Epigenetics最新文献

Chromatin structure plays a central role in regulating gene expression and maintaining cellular identity, yet the structural factors driving these processes in cardiac disease remain poorly defined. To investigate whether these factors can distinguish healthy from diseased cardiac cell populations, we generated a comprehensive list of chromatin structural genes based on an extensive literature review. Applying this list to a published single-nuclei RNA sequencing dataset from human hearts with and without dilated cardiomyopathy (DCM), we found that chromatin structural gene expression effectively stratified cardiomyocyte and fibroblast populations by disease status. Diseased cardiomyocytes exhibited reduced expression of contractile genes and increased expression of cardiomyopathy markers, while fibroblasts showed enhanced activation signatures. Among these factors, HMGN3 emerged as a candidate of interest, showing consistent downregulation in cardiomyocytes from DCM human patients, as well as in mouse (pressure overload) and pig (myocardial infarction) models of heart failure. Functional studies in AC16 cells revealed that HMGN3 depletion promoted apoptosis, induced significant changes in gene expression, and reorganized chromatin structure by altering the distribution of the H3K27ac histone mark. These findings identify HMGN3 as a potential regulator of chromatin architecture in diseased cardiomyocytes, highlight the utility of chromatin structural changes in distinguishing pathological cardiac states, and reinforce the role of chromatin organization in shaping the cardiac phenotype.

Heart failure (HF) is a major global health challenge, contributing to over 18 million deaths annually. While the roles of genetic and environmental factors are widely studied, the role of DNA methylation in HF pathogenesis is not fully understood. This study leverages the Hybrid Mouse Diversity Panel (HMDP) to investigate the relationship between DNA methylation, gene expression, and HF phenotypes under isoproterenol-induced cardiac stress. Using reduced representational bisulfite sequencing, we analyzed DNA methylation profiles in the left ventricles of 90 HMDP strains. Epigenome-wide association studies identified 56 CpG loci linked to HF phenotypes, with 18 loci predicting HF progression. Key genes, including Prkag2, Anks1a, and Mospd3, were implicated through integration with gene expression and phenotypic data. In vitro validation confirmed the roles of Anks1aand Mospd3 in attenuating isoproterenol-induced hypertrophy. Additionally, treatment with the DNA methyltransferase inhibitor RG108 mitigated cardiac hypertrophy, preserved ejection fraction, and restored methylation-sensitive gene expression, underscoring the therapeutic potential of targeting DNA methylation in HF. This study highlights the interplay between DNA methylation, gene expression, and HF progression, offering new insights into its molecular underpinnings. The findings emphasize the role of epigenetic regulation in HF and suggest DNA methylation as a promising target for therapeutic intervention.

Thymic Stromal Lymphopoietin (TSLP), an immunomodulatory cytokine, plays a pivotal role in the development and progression of atopic and allergic diseases. Atopy follows familial inheritance, and genome-wide studies have shown association of atopy with TSLP polymorphisms. Here, we analysed the conserved transcriptional regulatory elements in the human TSLP promoter, which revealed the presence of three CpG islands. Demethylation of the CpG island using 5-azacytidine or siRNA-mediated knockdown of DNA methyl transferases significantly upregulated TSLP expression. Sequence analysis revealed the presence of two overlapping SP1 transcription factor DNA-binding sites (DBSs), between -1494 and -1510 nucleotides on the human TSLP promoter. Further experiments showed that demethylation of the CpG island enables the binding of SP1 to its cognate DBS present on the TSLP promoter, resulting in its transcriptional activation. Moreover, retinoic acid-induced transcription of human TSLP was associated with CpG island demethylation and SP1 binding to the TSLP promoter. These findings unravel a distinct mechanism of transcriptional regulation of the human TSLP gene and suggest possible epigenetic regulation of TSLP expression in modulating atopic and allergic disease severity in different individuals.

