Search Results (1,386)

Basonuclin 2 (BNC2) is a highly conserved cysteine–histidine (C2H2)-type zinc-finger nuclear regulatory protein characterized by three pairs of zinc-finger domains, a putative nuclear localization signal, a serine-rich region, broad tissue distribution, and remarkable transcript diversity generated through alternative promoter usage, alternative splicing, and polyadenylation. Increasing evidence from human genetics, animal models, functional genomics, and transcriptomic studies indicates that BNC2 links nuclear regulatory mechanisms to tissue-specific developmental and disease phenotypes. In the nervous system, BNC2-positive neuronal populations and BNC2-derived circular RNAs have been implicated in energy-balance circuits and neuroinflammatory regulation. In the skeletal system, BNC2 contributes to osteochondral development, periosteal stem-cell activation, chromatin remodeling, fracture repair, and genetic susceptibility to adolescent idiopathic scoliosis. BNC2 variants have also been associated with congenital lower urinary tract obstruction, whereas its expression and regulatory landscape are closely related to germ-cell development, epithelial ovarian cancer susceptibility, pigmentation traits, fibrosis, and several tumor contexts. Mechanistically, BNC2-associated phenotypes appear to involve cysteine–histidine zinc-finger-mediated transcriptional regulation, non-coding enhancer activity, epigenetic alterations, RNA-processing-associated nuclear functions, and chromatin-remodeling-dependent control of cell proliferation, differentiation, and stromal activation. This review integrates current evidence on the molecular architecture and regulatory functions of BNC2, critically discusses its context-dependent roles across development and disease, and highlights unresolved questions regarding isoform-specific activity, cell-type-specific regulation, downstream target networks, and clinical translation. A clearer understanding of these mechanisms may support the future evaluation of BNC2 as a biomarker, genetic susceptibility locus, molecular stratification factor, and potential therapeutic regulatory node. Full article

Endocrine-disrupting chemicals (EDCs) are a heterogeneous group of exogenous compounds capable of interfering with hormonal homeostasis and endocrine-regulated physiological processes. Their widespread occurrence in food, water, air, consumer products and industrial materials has raised increasing concern regarding their contribution to chronic disease burden. This review synthesizes current evidence on the exposure characteristics, molecular mechanisms, health effects, and prevention strategies related to major EDC classes, including bisphenol A and phthalates, dioxins and polychlorinated biphenyls, per- and polyfluoroalkyl substances, pesticides, and brominated flame retardants. Evidence indicates that EDCs may act through receptor-mediated signaling, altered hormone synthesis and metabolism, oxidative stress, mitochondrial dysfunction, immune modulation, and epigenetic mechanisms, with effects that may vary according to dose, timing, sex, age, and developmental susceptibility. Reported health outcomes include metabolic and cardiovascular disorders, reproductive dysfunction, hormone-dependent cancers, thyroid disruption, immune dysregulation, and adverse developmental effects. Although complete avoidance is unrealistic, exposure reduction and risk mitigation can be achieved through coordinated individual, clinical, environmental, and regulatory interventions. A life-course approach is essential to limit the health burden associated with endocrine disruption. Full article

DNA methylation is a key epigenetic regulator in plant development. However, the changes in methylation patterns between the early and late stages of grape berry development, the two phases with the most pronounced morphological differences, and the respective roles of methylation at these stages remain largely unexplored. To investigate the dynamic DNA methylation changes during this stage and their regulatory role in fruit development, we constructed genome-wide methylation maps of grape at two key time points: the early development stage (7 days after flowering, 7DAF; hereafter referred to as S1) and the late development stages (78 days after flowering, 78DAF; hereafter referred to as S2). Global cytosine methylation increased from 12.57% (S1) to 14.16% (S2), driven primarily by a substantial increase in CHH methylation (from 5.88% to 7.92%; p < 0.001), whereas CG and CHG methylation showed no statistically significant change. Most differentially methylated regions (DMRs) were hypermethylated in S2, predominantly in the CHH context. Integrative methylome and transcriptome analysis revealed that CHH hypermethylation was associated with the downregulation of YABBY5 (a berry size repressor) and upregulation of UGPase (a cell wall biosynthesis gene), suggesting a potential regulatory role in fruit expansion. Because our study compares only two time points, it cannot distinguish between gradual and stage-specific methylation changes, and functional validation of the identified genes is required. Nevertheless, these findings provides a valuable resource for understanding stage-specific DNA methylation dynamics and their association with gene expression during grape berry development. Full article

