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The effects of diabetes mellitus include long-term damages, dysfunctions, and failures of various organs. An important complication of diabetes is the disturbance in the male reproductive system. Glucose metabolism is an important event in spermatogenesis. Moreover, glucose metabolism is also important for maintaining basic cell activity, as well as specific functions, such as motility and fertilization ability in mature sperm. Diabetic disease and experimentally induced diabetes both demonstrated that either type 1 diabetes or type 2 diabetes could have detrimental effects on male fertility, especially on sperm quality, such as sperm motility, sperm DNA integrity, and ingredients of seminal plasma. Epigenetic modifications are essential during spermatogenesis. The epigenetic regulation represents chromatin modifications including DNA methylation, histone modifications, remodeling of nucleosomes and the higher-order chromatin reorganization and noncoding RNAs. If spermatogenesis is affected during the critical developmental window, embryonic gonadal development, and germline differentiation, environmentally-induced epigenetic modifications may become permanent in the germ line epigenome and have a potential impact on subsequent generations through epigenetic transgenerational inheritance. Diabetes may influence the epigenetic modification during sperm spermatogenesis and that these epigenetic dysregulation may be inherited through the male germ line and passed onto more than one generation, which in turn may increase the risk of diabetes in offspring.

Linker histone H1.2 (H1.2), as a member of the histone H1 family involved in many cellular physiological regulatory functions, plays a vital role in maintaining nucleosome and chromatin stability. Cyclic GMP-AMP synthase (cGAS) is a critical cytoplasmic DNA sensor that activates the downstream STING pathway by synthesizing 2′3′-cGAMP, which, in turn, triggers IFN-I response following double-stranded DNA virus infection. This study demonstrates that histone H1.2 is an essential negative regulator of cGAS, inhibiting antiviral immunity during HSV-1 infection. Mechanistically, H1.2 affects the activity of the Lys240 site of cGAS to affect the combination of cGAS with chromatin and promotes the degradation of cGAS in the nucleus by recruiting TRIM28, finally suppressing its IFN response. Moreover, HSV-1 infection downregulates H1.2 expression by reducing the mRNA levels of its transcription factor Sp1, thus allowing cGAS release to activate type I interferon signaling. Additionally, plicamycin, a selective inhibitor of Sp1, can reduce H1.2 expression and enhance antiviral immunity in mice against HSV-1 infection. These findings elucidate the function and regulatory mechanisms of the Sp1-H1.2-cGAS axis in innate immunity and propose new targets and strategies for antiviral drug development.IMPORTANCEPrevious studies on histone H1.2 mainly focused on its function of DNA damage repair and chromatin stability. However, our research found the new function and mechanism of H1.2 in anti-infection immune regulation and confirmed H1.2 as an important negative regulatory molecule responsible for inhibition of cGAS, the important sensor in pathogenic recognition. In the nucleus, H1.2 maintained the inactive state of cGAS by promoting its combination to chromatin and recruiting TRIM28 to degrade the inactive cGAS. We revealed the mechanism of host cells regulating antiviral immunity through the Sp1-H1.2-cGAS axis and found plicamycin could be used as a potential anti-infective drug. These data may offer important reference value for innate immune research.

EBV + gastric cancer contains hypermethylated DNA, and despite this distinct molecular phenotype, there are currently no Epstein–Barr virus (EBV)-specific treatments available. Using an FDA-approved inhibitor to target hypermethylated DNA and multiomics approach to study the cellular response, we uncovered epigenetically altered transcriptional networks that may be further exploited to improve potential therapy. Among the pathways disrupted, retinoic acid signaling is of particular interest, as retinoid receptors such as retinoic acid receptor α and RARβ are frequently hypermethylated and repressed in EBV-associated gastric cancer. Our findings indicate that DNA methyltransferase inhibition can partially reverse all-trans retinoic acid (ATRA) receptor silencing, supporting further investigation of DNA methyltransferase inhibitor–ATRA combination strategies as a novel therapy for EBV + gastric cancer.

Lysine lactylation (Kla), an emerging post-translational modification, bidirectionally regulates cell fate decisions through epigenetic reprogramming and the direct modification of key ferroptosis proteins. It drives disease progression or mediates therapeutic resistance in inflammation, neurodegenerative diseases, cancer and ischemia-reperfusion injury, with its regulatory direction being disease-type-dependent. The present review discusses the functions of the Kla-ferroptosis regulatory network, unraveling the role of Kla-ferroptosis in diseases and its therapeutic implications. The present review aimed to provide novel perspectives for the treatment of human diseases.

Epstein-Barr virus (EBV) persists in infected cells by maintaining its episome through the viral protein EBNA1. We discovered that PIAS1 SUMOylates EBNA1 at specific sites, a process essential for EBNA1 to retain the viral episome and suppress reactivation. When SUMOylation is disrupted, the EBV-based replicon becomes less stable, and EBV is more likely to reactivate. These findings reveal a new layer of host control of EBV latency and reactivation and highlight PIAS1-mediated EBNA1 SUMOylation as a key mechanism regulating viral persistence.

