Epigenetics最新文献

Fumonisin B₁ (FB₁) is a common maize contaminant known to induce toxicity and carcinogenesis in humans and animals; however, its epigenetic mechanisms remain poorly understood. DNA methylation is an epigenetic modification that controls gene expression through DNA methyltransferase and demethylase activities. In this study, the effect of FB₁ on DNA methylation in brain glioblastoma U87MG cells was evaluated. FB₁ cytotoxicity was determined by the MTT assay and an IC₅₀ value of 880 µM FB₁ was obtained. The ELISA-based global DNA methylation assay displayed an increase in 5-methylcytosine levels. qPCR and western blot revealed a significant increase in DNA methyltransferase expressions (DNMT1, DNMT3A, and DNMT3B) and a significant decrease in demethylase expression (MBD2). This data indicates that FB₁ induces global DNA hypermethylation, through increased DNA methyltransferase expressions and DNA demethylase suppression in U87MG cells, thus suggesting an alternative mechanism of toxicity.

Premature ovarian failure (POF) affects 1-3.5% of women under 40 years of age, characterized by irreversible depletion of the follicular pool and decline in oocyte quality, with its pathogenesis remaining incompletely understood. Current mainstream therapies, such as hormone replacement therapy, only alleviate symptoms, fail to reverse the underlying functional decline, and carry long-term risks, necessitating the exploration of novel strategies targeting the etiology. This review systematically dissects the central role of epigenetic regulation in POF. First, DNA methylation governs female reproductive lifespan by reprogramming the dormant-activation balance of primordial follicles and maintaining epigenetic memory in oocytes. Second, histone modification homeostasis determines ovarian endocrine function by influencing granulosa cell senescence and steroid hormone synthesis. Additionally, non-coding RNAs form regulatory hubs by constructing competing endogenous RNA networks that integrate oxidative stress and developmental signaling pathways. These mechanisms provide new insights into the pathological basis of POF, identify potential biomarkers, and offer a theoretical framework for deciphering targeted intervention strategies and developing precision epigenetic therapies to delay POF progression.

This study aimed to explore the association between ACMSD methylation level in peripheral blood and brain dynamic functional connectivity (dFC) patterns in adolescents with MDD. Sixty-seven drug-naive, first-episode adolescents with MDD (mean age 14.55 ± 1.38 years, 24 males [35.8%]) and twenty-three healthy controls (HCs, mean age 14.34 ± 1.47 years, 10 males [43.5%]) completed resting-state structural and functional magnetic resonance imaging. DNA samples were collected from peripheral venous blood. Joint and Individual Variation Explained (JIVE) method was used to explore the joint and independent components of four domains of environmental factors (life adverse events, LAE; family environment, FE; family functioning, FF; childhood chronic stress, CCS). Dynamic independent component analysis was used to compute dynamic functional connectivity between brain regions. Associations between ACMSD methylation, environment and brain dFC patterns were assessed. JIVE calculated one joint (JIVE-joint) and seven individual components (JIVE-LAE-1, JIVE-FE-1, JIVE-FE-2, JIVE-FF-1, JIVE-FF-2, JIVE-CCS-1, and JIVE-CCS-2). ACMSD methylation was negatively correlated with JIVE-joint (r = -0.304, p = 0.012) and JIVE-CCS-1 (r = -0.299, p = 0.014) but positively correlated with JIVE-CCS-2 (r = 0.248, p = 0.043). Greater ACMSD methylation was associated with increased dFC strength between the left lateral occipital cortex and right postcentral gyrus (PostCG; T[65] = 4.02, p < 0.001, p-FDR = 0.010) and between the left temporal occipital fusiform cortex and right PostCG (T[65] = 3.86, p < 0.001, p-FDR = 0.035) in adolescent MDD patients. Methylation value of the ACMSD gene is more likely to be influenced by childhood chronic stress. This study may provided a new perspective for future epigenetic research on adolescent MDD.

