in a broad spectrum of human tissues including in bulk heart tissues and in purified cardiomyocytes ( 2– 5, 13– 18). However, the transcriptional regulatory programs responsible for cell type–specific and chamber-specific gene expression, and their potential links to noncoding risk variants for cardiovascular diseases and traits, remain to be fully defined.ĬCREs have been annotated in the human genome with the use of chromatin immunoprecipitation sequencing (ChIP-seq), deoxyribonuclease sequencing (DNase-seq), assay for transposase-accessible chromatin using sequencing (ATAC-seq), global run-on sequencing, etc. Recent single-cell/nucleus RNA sequencing (RNA-seq) ( 9– 11) and spatial transcriptomic ( 12) studies have revealed gene expression patterns in distinct cardiac cell types across developmental and adulthood stages in the human heart, including some that display gene expression patterns that are cardiac chamber/region specific ( 10, 11). However, a major barrier to understanding the genetic and molecular basis of cardiovascular diseases is the paucity of maps and tools to interrogate gene regulatory programs in the distinct cell types of the human heart. Mutations in transcription factors and chromatin regulators can result in heart disease ( 6, 7), and genetic variants associated with risk of cardiovascular disease are enriched within annotated candidate cis-regulatory elements (cCREs) in the human genome ( 8). Cis-regulatory elements such as enhancers and promoters are crucial for regulating gene expression ( 2– 5).
Overall, this atlas of human cardiac cCREs provides the foundation for illuminating cell type–specific gene regulation in human hearts during health and disease.ĭisruption of gene regulation is an important contributor to cardiovascular disease, the leading cause of morbidity and mortality worldwide ( 1). Additional functional studies revealed that two of these variants affect a cCRE controlling KCNH2/HERG expression and action potential repolarization. We further found cardiovascular disease–associated genetic variants enriched within these cCREs including 38 candidate causal atrial fibrillation variants localized to cardiomyocyte cCREs. 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.
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. Misregulated gene expression in human hearts can result in cardiovascular diseases that are leading causes of mortality worldwide.
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