Epigenetic clocks have been widely applied to assess biological ageing, with Age Acceleration (AA) serving as a key metric linked to adverse health outcomes, including mortality. However, the comparative predictive value of AAs derived from different epigenetic clocks for mortality risk has not been systematically evaluated. In this retrospective cohort study based on 1,942 NHANES participants (median age 65 years; 944 women), we examined the associations between AAs from multiple epigenetic clocks and the risks of all-cause, cancer-specific, and cardiac mortality. Restricted cubic spline models were used to assess the shape of these associations, and Cox proportional hazards regression was employed to quantify risk estimates. Model performance was compared using the Akaike Information Criterion (AIC) and concordance index (C-index). Our findings revealed that only GrimAge AA and GrimAge2 AA demonstrated approximately linear and positive associations with all three mortality outcomes. Both were significantly associated with increased risks of death, and these associations were consistent across most subgroups. GrimAge and GrimAge2 AAs showed very similar performance in predicting all-cause, cancer and cardiac mortality, with only small differences in AIC values and C-index scores. These findings suggest that both GrimAge and GrimAge2 are effective epigenetic biomarkers for mortality risk prediction and may be valuable tools in future ageing-related research.

Perceived discrimination, recognized as a chronic psychosocial stressor, has adverse consequences on health. DNA methylation (DNAm) may be a potential mechanism by which stressors get embedded into the human body at the molecular level and subsequently affect health outcomes. However, relatively little is known about the effects of perceived discrimination on DNAm. To identify the DNAm sites across the epigenome that are associated with discrimination, we conducted epigenome-wide association analyses (EWAS) of three discrimination measures (everyday discrimination, race-related major discrimination, and non-race-related major discrimination) in 1,151 participants, including 565 non-Hispanic White, 221 African American, and 365 Hispanic individuals, from the Multi-Ethnic Study of Atherosclerosis (MESA). We conducted both race/ethnicity-stratified analyses as well as trans-ancestry meta-analyses. At false discovery rate of 10%, 7 CpGs and 4 differentially methylated regions (DMRs) containing 11 CpGs were associated with perceived discrimination exposures in at least one racial/ethnic group or in meta-analysis. Identified CpGs and/or nearby genes have been implicated in cellular development pathways, transcription factor binding, cancer and multiple autoimmune and/or inflammatory diseases. Of the identified CpGs (7 individual CpGs and 11 within DMRs), two CpGs and one CpG within a DMR were associated with expression of cis genes NDUFS5, AK1RIN1, NCF4 and ADSSL1. Our study demonstrated the potential influence of discrimination on DNAm and subsequent gene expression.

The Systemic Immune-Inflammation Index (SII), a marker of systemic inflammation, has been linked to various age-related diseases, but its association with Epigenetic Age Acceleration (EAA) remains underexplored. This study aimed to investigate the SII and EAA relationship. We analysed data from 1,915 participants from the National Health and Nutrition Examination Survey (NHANES). SII was calculated as platelet count × (neutrophil count/lymphocyte count). EAA was defined as HorvathAccel, HannumAccel, Skin&BloodAccel, PhenoAgeAccel, GrimAge2Accel, and DunedinPoAm. These metrics were derived utilizing the residual method. Multivariate linear regression, smooth curve fitting, threshold effect analyses, and subgroup analyses were employed to assess the relationship between the SII and EAA. Higher SII levels were significantly associated with HannumAccel, PhenoAgeAccel, GrimAge2Accel, and DunedinPoAm. Threshold effect analyses revealed non-linear relationships, with inflection points at SII values of 24.200, 12.553, 7.766, and 10.133, respectively. Subgroup analyses identified sex, age, poverty-to-income ratio, and marital status as significant effect modifiers. The elevated SII was associated with accelerated epigenetic ageing.

Fibrosis, cardiac remodelling, and inflammation are hallmarks of heart failure. To date, there is no available pharmacological cure for heart failure, but mechanical unloading by implantation of a left ventricular assist device (LVAD) can lead to improved cardiac function in a subset of patients. This study aimed to identify the transcriptional response of left ventricular (LV) cardiac myocytes to mechanical unloading in a mouse model of reversible LV pressure overload and in failing human hearts after LVAD implantation. We found that partial recovery of ventricular dysfunction, LV hypertrophy, and gene expression programmes occurred in mice under reversible transverse aortic constriction (rTAC). Gene expression analysis in cardiac myocytes identified a lasting repression of mitochondrial gene expression resulting in compromised fatty acid oxidation in the mouse model of reversible pressure overload and in human LV samples after LVAD therapy and a persistent upregulation of epigenetic and transcriptional regulators. These findings underpin that recovery from heart failure involves complex gene regulatory networks and that mitochondrial dysfunction remains a challenge even after mechanical unloading. Further studies are needed to investigate the functional role of these factors in reverse remodelling and recovery of failing hearts.

