Cardiac cell type-specific gene regulatory programs and disease risk association

James D Hocker, Olivier B Poirion, Fugui Zhu, Justin Buchanan, Kai Zhang, Joshua Chiou, Tsui-Min Wang, Qingquan Zhang, Xiaomeng Hou, Yang E Li, Yanxiao Zhang, Elie N Farah, Allen Wang, Andrew D McCulloch, Kyle J Gaulton, Bing Ren, Neil C Chi, Sebastian Preissl.
Sci Adv.. 2021-05-14;7(20):eabf1444.
Misregulated gene expression in human hearts can result in cardiovascular diseases that are leading causes of mortality worldwide. However, the limited information on the genomic location of candidate cis-regulatory elements (cCREs) 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 found 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 atlas of human cardiac cCREs provides the foundation for illuminating cell type-specific gene regulation in human hearts during health and disease.