Abstract
Over 500 genetic loci have been associated with risk of cardiovascular diseases (CVDs); however, most loci are located in gene-distal non-coding regions and their target genes are not known. Here, we generated high-resolution promoter capture Hi-C (PCHi-C) maps in human induced pluripotent stem cells (iPSCs) and iPSC-derived cardiomyocytes (CMs) to provide a resource for identifying and prioritizing the functional targets of CVD associations. We validate these maps by demonstrating that promoters preferentially contact distal sequences enriched for tissue-specific transcription factor motifs and are enriched for chromatin marks that correlate with dynamic changes in gene expression. Using the CM PCHi-C map, we linked 1999 CVD-associated SNPs to 347 target genes. Remarkably, more than 90% of SNP-target gene interactions did not involve the nearest gene, while 40% of SNPs interacted with at least two genes, demonstrating the importance of considering long-range chromatin interactions when interpreting functional targets of disease loci.
Highlights
A major goal in human genetics research is to understand genetic contributions to complex diseases, the molecular mechanisms by which common DNA variants impact disease etiology
Results induced pluripotent stem cells (iPSCs)-derived cardiomyocytes provide an effective model to study the architecture of cardiovascular diseases (CVDs) genetics
We observed that matched cell types exhibited three-fold greater overlap in the number of promoter-distal H3K27ac ChIP-seq peaks than non-matched cell types (Figure 1—figure supplement 1C,D), indicating that both iPSCs and CMs recapitulate tissue-specific epigenetic states of human stem cells and primary cardiomyocytes, respectively
Summary
A major goal in human genetics research is to understand genetic contributions to complex diseases, the molecular mechanisms by which common DNA variants impact disease etiology. Most genome-wide association studies (GWAS) implicate non-coding variants that are far from genes, complicating interpretation of their mode of action and correct identification of the target gene (Maurano et al, 2012). Mounting evidence suggests that disease variants disrupt the function of cis-acting regulatory elements, such as enhancers, which in turn affects expression of the specific gene or genes that are functional targets of these elements (Wright et al, 2010; Musunuru et al, 2010; Cowper-Sal lari et al, 2012; Smemo et al, 2014; Claussnitzer et al, 2015). Chromosome conformation capture techniques such as Hi-C (Lieberman-Aiden et al, 2009) enable the genome-wide mapping of long-range chromatin contacts and represent a promising strategy to identify distal gene targets of disease-associated genetic variants. Despite the increasing abundance of Hi-C maps, most datasets are of limited resolution (>40 kb) and do not precisely identify the genomic regions in contact with gene promoters
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