A gene regulatory element modulates myosin expression and controls cardiomyocyte response to stress

A hallmark of heart disease is gene dysregulation and reactivation of fetal gene programs. Reactivation of these fetal programs has compensatory effects during heart failure, depending on the type and stage of the underlying cardiomyopathy. Thousands of putative cardiac gene regulatory elements have been identified that may control these programs, but their functions are largely unknown. Here, we profile genome-wide changes to gene expression and chromatin structure in cardiomyocytes derived from human pluripotent stem cells. We identify and characterize a gene regulatory element essential for regulating MYH6 expression, which encodes human fetal myosin. Using chromatin conformation assays in combination with epigenome editing, we find that gene regulation is mediated by a direct interaction between MYH6 and the enhancer. We also find that enhancer activation alters cardiomyocyte response to the hypertrophy-inducing peptide endothelin-1. Enhancer activation prevents polyploidization as well as changes in calcium dynamics and metabolism following stress with endothelin-1. Collectively, these results identify regulatory mechanisms of cardiac gene programs that modulate cardiomyocyte maturation, affect cellular stress response, and could serve as potential therapeutic targets.