Short-Chain Enoyl-CoA Hydratase Mediates Histone Crotonylation and Contributes to Cardiac Homeostasis

osttranslational modifications of histones are critically involved in gene expression and regulate pathophysiologic processes such as cardiovascular diseases. Metabolic enzymes modulate the intracellular levels of metabolites to support posttranslational modifications. For example, histone crotonylation (H3K18cr and H2BK12cr) can trigger gene transcription and regulate metabolism, DNA repair, depression, and reproductive development. The roles of histone crotonylation in pathophysiologic processes of cardiovascular diseases-cardiac hypertrophy, for example-remain unknown. Short-chain enoyl-coenzyme A (CoA) hydratase (encoded by ECHS1) is a hydratase that has the highest activity for hydrolyzing crotonyl-CoA, reducing intracellular crotonyl-CoA, the orchestrator of histone crotonylation (Figure In human newborns or children, mutations in the ECHS1 gene lead to cardiomyopathies (>60%), such as hypertrophic cardiomyopathy, with unknown mechanisms. ownregulation of ECHS1 was observed in human hearts with hypertrophic cardiomyopathy (Figure ECHS1 downregulation was coupled with the upregulation of H3K18cr and H2BK12cr (Figure