Epigenomics最新文献

Background: G-quadruplex (G4) structures are enriched in key genomic regions and regulate gene expression and chromosomal stability. However, their role in de novo DNA methylation remains unclear. DNA methyltransferase 3A (DNMT3A) and DNA methyltransferase 3B (DNMT3B) are vital for cancer initiation and progression. This study investigated the role of G4 structures in regulating DNMT3A and DNMT3B expression and their epigenetic function in breast cancer.

Methods: G4 structures in DNMT3A and DNMT3B were identified using Quadruplex forming G-Rich Sequences Mapper, circular dichroism, and gel mobility shift assays. The effects of the G4 stabilizer pyridostatin on breast cancer 4T1 cell proliferation, migration, DNMT3A and DNMT3B expression, and promoter methylation of Breast Cancer 1 (BRCA1), E-cadherin (CDH1), and Ras Association Domain Family Member 1 (RASSF1) were evaluated.

Results: G4-forming sequences were found in the core promoter regions of DNMT3A and DNMT3B. They formed parallel G4 structures in vitro. Pyridostatin enhanced G4 stability, inhibited 4T1 cell proliferation and migration, downregulated DNMT3A and DNMT3B expression, reduced promoter methylation of BRCA1 and RASSF1, and altered target gene expression.

Conclusion: Promoter G4 structures actively regulate gene expression by modulating de novo DNA methylation, suggesting that targeting G4s may represent a novel therapeutic strategy for breast cancer.

Atrioventricular block (AVB) is a frequent arrhythmia and can arise from both genetic predisposition and epigenetic regulation. This review provides a synopsis of the latest findings concerning the interactions of genetic-epigenetic interactions with an emphasis on mechanisms that are most likely responsible for pathobiological pathways relating to the cause of AVB. For instance, hypermethylation of the SCN5A promoter or hypomethylation ofgene transcriptionally regulates the activity of the sodium channels, and their conduction likely results in conduction disorders. We also know that miR-1 and miR-133 are significantly dysregulated in arrhythmogenic remodeling. DNA methylation of ion channels in genes is most commonly cited form of epigenetic factor among all factors mentioned above, followed by histone modifications also directed to transcription factors related to conduction. We performed a structured literature search on PubMed, Scopus, and Web of Science (2000-2025) that included human and animal studies that examined genetic and epigenetic mechanism relative to AVB. Current studies indicate a multi-tier regulatory network that incorporates inherited and environmental factors but lacks longitudinal, integrated multi-omics studies that clarify the causal pathway interaction between these systems. If we can identify interaction of genetic and epigenetic factors, we can develop valuable diagnostic and therapeutic strategies targeting AVB.

Objective: This preliminary study aimed to identify microRNA (miRNA) signatures associated with bipolar disorder (BD) by profiling blood-derived extracellular vesicles (EVs) of both putative neuronal origin and from all sources.

Method: In two parallel studies of individuals with BD and controls (CON), we characterized miRNA expression profiles of blood EVs selected for L1CAM, a putative marker of neuronal origin (n = 20 BD/20 CON), as well as bulk EVs (n = 21 BD/20 CON). For each study, analyses identified miRNAs differentially expressed between groups, followed by functional interrogation and testing for associations with clinical features.

Results: Results of Study 1 showed 34 miRNAs differentially expressed between groups and implicated PTEN, a gene whose protein levels were previously found to be altered in postmortem brain studies of BD. Results of Study 2 showed 10 miRNAs differentially expressed between groups. Limited overlap was identified between studies, with only hsa-miR-1-3p identified with the same direction of change across both types of EVs. Differentially expressed miRNAs were significantly associated with clinical features of BD only in Study 1.

Conclusions: Our results, albeit preliminary, reiterate a crucial role for miRNAs in the pathophysiology of BD and suggest that miRNA signatures of putative neuronal origin may more closely correspond to clinical features.