Tumor metastasis constitutes a frequent contributor to high mortality rates, with EMT intimately implicated in this disseminative process. Accumulating evidence in recent years indicates that neoplastic cells undergoing EMT frequently exhibit concurrent metabolic reprogramming. Multiple modalities—including glycolysis, mitochondrial oxidative phosphorylation, lipid metabolism, as well as amino acid metabolism—cooperatively supply energy, facilitate membrane remodeling, and sustain redox homeostasis. Specifically, glycolytic flux, oxidative phosphorylation, lipid turnover, and amino acid catabolism/anabolism function in a concerted manner to meet the bioenergetic demands, support biogenesis of cellular membranes, and preserve the intracellular redox equilibrium during phenotypic conversion. Notably, intermediate metabolites can in turn modulate the trajectory of EMT through signal transduction cascades or epigenetic modifications. This review systematically delineates the bidirectional regulatory circuitry interconnecting EMT and metabolic reprogramming; furthermore, it examines the implications of this crosstalk for neoplastic disease progression. Finally, therapeutic strategies targeting the nexus of metabolic reprogramming and EMT are summarized. Full article

Early life stress (ELS) and adverse childhood experiences are critical determinants of neurodevelopmental trajectories and long-term somatic and psychiatric health outcomes. This narrative review synthesizes current evidence, identified through searches in PubMed, Scopus, and Web of Science, on the neurobiological and epigenetic mechanisms through which early environmental exposures shape developmental programming and stress responsivity across the lifespan. A central framework is the dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, which mediates adaptive and maladaptive stress responses. During sensitive developmental periods, including prenatal, perinatal, and early postnatal stages, increased neuroplasticity confers heightened vulnerability to environmental influences, resulting in persistent alterations in stress regulation systems, brain circuitry, and endocrine function. The review further examines the role of maternal stress during gestation, with emphasis on placental regulatory mechanisms and fetal programming processes that establish long-term physiological set points. In parallel, emerging evidence on paternal stress is considered, highlighting potential contributions of germline epigenetic modifications and postnatal environmental transmission pathways. At the molecular level, epigenetic mechanisms—including DNA methylation, histone modifications, and non-coding RNA regulation—are discussed as key mediators linking early environmental exposures to stable changes in gene expression without alterations in DNA sequence. Collectively, the evidence supports ELS as a fundamental biological embedding process with enduring consequences for health across the lifespan. A deeper understanding of these mechanisms, alongside the identification of reliable biomarkers, is essential for early detection and the development of targeted preventive and intervention strategies in pediatric populations. Full article

The dynamic crosstalk between the tumor microenvironment (TME) and triple negative breast cancer (TNBC) cells plays a critical role in tumor progression and treatment resistance. Recent studies have highlighted the involvement of IL-20 receptor subunit alpha (IL-20RA) signaling in BC, where its overexpression modulates oncogenic pathways contributing to invasion and metastasis. Epigenetic dysregulation by Bromodomain and Extra-Terminal domain (BET) proteins critically influences key oncogenic pathways and cytokine expression in TNBC. Given that the BET-inhibitor JQ1 blocks TNBC cell growth, in this study we investigated its potential regulatory effects on the IL-20RA pathway. IL-20RA was found expressed across multiple BC cell lines compared to non-tumorigenic cells, with the highest levels detected in MDA-MB-231 and MDA-MB-468 cells. In both cell lines, JQ1 treatment significantly downregulated IL-20RA expression at gene and protein levels, accompanied by a reduction in the oncogenic JAK/STAT signaling pathway, and programmed death-ligand 1 (PD-L1) expression. Parallel in vivo experiments using TNBC xenograft models confirmed these findings, showing reduced IL-20RA and PD-L1 expression alongside decreased phosphorylation of JAK and STAT3. Overall, this study uncovers a novel interplay between BET inhibition and the IL-20RA/STAT3 axis, suggesting JQ1 as a valid therapeutic option for TNBC characterized by high IL-20RA expression. Full article

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, characterized by a multi-step carcinogenesis process involving genetic mutations and epigenetic alterations. Despite advances in screening and therapy, challenges such as treatment resistance, recurrence, and metastasis persist. Emerging evidence highlights the critical role of epigenetic modifications, particularly N7-methylguanosine (m7G), in post-transcriptional regulation. This ubiquitous RNA modification participates extensively in tumor biological behaviors by regulating RNA stability, processing, and translation. Studies have shown that dysregulation of m7G modification is closely associated with adverse clinical outcomes in CRC. This review systematically summarizes the biological functions of m7G modification and its key regulatory proteins (such as METTL1/WDR4, eIF4E, etc.), with a focus on their roles in the pathogenesis, progression, prognosis, and diagnosis of, as well as therapy for, colorectal cancer. m7G modification and related molecules hold potential as novel biomarkers and therapeutic targets, thereby providing new strategies for the precision diagnosis and treatment of colorectal cancer. Full article