The interaction between HIV-1 and the cellular protein CPSF6 has been known for over 15 years; however, depletion of CPSF6 does not impair productive infection. An alternative possibility is that the virus exploits this protein to modulate cellular processes. This study demonstrates that HIV-1 infection alters the cellular function of CPSF6, an essential regulator of alternative polyadenylation—a mechanism that controls 70% of gene expression. Here, we show that HIV-1 regulates gene expression by disrupting the alternative polyadenylation function of CPSF6 through direct interaction. Overall, this reveals a novel strategy employed by the virus to modulate cellular gene expression.

In flowering plants, the female gametophyte (FG) initiates from the formation of the megaspore mother cell (MMC). Among a pool of the somatic cells in the ovule primordium, only one hypodermal cell undergoes a transition of cell fate to become the MMC. Subsequently, the MMC undergoes a series of meiosis and mitosis to form the mature FG harboring seven cells with eight nuclei. Although SPL/NZZ , the core transcription factor for MMC formation, was identified several decades ago, which and why only one somatic cell is chosen as the MMC have long remained mysterious. A growing body of evidence reveal that MMC formation is associated with epigenetic regulation at multiple layers, including dynamic distribution of histone variants and histone modifications, small RNAs, and DNA methylation. In this review, we summarize the progress of epigenetic regulation in the MMC formation, emphasizing the roles of chromosome condensation, histone variants, histone methylation, small RNAs, and DNA methylation.

The neural crest transcription factor BRN3A is essential for the proliferation and survival of melanoma cells. It is frequently expressed in melanoma but not in normal melanocytes or benign nevi. The mechanisms underlying the aberrant expression of BRN3A are unknown. Here, we investigated the epigenetic regulation of BRN3A in melanocytes and melanoma cell lines treated with DNA methyltransferase (DNMT), histone acetyltransferase (HAT), and histone deacetylase (HDAC) inhibitors. DNMT and HAT inhibition did not significantly alter BRN3A expression levels, whereas panHDAC inhibition by trichostatin A led to increased expression. Treatment with the isoform-specific HDAC inhibitor mocetinostat, but not with PCI-34051, also increased BRN3A expression levels, suggesting that class I HDACs HDAC1, HDAC2, and HDAC3, and class IV HDAC11, were involved in the regulation of BRN3A expression. Transient silencing of HDACs 1, 2, 3, and 11 by siRNAs revealed that, specifically, HDAC2 inhibition was able to increase BRN3A expression. ChIP-Seq analysis uncovered that HDAC2 inhibition specifically increased H3K27ac levels at a distal enhancer region of the BRN3A gene. Altogether, our data suggest that HDAC2 is a key epigenetic regulator of BRN3A in melanocytes and melanoma cells. These results highlight the importance of epigenetic mechanisms in regulating melanoma oncogenes.

Functional studies of organisms and human models have revealed that epigenetic changes can significantly impact the process of aging. Non-coding RNA (ncRNA), one of epigenetic regulators, plays an important role in modifying the expression of mRNAs and their proteins. It can mediate the phenotype of cells. It has been reported that nc886 (=vtRNA2-1 or pre-miR-886), a long ncRNA, can suppress tumor formation and photo-damages of keratinocytes caused by UVB. The aim of this study was to determine the role of nc886 in replicative senescence of fibroblasts and determine whether substances capable of controlling nc886 expression could regulate cellular senescence. In replicative senescence fibroblasts, nc886 expression was decreased while methylated nc886 was increased. There were changes of senescence biomarkers including SA-β-gal activity and expression of p16INK4A and p21Waf1/Cip1 in senescent cells. These findings indicate that the decrease of nc886 associated with aging is related to cellular senescence of fibroblasts and that increasing nc886 expression has potential to suppress cellular senescence. AbsoluTea Concentrate 2.0 (ATC) increased nc886 expression and ameliorated cellular senescence of fibroblasts by inhibiting age-related biomarkers. These results indicate that nc886 has potential as a new target for anti-aging and that ATC can be a potent epigenetic anti-aging ingredient.

Lactate has moved from being viewed as an inert glycolytic end-product to a pleiotropic metabolite that shapes cellular signaling and gene regulation. A major inflection point is the identification of lysine lactylation (Kla), a post-translational modification that can couple glycolytic state to chromatin remodeling and protein function. In the central nervous system, lactate production, compartmentalization, and transport—coordinated by cell-type–specific expression of lactate dehydrogenases and monocarboxylate transporters within the neurovascular unit—create dynamic microenvironments that are increasingly recognized as determinants of neuroinflammatory tone. Emerging evidence indicates that Kla occurs on both histone and non-histone substrates and can reprogram inflammatory and stress-response networks in microglia, astrocytes, endothelial cells, and neurons, intersecting with canonical pathways such as NF-κB, inflammasome signaling, and cytokine-driven transcriptional programs. However, the field faces key mechanistic and translational gaps, including incomplete definition of Kla “writers/erasers/readers,” uncertainty about the quantitative relationship between lactate flux and site-specific lactylation, and marked context dependence across disease stage, cell state, and brain region. This review integrates current understanding of CNS lactate metabolism and trafficking with the expanding landscape of Kla biology, synthesizes cell- and disease-specific evidence across acute injury and neurodegeneration, and outlines priorities for causal mapping, biomarker development, and time-windowed, cell-targeted therapeutic strategies that attenuate maladaptive inflammation without compromising repair.