MicroRNA-17-5p (miR-17-5p) is a regulatory molecule underpinning a range of diseases and for which various innovative therapeutic strategies across diverse pathologies are possible. Encoded by the miR-17-92 cluster, miR-17-5p exerts pleiotropic functions across cancers, inflammatory conditions, and genetic disorders such as cystic fibrosis (CF). Its capacity to fine-tune processes including autophagy, epithelial-mesenchymal transition, inflammation, and immune modulation places miR-17-5p at the nexus of disease progression and therapeutic intervention. In cancer, miR-17-5p exhibits context-dependent duality, acting as a tumor promoter or suppressor by regulating proliferation, metastasis, and therapeutic resistance pathways. In inflammatory and genetic diseases, including CF and neurodegenerative disorders, miR-17-5p orchestrates immune homeostasis, autophagy, and tissue remodeling, contributing to either disease exacerbation or resolution. Recent advances in RNA delivery technologies including nanocarriers, exosome-based systems, and receptor-targeted delivery platforms have unlocked new possibilities for miR-17-5p modulation with enhanced precision and minimized off-target effects. These innovations hold promise for restoring cellular homeostasis in CF, Alzheimer's disease, and cancers by precisely tuning miR-17-5p expression to match disease-specific requirements. This review highlights the versatile role of miR-17-5p in diverse pathological processes and emphasizes its promise as a biomarker and therapeutic target, offering a path toward more personalized and effective treatments across multiple disease areas.

Liver diseases represent a major global health challenge, responsible for over two million deaths annually. Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), are the primary contributors to liver fibrosis and hepatocarcinoma (HCC). Epigenetic mechanisms, including DNA methylation, histone modifications, and miRNAs, play a crucial role in the pathogenesis of liver disorders, presenting promising therapeutic targets due to their reversibility. Pirfenidone, an antifibrotic agent approved for idiopathic pulmonary fibrosis (IPF) and hepatic fibrosis in Mexico, has shown significant potential to modulate epigenetic pathways. This review discusses the molecular and epigenetic mechanisms by which PFD exerts hepatoprotective effects, including modulation of miRNA expression, restoration of DNA methylation patterns, and regulation of histone acetylation and methylation. Notable findings include PFD-mediated downregulation of pro-fibrotic miRNAs, hypermethylation of TGFB1, and inhibition of JMJD2B histone demethylase. Together, these findings suggest that PFD not only targets fibrotic and inflammatory pathways but also acts as a novel epigenetic regulator, positioning it as a promising therapeutic candidate for MASLD, MASH, and HCC.

Background: Reliable biomarkers are warranted to identify patients with metabolic dysfunction-associated steatotic liver disease (MASLD), including metabolic dysfunction-associated steatohepatitis (MASH), at risk for developing hepatocellular carcinoma (HCC).

Research and methods: We evaluated whether circulating histones can predict this risk. Plasma histones were measured using imaging flow cytometry in patients with MASLD (n = 25), MASH (n = 25), HCC (n = 40), and 30 healthy controls.

Results: We detected (p < 0.05), compared to controls: 1) elevated levels of H2A, H3, H2A/H2B/H3/H4, macroH2A1.1, macroH2A1.2 in MASLD/MASH and HCC; 2) decreased levels of macroH2A1.2/H2B/H3/H4 in MASLD/MASH and increased in HCC; 3) reduced H4 levels discriminating between MASH and non-MASH. Machine-learning analysis showed that being diabetic/dyslipidemic, having decreased H2A (p = 0.002) and H4 (p = 0.0156) levels favor MASH.

Conclusions: Our data indicate plasma histones H2A and H4 as new biomarkers of liver disease progression. The identification of histone-based biomarkers using imaging flow cytometry could provide a rapid approach to discriminate between non-MASH and MASH, and to predict the risk of HCC development.

Background: Chronic interpersonal stress has been linked to accelerated biological aging, but questions remain about which relationship stress domains may be most consequential during midlife.

Research design and methods: Linear regression models quantified the cross-sectional associations between domain-specific relationship stressors (marital risk, partner strain, family strain, friendship strain) and next-generation epigenetic clocks (DunedinPACE and GrimAge2) in 1,310 midlife adults from the Midlife in the United States study (mean age = 51, SD = 13).

Results: Controlling for sociodemographic and health behaviors, we found that friendship strain was uniquely associated with accelerated aging (GrimAge2: 0.03 SD increase, 95% CI: 0.01, 0.05, p = 0.003; DunedinPACE: 0.05 SD increase, 95% CI: 0.01, 0.09, p = 0.030). No statistically significant associations were observed for the other stressors with GrimAge2 or DunedinPACE in fully adjusted models.