Clear cell renal cell carcinoma (ccRCC) is notorious for its clinical unpredictability. While Aquaporin-1 (AQP1) is a major water channel in healthy kidneys, its specific role and regulatory mechanisms in ccRCC remain unclear. Using bioinformatics analysis of 610 TCGA-KIRC patients (RNA sequencing and DNA methylation), single-cell transcriptomics of 27,402 cells, and experimental validation (CCK-8, scratch, Transwell, and xenograft assays, with Western blotting, HE staining, and immunohistochemistry), we systematically characterized AQP1 expression, regulation, and function. AQP1 was significantly downregulated in ccRCC via promoter hypermethylation, with single-cell analysis confirming tumor cell-specific loss. Low AQP1 correlated with worse prognosis; multivariate Cox regression identified AQP1 as an independent protective factor (HR = 0.510, p < 0.001), and a prognostic nomogram showed good predictive accuracy for 1-, 3-, and 5-year survival. AQP1 overexpression suppressed proliferation, migration, invasion, and xenograft growth, accompanied by upregulation of TNF-α, TNFRSF1A, Bax, and Cleaved Caspase-3 and reduced Vimentin, suggesting activation of TNF-related pro-apoptotic signaling. AQP1 is epigenetically silenced in ccRCC and suppresses tumor growth via TNF-mediated apoptosis, establishing it as an independent prognostic biomarker and candidate therapeutic target. Full article

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, characterized by marked molecular heterogeneity, late-stage diagnosis, and limited therapeutic options. Emerging evidence highlights the interplay between cytoskeletal dynamics, epigenetic regulation, and oncogenic signaling pathways in hepatocarcinogenesis. Histone deacetylase 6 (HDAC6), a key regulator of cytoplasmic protein acetylation, modulates α-tubulin stability, while CTNNB1 (β-catenin) serves as a central effector of the Wnt signaling pathway. However, the existence and functional relevance of a coordinated HDAC6–TUBA1A–CTNNB1 regulatory axis in HCC remain insufficiently explored. We conducted a comprehensive integrative bioinformatic analysis using multiple publicly available datasets and platforms, including TCGA, GEO, GEPIA3, TNMplot, UALCAN, TIMER2.0, STRING, ENCORI, HPA, TargetScan, miRDB, CRISPRdb, GSCALite, and exoRBase. Gene expression, promoter methylation, survival associations, immune infiltration, regulatory RNA interactions, and therapeutic targetability were systematically evaluated. HDAC6 expression was significantly downregulated in HCC tissues, whereas TUBA1A and CTNNB1 were upregulated. Reduced HDAC6 expression was associated with poorer survival outcomes, while TUBA1A and CTNNB1 showed no significant prognostic value. Methylation analysis revealed gene-specific epigenetic alterations, including hypomethylation of CTNNB1 and differential methylation patterns in HDAC6 and TUBA1A. Immune infiltration analysis demonstrated that HDAC6 expression positively correlated with cytotoxic immune cell populations and negatively with immunosuppressive subsets. Regulatory network analyses identified lncRNA–miRNA–mRNA interactions, particularly involving SNHG1. Furthermore, in silico CRISPR targetability and extracellular vesicle (EV) transcript profiling suggested potential translational applicability of this axis. Our findings support a hypothesis of the existence of a dysregulated HDAC6–α-tubulin–β-catenin axis in HCC, linking cytoskeletal remodeling with oncogenic signaling and immune modulation. This axis may indicate a promising candidate for biomarker development and targeted therapeutic strategies, warranting further experimental validation. Full article

The active vitamin D metabolite, 1,25-dihydroxycholecalciferol [1,25(OH)₂D], exerts its biological effects through binding to the vitamin D receptor (VDR), a ligand-activated transcription factor regulating the expression of genes involved in calcium and phosphate homeostasis, immune modulation, and cell proliferation and differentiation. In addition to direct transcriptional regulation, 1,25(OH)₂D signaling also involves epigenetic mechanisms. A total of 90 studies were included in this narrative review, comprising experimental studies (n = 45), observational studies (n = 17), population-based studies (n = 8), interventional studies (n = 15), and mixed-design studies (n = 5). Experimental studies in cell cultures and animal models demonstrate that 1,25(OH)₂D may affect several major epigenetic regulatory pathways, including chromatin remodeling, DNA methylation, histone modifications, and the expression of non-coding RNAs, particularly microRNAs. Preclinical evidence suggests that the epigenetic actions of 1,25(OH)₂D are involved in metabolic regulation, immune responses, bone development, fibrotic processes, carcinogenesis, ageing, and fetal programming. However, evidence from observational studies and randomized controlled trials remains limited and inconclusive. Some studies have reported alterations in miRNA expression, methylation of selected loci, and epigenetic age markers. The clinical relevance of 1,25(OH)₂D–mediated epigenetic regulation has not yet been fully established. The interpretation of available findings is limited by substantial heterogeneity in study populations, exposure and intervention protocols, environmental factors, interindividual variability in response to vitamin D supplementation associated with genetic polymorphisms and methylation status, and the restricted range of analyzed cell types. This subject requires randomized controlled trials integrating molecular endpoints with clinically relevant outcomes. Full article

