Journal
SCIENCE ADVANCES
Volume 7, Issue 20, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abf1444
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Funding
- Ludwig Institute for Cancer Research
- National Institutes of Health [1UM1HL128773-01, U01 HL126273, R01 HL137100]
- Ruth L. Kirschstein Institutional National Research Service Award from the National Institute of General Medical Sciences [T32 GM008666]
- UC San Diego School of Medicine
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This study identified cCREs in the human heart and found their associations with cardiac cell types and heart failure. It also discovered that genetic variants associated with cardiovascular diseases are enriched within these cCREs, with some potentially linked to atrial fibrillation.
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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