Conclusions: These findings identify friendship strain as a potential specific risk factor for accelerated biological aging in midlife. Future research should investigate behavioral and physiological mechanisms linking friendship quality to cellular aging.

The MAGE-A family consists of proteins with restricted expression profiles in normal tissues but expressed in multiple solid tumor types including triple-negative breast cancer (TNBC). In this review, we describe and discuss the potential of MAGE-A family members as therapeutic targets in TNBC. Preclinical studies have shown that MAGE-A is more frequently expressed in TNBC compared with other breast cancer subtypes. MAGE-A protein expression induces epithelial-mesenchymal transition, invasive and metastatic capabilities of TNBC cells via AMPK degradation and p53 downregulation. MAGE-A expression is primarily regulated epigenetically through DNA methylation, histone modifications, and aberrant expression of non-coding RNAs. In terms of therapy, multi-epitope peptide-based vaccines against MAGE-A antigens have demonstrated efficacy in preclinical studies by promoting cytotoxic T cell-mediated killing of TNBC cells. Extensive preclinical evidence has led to multiple ongoing early-phase clinical trials to investigate the safety and efficacy of MAGE-A immunotherapies in TNBC patients. Novel therapeutic strategies targeting MAGE-A include multi-epitope MAGE-A peptide vaccines to mitigate heterogeneous MAGE-A expression and MHC restrictions in peptide-HLA matching. Future clinical trials evaluating MAGE-A peptide vaccines, and in combination with epigenetic drugs such as hypomethylating agents that re-express MAGE-A, hold potential to improve clinical outcomes for TNBC patients.

Background: Populations in subarctic regions, like Yakutia in the Russian Sakha Republic, have adapted to extreme environmental conditions, including intense cold, pronounced shifts in daylight, and variable food availability. However, the biological mechanisms underlying these adaptations remain poorly understood despite insights from genome-wide (GWAS) and epigenome-wide association studies (EWAS).

Methods: Since protein profiles may more directly reflect functional physiology, we analyzed DNA methylation data from 245 healthy Russian participants using methylation-based estimators of circulating protein levels to investigate estimated proteomic differences between residents of Yakutia and Central Russia.

Results: We identified regional variation in 25 protein surrogates enriched in pathways, including MET receptor activation and PI3K-Akt signaling. Some proteins mapped to previously identified GWAS genes. To our knowledge, none mapped to previously identified, differentially methylated in EWAS genes, suggesting that methylation-based protein estimation may capture distinct, complementary aspects of physiological regulation.

Conclusion: These findings align with prior -omics research by highlighting regional molecular differences possibly associated with cold adaptation. They also underscore the potential of methylation-derived proteomic proxies as a useful, indirect approach for studying proteomic variation when direct protein measurements are unavailable. While promising, this method warrants further validation, particularly with respect to potential genetic confounding.

Transcriptional regulation is a crucial biological process that enables accurate gene expression, allowing cells to maintain their identity and respond to environmental stimuli. CCCTC-binding factor is a fundamental protein that actively involves itself in transcriptional regulation, serving as a highly conserved architectural regulator. CTCF is traditionally acknowledged for its function in chromatin organization and insulation. It coordinates active or repressed transcription by establishing topologically associated domains and also helps in preserving enhancer-promoter identity. In addition to its DNA-binding roles, CTCF significantly participates in RNA biology. It engages with nascent RNA, pre-mRNA, and long non-coding RNAs via its RNA-binding domain, thereby affecting different transcriptional dynamics. Simultaneously, the swiftly advancing domain of epitranscriptomics has revealed other RNA modifications, such as N6-methyladenosine (m⁶A), 5-methylcytosine (m⁵C), and pseudouridine (Ψ), which jointly regulate RNA stability, transport, translation, and destruction. Hence, the dysregulation of these changes or CTCFactivity is closely linked to oncogenesis, developmental problems, and resistance to therapy. The intersection of CTCF-mediated genomic architecture with epitranscriptomic regulation highlights its function as a complex integrator of chromatin and RNA networks. This review consolidates contemporary understanding of CTCF's twin activities in DNA and RNA binding, examining how their interaction influences transcriptional regulation, RNA processing, and disease relevance.