Ischemic stroke elicits a rapid and sustained innate immune response that critically contributes to blood–brain barrier (BBB) breakdown and secondary neuronal injury. Among the cellular mediators involved, neutrophil extracellular traps (NETs) have emerged as potent effectors of neurovascular damage. However, the regulatory mechanisms governing NET formation and their prolonged impact on BBB integrity remain incompletely understood. Increasing evidence indicates that NET formation is an epigenetically regulated process, requiring chromatin remodeling, histone modifications, DNA methylation changes and non-coding RNA-mediated control within neutrophils under ischemic conditions. These epigenetic events license the extrusion of DNA–histone–enzyme complexes that directly injure endothelial cells, degrade tight junction proteins, activate innate immune signaling pathways and amplify neuroinflammatory cascades at the neurovascular unit. Moreover, NET-derived chromatin and associated mediators can induce transcriptional and epigenetic alterations in BBB cells, thereby sustaining barrier permeability and impairing vascular repair mechanisms. In this review, we synthesize current knowledge on the epigenetic regulation of NET formation and delineate how epigenetically regulated NETs function as key disruptors of BBB integrity in ischemic stroke. Understanding this NETosis–epigenetics–BBB axis may uncover novel therapeutic strategies aimed at preserving neurovascular integrity and limiting post-stroke brain injury. Full article

Chronic infection with the hepatitis C virus (HCV) is the most significant risk factor for the development of hepatocellular carcinoma (HCC). It has been shown that the progression of HCV-related liver disease is mediated by both viral and host-specific factors. The HCV replication cycle is a host-dependent process that relies on intracellular signalling pathways within target cells. Thus, intracellular signal transduction plays a pivotal role in the modification of interactions between the host and HCV. These pathways are key regulators of liver diseases, including cirrhosis and HCC. In addition, HCV induces epigenetic modifications in the host genome that inhibit the expression of various tumour-suppressor genes. Some of these changes persist even after successful antiviral treatment and represent a continued risk for HCC development. Despite significant progress in the management of chronic HCV infection, this challenge remains unresolved. In this narrative review, we summarise the mechanisms of HCV-induced disease progression, focusing on the host immune response, the regulatory roles of viral and cellular proteins, and viral survival strategies during chronic infection. We also discuss HCV-induced epigenetic alterations that contribute to hepatocarcinogenesis both during infection and after viral clearance. These insights are important for identifying novel, reliable molecular biomarkers for patient surveillance and for designing new therapeutic approaches. Full article

