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. 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.