Association of intronic DNA methylation and hydroxymethylation alterations in the epigenetic etiology of dilated cardiomyopathy

In this study, we investigated the role of DNA methylation (5mC) and hydroxymethylation (5hmC) as epigenetic modifications that regulate gene activity in the etiopathology of dilated cardiomyopathy (DCM). Genomic 5mC and 5hmC in wild-type (WT) and DCM mouse hearts were profiled by Chip-seq, and gene expression levels were analyzed by RNA-seq. Both 5mC-altered genes (957) and 5hmC-altered genes (2022) were identified in DCM hearts. Diverse gene ontology (GO) and KEGG pathways were enriched for DCM phenotypes, such as inflammation, tissue fibrosis, cell death, cardiac remodeling, cardiomyocyte growth, and differentiation, as well as sarcomere structure. Hierarchical clustering of mapped genes affected by 5mC and 5hmC clearly differentiated DCM from WT phenotype. Genome-wide 5mC and 5hmC contents play a major role in DCM pathogenesis.