1. Cardiac cell type–specific gene regulatory programs and disease risk association
- Author
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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, and Preissl, Sebastian
- Subjects
Biotechnology ,Cardiovascular ,Genetics ,Human Genome ,Heart Disease ,Aetiology ,2.1 Biological and endogenous factors ,Good Health and Well Being ,Heart ,Humans ,Promoter Regions ,Genetic ,Regulatory Sequences ,Nucleic Acid ,Transcription Factors - 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.
- Published
- 2021