A gene regulatory element modulates myosin expression and alters cellular response to stress

A hallmark of heart disease is gene dysregulation and reactivation of fetal gene programs. Reactivation of these fetal programs can provide cardioprotective or compensatory effects during heart failure depending on the type and stage of the underlying cardiomyopathy. Many putative cardiac gene regulatory elements have been identified that may control these programs, but their functions are largely unknown. 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 important for the regulation of MYH6 that encodes human fetal myosin and is critical to the pathogenesis of hypertrophic and dilated cardiomyopathies. Using chromatin conformation assays in combination with epigenome editing, we find that gene regulation is mediated through direct interaction between MYH6 and the enhancer. We also find that activation of the enhancer alters cardiomyocyte response to the hypertrophy-inducing peptide endothelin-1. Collectively, these results identify regulatory mechanisms of cardiac gene expression programs that act through critical developmental factors and modulate cellular response to stress. Overall design: Differential analysis of chromatin looping after repression of an MYH6/MYH7 enhancer in cardiomyocytes derived from human pluripotent stem cells, assessed using HiCAR protocols.