Integrative DNA methylome and transcriptome analysis identify potential genes on the influence of dilated cardiomyopathy-associated heart failure.

Objective: Dilated cardiomyopathy (DCM)-associated heart failure (HF) presents a significant clinical challenge, underlying epigenetic mechanisms remaining poorly understood. This study aims to investigate the interplay between DNA methylation and gene expression in the hearts of patients with DCM-associated HF (DCM-HF).

Methods: Atrial tissues were collected from five healthy donors and five heart transplant recipients suffering from heart failure due to DCM. We conducted RNA-sequencing (RNA-seq) to analyze mRNA expression profiles and performed whole-genome bisulfite sequencing (WGBS) to evaluate DNA methylation levels. Correlation analyses between RNA-seq and WGBS data were executed by integrating differentially expressed genes (DEGs) with genes associated with differentially methylated regions (DMRs) located in the promoter regions.

Results: The RNA-seq analysis identified a total of 681 DEGs, comprising 406 significantly downregulated genes and 275 upregulated genes in DCM-HF tissues, which were enriched in pathways related to cardiomyopathy. WGBS revealed 16,158 hypomethylated and 6,857 hypermethylated differentially methylated regions (DMRs), with 3,185 of these located in promoter regions. The integration of promoter-hypomethylated and hypermethylated DMRs-related genes (DMGs) with DEGs resulted in the identification of 46 hub genes associated with cardiac development and function. Protein-protein interaction and disease association analyses highlighted five key genes-NPPA, NPPB, ACTN2, NEBL, and MYO18B-that exhibited promoter hypomethylation and increased expression, potentially linked to the activity of transcription factors such as HIF1A and KLF4.

Conclusions: These findings suggest that the epigenetic dysregulation of cardiac stress-response and structural genes contributes to the pathogenesis of DCM-HF. Furthermore, the detection of promoter methylation levels in these loci may offer new opportunities for developing diagnostic tools and therapeutic strategies for DCM-HF management.