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

  • Author(s): Hocker, James D;
  • Poirion, Olivier B;
  • Zhu, Fugui;
  • Buchanan, Justin;
  • Zhang, Kai;
  • Chiou, Joshua;
  • Wang, Tsui-Min;
  • Zhang, Qingquan;
  • Hou, Xiaomeng;
  • Li, Yang E;
  • Zhang, Yanxiao;
  • Farah, Elie N;
  • Wang, Allen;
  • McCulloch, Andrew D;
  • Gaulton, Kyle J;
  • Ren, Bing;
  • Chi, Neil C;
  • Preissl, Sebastian
  • et al.
Abstract

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.

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