Methylome-driven regulation of miRNA expression and its relationship to cardiac dysfunction in idiopathic dilated cardiomyopathy

Idiopathic dilated cardiomyopathy (iDCM) is a multifactorial disease with a complex pathogenesis involving diverse molecular mechanisms. Among these, epigenetic mechanisms, including both DNA methylation and microRNAs (miRNAs)-mediated regulation, play an important role in determining the disease phenotype. However, the interplay between the DNA methylome and the miRNA transcriptome in iDCM remains largely unexplored. We conducted a cross-cohort multiomic integrative analysis of left ventricular (LV) tissue samples from iDCM patients and control (CNT) donors. DNA methylation profiling was performed using the Infinium MethylationEPIC BeadChip, whereas ncRNA-seq was used to assess transcriptomic changes. We identified a subset of 7 miRNAs exhibiting both differential methylation in their promoter regions and differential expression in their primary and mature forms. Notably, two of these miRNAs, hsa-miR-433-3p (r = 0.671, p < 0.01) and hsa-miR-493-5p (r = 0.585, p < 0.01), which are involved in fibrotic pathways appear to be significantly correlated with the left ventricular ejection fraction (LVEF), an established echocardiographic marker of cardiac function. Importantly, both miRNAs have predicted or validated target genes involved in fibrotic pathways, suggesting a potential link between DNA methylation, miRNA expression, cardiac remodeling, and the disease phenotype. This study enhances our understanding of the epigenetic mechanisms shaping the miRNA transcriptomic landscape in iDCM, revealing suggesting potential roles for these miRNAs in cardiac dysfunction and myocardial fibrosis. Overall design: We analyzed 50 human heart samples from left ventricular apex of patients diagnosed with idiopathic dilated cardiomyopathy (n=20) and ischemic cardiomyopathy (n=22) undergoing heart transplantation, as well as from control donors (n=8).