Breast cancer is the most common cancer among women, with differences in clinical features due to its distinct molecular subtypes. Current studies have demonstrated that epigenetic modifications play a crucial role in regulating the progression of breast cancer. Among these mechanisms, DNA demethylation and its reverse process have been studied extensively for their roles in activating or silencing cancer related gene expression. Specifically, Ten-Eleven Translocation (TET) enzymes are involved in the conversion process from 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), which results in a significant difference in the global level of 5hmC in breast cancer compared with normal tissues. In this review, we summarize the functions of TET proteins and the regulated 5hmC levels in the pathogenesis of breast cancer. Discussions on the clinical values of 5hmC in early diagnosis and the prediction of prognosis are also mentioned.

RNA N6-methyladenosine (m6A) plays diverse roles in RNA metabolism and its deregulation contributes to tumor initiation and progression. Clear cell renal cell carcinoma (ccRCC) is characterized by near ubiquitous loss of VHL followed by mutations in epigenetic regulators PBRM1, SETD2, and BAP1. Mutations in SETD2, a histone H3 lysine 36 trimethylase (H3K36me3), are associated with reduced survival, greater metastatic propensity, and metabolic reprogramming. While m6A and H3K36me3 deregulation are separately implicated in renal tumorigenesis, H3K36me3 may participate directly in m6A targeting, but the m6A-H3K36me3 interplay has not been investigated in the context of ccRCC. Using RCC-relevant SETD2 isogenic knockout and rescue cell line models, we demonstrate a dynamic redistribution of m6A in the SETD2 depleted transcriptome, with a subset of transcripts involved in metabolic reprogramming demonstrating SETD2 dependent m6A and expression level changes. Using a panel of six histone modifications we show that m6A redistributes to regions enriched in gained active enhancers upon SETD2 inactivation. Finally, we demonstrate a reversal of transcriptomic programs involved in SETD2 loss mediated metabolic reprogramming, and reduced cell viability through pharmacologic inhibition or genetic ablation of m6A writer METTL3 specific to SETD2 deficient cells. Thus, targeting m6A may represent a novel therapeutic vulnerability in SETD2 mutant ccRCC.

This study aims to discover drug targeted genes and explore the potential epigenetics mechanisms in bronchiectasis. Cis-expression quantitative trait locus (eQTL) was obtained as exposure, and bronchiectasis from the FinnGen cohort was used as outcome. Mendelian Randomization (MR) was performed to identify therapeutic targets associated with bronchiectasis. Colocalization and summary-data-based MR (SMR) analyses were carried out to further confirm the causal roles of candidate genes in bronchiectasis. The value of these drug targets was validated via drug prediction and molecular docking. Finally, we used mediation analysis to identify the DNA methylation QTLs to bronchiectasis mediated by candidate genes. Ten drug targets were significantly associated with bronchiectasis. Strong evidence for the colocalization of ACVR2A and VRK2 with bronchiectasis was found (PP.H4 > 0.75). SMR analysis revealed that higher expressions of DDR1 and VRK2 were linked to a higher risk of bronchiectasis, and higher expressions of SCD5, TNFRSF4 and XCL2 were linked to a lower risk of bronchiectasis. Finally, mediation analysis revealed potential causality effect of the DNA methylation site cg21568453 to bronchiectasis risk via VRK2. The increased expression of VRK2 regulated by DNA methylation at cg21568453 may promote the occurrence of bronchiectasis.

KMT5C-mediated histone H4 lysine 20 trimethylation (H4K20me3) has traditionally been linked to heterochromatin formation and maintenance, playing a crucial role in maintaining genome integrity. Emerging evidence, however, indicates that perturbations of KMT5C-H4K20me3 are also implicated in various cancers, positioning KMT5C-H4K20me3 as a promising target for anti-cancer therapies. Despite this, the precise mechanisms underlying KMT5C recruitment to its genomic targets and the specific genes it regulates remain poorly understood. In this review, we explore the dysregulation of KMT5C-mediated H4K20me3 in cancer, providing a comprehensive overview of its known functions. We also highlight recent findings that suggest a novel, non-canonical pathway for H4K20me3 deposition by KMT5C, and, while early on, insight into future opportunities for therapeutic intervention.

