Project: PRJNA698274
Misregulated gene expression in human hearts can result in cardiovascular diseases that are leading causes of morbidity and mortality worldwide. However, the limited information on the genomic location of candidate cis-regulatory elements (cCRE) such as enhancers and promoters in distinct cardiac cell types has restricted the understanding of these diseases. Here, we defined >287,000 cCREs in the four chambers of the human heart at single-cell resolution, which revealed cCREs and candidate transcription factors associated with cardiac cell types in a region-dependent manner and during heart failure. We further discovered cardiovascular disease-associated genetic variants enriched within these cCREs including 38 candidate causal atrial fibrillation variants localized to cardiomyocyte cCREs. Additional functional studies revealed that two of these variants affect a cCRE controlling KCNH2/HERG expression and action potential repolarization. Overall, this comprehensive atlas of human cardiac cCREs provides the foundation for illuminating cell type-specific gene regulation in human hearts during health and disease. Overall design: We performed single nucleus ATAC-seq to define a comprehensive catalogue of candidate cis-regulatory elements (cCREs) for the cell types in four regions of non-failing human hearts and generate in parallel snRNA-seq datasets for a subset to delineate gene expression patterns. We used the cCRE catalogue to computationally deconvolute dynamic enhancers in failing hearts and to assign cardiovascular disease risk variants to cCREs in individual cardiac cell types. Finally, we applied reporter assays, genome editing and electrophysiogical measurements in in vitro differentiated human cardiomyocytes to validate the molecular mechanisms of cardiovascular disease risk variants. The raw sequencing data are available through dbGaP (controlled access): phs002204.v1.p1