Background/Objectives: As important post-transcriptional and epigenetic regulators of gene expression, miRNAs play a pivotal role in modulating host–virus interactions. While prior reviews have addressed either direct miRNA–HIV genome interactions or miRNA-mediated immune modulation in isolation, the integrated dual functionality of these molecules has not been systematically characterized. This review aimed to comprehensively explore how miRNAs that target the HIV-1 genome simultaneously modulate key innate and adaptive host immune signaling pathways. The conceptual novelty of this study is determined not by the identification of previously unknown miRNA-target gene pairs, but by the systemic integration of two regulatory levels (direct inhibition of the viral genome and modulation of the host cell immune signaling pathways) within a unified analytical framework. Such an integrated approach reveals a proviral regulatory network that remains non-obvious when each of these levels is examined separately. Methods: A narrative review was conducted using PubMed, Scopus, Web of Science, and Google Scholar (all years through 2025). In Stage 1, publications reporting experimentally confirmed interactions between host miRNAs and the HIV-1 genome were identified, yielding a curated set of 15 miRNAs. In Stage 2, target genes for each miRNA were retrieved from miRTarBase, TarBase (experimentally validated) and TargetScan 8.0 (in silico predicted). In Stage 3, target genes were manually mapped to key immune signaling pathways (TLR, NF-κB, JAK-STAT). In Stage 4, targeted literature searches were performed for each miRNA–target gene pair to identify direct experimental evidence of interaction. All stages were performed by two independent researchers, with discrepancies resolved by a third. Results: Fifteen host miRNAs with experimentally confirmed binding to the HIV-1 genome were identified, targeting viral genes including nef, pol, vpr, gag, env, vif, and the 3′-UTR. Thirteen of these miRNAs were found to regulate components of major immune pathways. miR-92a-3p, miR-29a/b-3p, miR-150-5p, and miR-125b-5p emerged as the most pleiotropic regulators, simultaneously suppressing TLR signaling (TLR3, TLR7, TLR8, MyD88, TRAF3/6, IRAK1/4), NF-κB components (REL, RELA, NFKB1), JAK-STAT effectors (STAT1–3, STAT5A/B, JAK2), and negative regulators of cytokine signaling (SOCS and PIAS family proteins). miR-133b and miR-196b-5p were found to selectively regulate SOCS/PIAS proteins without involvement in other analyzed pathways, suggesting potential for selective therapeutic targeting. Conclusions: The analyzed miRNAs exhibit functional dualism, acting as direct post-transcriptional suppressors of the HIV-1 genome while simultaneously functioning as epigenetic modulators of host immune signaling. These two modes of action are not independent but together form a conceptual framework of a self-reinforcing proviral regulatory network that, based on the synthesis of published evidence, is proposed to promote viral latency and immune evasion. The identified miRNAs represent promising, albeit complex, targets for novel therapeutic strategies aimed at eliminating latent HIV reservoirs. Full article

DNA methylation, the covalent addition of methyl groups to cytosine (5mC) or adenine (6mA) in DNA, is a fundamental mechanism of epigenetic inheritance conserved from bacteria to humans. Fungi provide a uniquely informative window into the evolutionary logic of methylation systems. Spanning more than 1 billion years of diversification, the kingdom encompasses species that have lost cytosine methylation entirely, lineages that use 5mC to silence transposons and drive the irreversible genome-defense process known as repeat-induced point mutation (RIP), and early-diverging lineages, in which 6mA has emerged as a prominent chromatin mark. The methyltransferases underlying these strategies (DIM-2, RID, DNMT1-RFD, DNMT5, and the MT-A70 complex) and the recently characterized demethylases Dmt1 and CcTet are structurally and mechanistically distinct from their mammalian counterparts. Here we review the mechanisms, targets, and biological functions of fungal DNA methyltransferases and demethylases, incorporating cryo-EM structural insights into DIM-2 and DNMT5 catalysis, analyses of DNMT gene loss as a continuous evolutionary process, the antiviral role of DIM-2 in vegetative hyphae, and the emerging model of 6mA as a heritable regulatory mark in early-diverging lineages. By integrating these advances, this review offers the updated and comprehensive account of DNA methylation across fungi. Full article

Sperm cryopreservation is an integral part of gene pool conservation programs for local poultry breeds. It is known that cryostress can cause significant changes in the expression profiles of microRNAs and their target genes—key players in spermatogenesis—in Gallus gallus domesticus. However, the transmission of these changes across generations remains poorly understood. The aim of this study was to evaluate the transgenerational epigenetic effects of rooster sperm cryopreservation on molecular genetics and histological parameters in the gonads of offspring (F1) during the embryonic (10 days) and postnatal (1 day) periods. The analysis included a comprehensive histomorphometric analysis of the gonads and a quantitative assessment of the expression of microRNAs (gga-miR-6701-3p, gga-miR-301a-5p) and their target genes (DMRT1, TGFB2), using qRT-PCR. Histological analysis of the gonads of 10-day-old embryos revealed early morphological abnormalities in the F1 (n = 10) offspring obtained from frozen–thawed semen (experimental group). It was found that day-old F1 chicks (n = 17) obtained from frozen semen had testes with a significantly reduced number of seminiferous tubules (−36%, p < 0.05) with an increased diameter (+22%, p < 0.05) and an increased number of undifferentiated gonocytes (+53%, p < 0.001) compared to chicks obtained from native semen (control group, n = 20). A decrease in the expression of DMRT1 and TGFB2 in the gonads of embryos (−48% and −29%, respectively, p < 0.05) and day-old chicks (−12% and −43%, p < 0.001 for TGFB2) was found, accompanied by an inversion of microRNA dynamics: miR-6701-3p was decreased and miR-301a-5p was increased. The obtained data provide important evidence of transgenerational effects in birds and contribute to the search for solutions to problems associated with maintaining sperm quality after cryopreservation, and indicate that cryopreservation does not simply reduce the level of molecular activity, but disrupts the ontogenetic regulatory program embedded in the genome. Full article