Lactate, long regarded as a metabolic byproduct of anaerobic glycolysis, has emerged as a key regulator of cardiovascular health. Its roles extend beyond energy metabolism and include cell signaling through hydroxycarboxylic acid receptor 1 (HCAR1/GPR81) and epigenetic regulation via lactylation. These interconnected mechanisms influence diverse processes in the cardiovascular system such as energy production, angiogenesis, inflammation, and fibrosis. In this review we provide a chronological exploration of lactate's functions, focusing on its role in cardiovascular physiology and with a particular emphasis on its role in epigenetics, highlighting the connecting points among these mechanisms and proposing areas for future research.

Epigenetic manipulations have the potential to improve traits in farmed fish. To explore this opportunity in the gilthead seabream (Sparus aurata), the catalytic domains of five DNA methyltransferases (DNMTs) were predicted by homology modeling, and their interaction with the inhibitor 5-aza-2'-deoxycytidine (DAC) was assessed by docking, revealing that the inhibitor can bind all DNMTs with similar energy. Then, pituitary and liver explants from gilthead seabream were exposed to DAC for 24 h, and changes in genome-wide DNA methylation (RRBS) and gene expression (RNA-seq) were assessed. In the liver, functional enrichment revealed upregulation of ribosome biogenesis and protein synthesis, while mitochondrial functioning, genome stability, and DNA and amino acid metabolism were downregulated. Exposed pituitaries displayed upregulation of ribosomal biogenesis and protein synthesis, alongside mitochondrial functioning and genome stability. Nucleotide-level methylomes were obtained for the first time in this species, with hypomethylated sites observed in 3'UTRs, promoter regions, and introns of highly expressed genes across both tissues. A higher level of DNA methylation at exons was found in highly expressed genes in the liver. The seabream pituitary was more permissive to DNA methylation remodeling than the liver. Functional Epigenetic Module analysis revealed seven interactome hotspots in liver and four in pituitary, mostly related to protein trafficking and signal transduction in the liver, and mitochondrial functioning in the pituitary, indicating that these functions can potentially be targeted by epigenetic interventions in seabream. The data resources generated in our study may be used to explore novel avenues to boost seabream performance and welfare.

Investigating the role of DNA methylation in the development of pancreatic cancer (PC) may facilitate identification of potential targets for both diagnosis and treatment. We carried out a comprehensive epigenome-wide Mendelian randomization (EWMR) analysis to investigate the correlation of genetically predicted blood CpG sites with PC. Following this, we conducted various sensitivity analyses and repeated analyses using different selection criteria for instrumental variables and conditional Bayesian colocalization to guarantee the reliability of the results. External validation and a meta-analysis were then performed to further validate these results. Next, we conducted CpG site enrichment analysis, overlap with phenome-wide association studies (PheWAS) catalog analysis, overlap with epigenome-wide association studies (EWAS) Toolkit analysis, and drug target analysis to explore the enrichment, biological functions, and potential therapeutic targets associated with these sites. Finally, we used the SMR-IVW software to perform mediation analysis, aiming to uncover potential tumorigenesis pathways of PC at the transcriptional level from three distinct perspectives. Results showed 253 CpG sites passing sensitivity analysis were significantly associated with PC and 159 CpG sites were validated in at least one replication. After meta-analysis, 38 CpG sites were retained, and all 253 CpG sites were classified into three tiers. Among these, cg26373071 (CLPTM1L), cg14271713, cg11652496 (PSTPIP1), and cg20575191 (PSTPIP1) were placed in tier 1 with strong support. Finally, this study identified genetic susceptibility linked to 253 PC-related CpG sites. This study provides insights into the disease's origins and underscores potential targets for future research.