Decoding promoter-enhancer interactions in human cardiac myocytes

Abstract

The heart is a heterocellular organ consisting of several cell types including cardiomyocytes. Cell-type specific gene expression and response to stimuli is modulated by active distal regulatory elements termed enhancers. Cardiac enhancers are enriched for disease-associated variants and spatially interact with distal target promoters. However, enhancer-promoter interactions and spatial chromatin organization of human adult cardiac myocytes have not been analyzed so far limiting the interpretation of disease-associated regulatory elements in these cells. Here we generated high resolution spatial chromatin interaction data for atrial, left ventricular and failing human adult cardiac myocytes and identified cell-type specific interaction signatures. An integrative analysis with comprehensive epigenetic data reveals cardiac myocyte-specific, chamber-specific and disease-relevant enhancer-promoter interactions in cardiac myocytes. We further identified the cardiac disease risk association of promoter-interacting versus non-interacting enhancers and experimentally proofed the functional importance of enhancers harboring long QT risk loci. Our data shows that decoding cell type-specific regulatory elements and their interacting promoters provides insights into regulatory mechanisms essential for cell function and genetic risk factors as demonstrated here for human cardiac myocytes. This data will facilitate the interpretation of non-coding genetic risk factors in future genome-wide association studies. These data will allow predicting whether non-coding genetic variants promote disease in adult cardiac myocytes or not.