GSE123976
DNA Methylation Reprograms Metabolic Gene Expression in End-Stage Human Heart Failure
Heart Failure (HF) is a complex clinical disease and leading cause of hospitalization in the United States. Although precision-based treatment options are ultimately preferred, understanding the common underlying features of HF is also needed to develop universal therapies that address its pathogenesis. Among the etiology-independent molecular changes known to occur in HF is a global shift in the heart's metabolic substrate preference. Transcriptional reprogramming of the heart has been shown to mediate this metabolic switch towards glycolytic metabolism; however, the molecular machinery that reactivate dormant genes remain largely unknown. In the current study, we hypothesized that the cardiac epigenome regulates metabolism via alterations in DNA methylation. Overall design: We used paired whole-genome bisulfite sequencing and next-generation RNA sequencing of left ventricle tissue from 6 patients with end-stage heart failure and 3 non-failing donor hearts. Distribution of genome-wide methylation changes was localized to both the promoter-associated and gene body-associated CpG sites in HF relative to non-failing hearts. Gene set enrichment of genes coupled with promoter hyper-methylation identified suppression of oxidative metabolic pathways, whereas hypo-methylated promoters identified genes associated with anaerobic glycolysis. Furthermore, we found the Nuclear Respiratory Factor 1 (NRF1) binding site as a candidate DNA methylation-sensitive regulator of cardiac fatty acid oxidation. The current study therefore underscores the importance of DNA methylation as a molecular feature describes the failing hearts fetal-like metabolic preference.