Epithelial ovarian cancer (EOC) is a heterogeneous malignancy with distinct histological subtypes, and DNA methylation has emerged as a promising biomarker for early detection. However, the role of methylation patterns in EOC heterogeneity and prognosis remains unclear. In this study, genome-wide association studies (GWAS) data from the Ovarian Cancer Association Consortium (OCAC) and Methylation quantitative trait loci (mQTL) data from the Genetics of DNA Methylation Consortium (GoDMC) were analysed using two-sample Mendelian randomization (MR). We investigated the genetic effects of CpG methylation on the risk and prognosis of five major EOC histotypes. To further explore the mechanisms by which DNA methylation affects EOC outcomes, we performed mediation analysis to evaluate the role of immunophenotypes. Our analysis identified 94 CpG sites associated with high-grade serous ovarian cancer (HGSOC), 9 of which were linked to prognosis. Additional significant associations were found for clear cell, low-grade serous, endometrioid, and mucinous subtypes. Hypomethylation at specific CpG sites was linked to increased EOC risk and shorter survival. Mediation analysis revealed significant interactions between CpG methylation and immunophenotypes, suggesting that immune modulation mediates the effects of DNA methylation on EOC outcomes. These results provide novel insights into the importance of epigenetic and immune-related factors in EOC pathogenesis.

Understanding the factors involved in myocardial recovery after unloading is of utmost importance to unveil new therapies in patients with heart failure (HF). Lack of myocardial recovery might be explained by long-lasting molecular alterations which persist despite normalization of cardiac stress. In this issue of Epigenetics, Roth et al. present an elegant translational study addressing this important aspect at the molecular level. By leveraging a mouse model of reversible transverse aortic constriction (rTAC) and human LV samples from HF patients undergoing LVAD therapy, the authors show that cardiac unloading is associated with a persistent deregulation of transcriptional programmes implicated in mitochondrial respiration, fatty acid and acyl-CoA metabolism, suggesting a long-lasting metabolic deterioration of the failing heart. Of interest, the authors identified several chromatin remodellers (Hdac4, Smarca2, and Brd4) potentially explaining the observed transcriptional alterations. Taken together, these novel findings suggest that 'DNA forgives but does not forget,' thus leaving an epigenetic scar which hampers the recovery of the failing heart after unloading. Disentangling the epigenetic factors involved in such 'transcriptional memory' may set the stage for new interventions resetting the cardiomyocyte transcriptome and myocardial energetics thus fostering a true myocardial recovery in HF.

Poly-epigenetic scores (PEGS) are surrogate measures that help capture individual-level risk. Understanding how the associations between PEGS and cardiometabolic risk factors vary by demographics and health behaviors is crucial for lowering the burden of cardiometabolic diseases. We used results from established epigenome-wide association studies to construct trait-specific PEGS from whole blood DNA methylation for systolic and diastolic blood pressure (SBP, DBP), body mass index (BMI), C-reactive protein (CRP), high- and low-density lipoprotein cholesterol (HDL-C, LDL-C), triglycerides (TG), and fasting glucose. Overall and race-stratified associations between PEGS and corresponding traits were examined in adults >50 years from the Health and Retirement Study (n = 3,996, mean age = 79.5 years). We investigated how demographics (age, sex, educational attainment) and health behaviors (smoking, alcohol consumption, physical activity) modified these associations. All PEGS were positively associated with their corresponding cardiometabolic traits (p < 0.05), and most associations persisted across all racial/ethnic groups. Associations for BMI, HDL-C, and TG were stronger in younger participants, and BMI and HDL-C associations were stronger in females. The CRP association was stronger among those with a high school degree. Finally, the HDL-C association was stronger among current smokers. These findings support PEGS as robust surrogate measures and suggest the associations may differ among subgroups.