guanine-rich sequences prone to forming G-quadruplex structures. The pro-mutagenic nature of 8-oxoG and the lack of dedicated, functionally separate writer and reader proteins challenge its classification as a true epigenetic DNA mark, distinguishing it from canonical epigenetic nucleobases like 5-methylcytosine and 5-hydroxymethylcytosine. On the other hand, 8-oxoG is well suited for the role of a regulatory signal localized to DNA and involved in the cellular response to oxidative stress and the associated physiological stimuli. Full article

The dynamic regulation of histone methylation is a key mechanism for epigenetic regulation of gene expression. As histone demethylases dependent on divalent iron ions and α-ketoglutarate, the JmjC family plays an important role in plant life activities. Fifty JmjC domain-containing proteins in Arabidopsis thaliana (21) and Brassica rapa (29) are divided into seven distinct groups, with each group endowed with specific functions due to unique structural domains. Some members achieve functional specificity by recognizing specific DNA motifs or interacting with transcription factors, and others exhibit special functional modes due to mutations in their binding sites. By targeting specific genes (such as FLC, FT, WRKY family, PR genes, etc.), they regulate growth and development processes, as well as responses to multiple biotic and abiotic stresses. Focusing on inter-species divergence of Arabidopsis and Brassica, this review summarized JmjC proteins’ structural classification, substrate specificity, and mechanisms, providing a basis for dissecting plant epigenetic networks and guiding Brassica crop breeding desired bolting traits (early or late bolting), high stress resistance and so on. Full article

Nutrient deprivation causes dedifferentiation in solid tumors, driving an aggressive phenotype. We previously showed that glucose starvation-induced dedifferentiation is driven by epigenetic changes induced by a deficit of alpha-ketoglutarate (α-KG). Deficient activity of α-KG-dependent histone demethylases leads to unbalanced hypermethylation of histone 3 on lysine 27 (H3K27) by methyltransferase EZH2. H3K27 hypermethylation is a key mechanism of starvation-induced dedifferentiation. Here, we investigate a new aspect of this mechanism and show that epitranscriptomic changes are also induced by glucose restriction. Specifically, hypermethylation of select long non-coding RNAs leads to their upregulation under glucose deprivation as a consequence of reduced activity of the RNA demethylase FTO. We identified LINC00662 as an lncRNA required for EZH2 recruitment to target gene promoters induced by low glucose. These findings characterize the epigenetic response to glucose restriction beyond histone methylation, revealing that RNA methylation of lncRNAs such as LINC00662 represents a parallel mechanism converging on EZH2. Full article

The malate–aspartate shuttle (MAS) is an NADH shuttle that transports cytoplasmic reducing equivalents to the mitochondria for producing energy. We previously demonstrated that K-demethylase 2A (KDM2A), a jmjC-type histone demethylase, decreases ribosomal RNA (rRNA) transcription via demethylation of H3K36me2 in the rRNA gene promoter region in response to energy reduction in MCF-7 cells. However, whether MAS inhibition is involved in KDM2A activity has not been investigated. In this study, we demonstrate that aminooxyacetic acid (AOA), which inhibits aspartate transaminase (AST/GOT) in MAS, decreased intracellular ATP levels and reduced rRNA transcription via KDM2A-dependent reduction in H3K36me2 levels in the rRNA gene promoter in MCF-7 cells. On the other hand, N-phenylmaleimide (NPM), which inhibits the mitochondrial αKG/malate carrier SLC25A11 in MAS, also decreased intracellular ATP levels but did not induce KDM2A activity. Additionally, NPM pretreatment or knockdown of SLC25A11 inhibited AOA-induced KDM2A activity. Dimethyl αKG, a cell-permeable αKG, restored KDM2A activity inhibited by NPM-pretreatment in AOA-treated cells. These results demonstrate that AOA and NPM have different abilities to induce a decrease in rRNA transcription via KDM2A. Furthermore, the αKG/malate carrier SLC25A11 is associated with KDM2A-dependent reduction in rRNA transcription via demethylation under MAS inhibition. Full article

JC virus (JCV) replicates within the nuclei of glial cells in the human brain and causes progressive multifocal leukoencephalopathy. JCV possesses a small, circular, double-stranded DNA genome, divided into early and late protein-coding regions. The non-coding control region (NCCR) functions bidirectionally for both early and late genes, and the agnogene is located downstream of TCR and upstream of three capsid proteins in the late region. Previously, in cell culture systems, we demonstrated that these capsid proteins accumulate in intranuclear domains known as promyelocytic leukemia nuclear bodies (PML-NBs), where they assemble into virus-like particles (VLPs). To investigate the agnogene’s function, VLPs were formed in its presence or absence, and differential gene expression was analyzed using microarray technology. The results revealed altered expression of histone-modifying enzymes, including methyltransferases (EHMT1, PRMT7) and demethylases (KDM2B, KDM5C, KDM6B), as well as various kinases and phosphatases. Notably, CTDP1, which dephosphorylates the C-terminal domain of an RNA polymerase II subunit, was also differentially expressed. The changes were predominant in the presence of the agnogene. These findings indicate that the agnogene and/or its protein product likely influence epigenetic regulation associated with PML-NBs, which may influence cell cycle control. Consistently, in human brain tissue, JCV-infected glial cells displayed maintenance of a diploid chromosomal complement, likely through G2 arrest. The precise mechanism of this, however, remains to be elucidated. Full article

Myocardial infarction triggers limited repair in adult mammals but robust regeneration in zebrafish. Epigenetic regulation and immune responses are recognized as critical for successful regeneration. However, the molecular links between these processes have not been fully elucidated. By performing single-cell RNA sequencing of zebrafish ventricular cardiomyocytes after injury, we identified a regeneration-induced immunomodulatory cluster that specifically expressed the histone demethylase gene kdm7aa. Functional perturbations, including CRISPR/Cas9-mediated kdm7aa mutation and pharmacological inhibition of Kdm7aa activity using TC-E5002, impaired cardiac regeneration. Bulk RNA sequencing showed that kdm7aa drives an inflammatory transcriptional program, prominently activating chemokines such as cxcl8a and cxcl19 that coordinate immune cell recruitment. Cross-species analyses revealed injury-induced Kdm7a upregulation in regeneration-competent neonatal mouse hearts but not in adult mouse or human hearts. These data identified Kdm7aa as a regeneration-induced epigenetic regulator that enabled cardiomyocytes to adopt a transient immune-activating phenotype, linking histone demethylation to chemokine signaling and suggesting a potential therapeutic strategy to enhance mammalian cardiac repair. Full article

JmjC domain proteins play crucial roles in plant growth and development, regulation of epigenetic processes, flowering control, and stress defence. However, these proteins have not been systematically identified or characterised in tomato. Here, we performed a genome-wide identification of JmjC domain-containing genes (JMJ family) in tomato and identified 23 SlJMJ genes within the tomato genome. Expression analysis indicated that SlJMJ15 was responsive to drought stress, prompting us to investigate its functional role in tomato plants. We found that SlJMJ15-RNAi lines displayed a severe dwarf phenotype, whereas SlJMJ15-overexpression lines exhibited increased drought sensitivity compared to wild-type plants, indicating that SlJMJ15 negatively regulates drought tolerance in tomatoes. Further investigation suggests that SlJMJ15 may reduce drought tolerance in tomatoes by modulating the expression of key genes involved in abscisic acid signalling pathways through its demethylation activity. This study deepens our understanding of the roles of SlJMJ family genes in tomato growth and abiotic stress responses, laying the foundation for developing strategies to improve drought stress tolerance in tomatoes. Full article