Abstract
Long-range chromosomal interactions bring distal regulatory elements and promoters together to regulate gene expression in biological processes. By performing promoter capture Hi-C (PCHi-C) on human embryonic stem cell-derived cardiomyocytes (hESC-CMs), we show that such promoter interactions are a key mechanism by which enhancers contact their target genes after hESC-CM differentiation from hESCs. We also show that the promoter interactome of hESC-CMs is associated with expression quantitative trait loci (eQTLs) in cardiac left ventricular tissue; captures the dynamic process of genome reorganisation after hESC-CM differentiation; overlaps genome-wide association study (GWAS) regions associated with heart rate; and identifies new candidate genes in such regions. These findings indicate that regulatory elements in hESC-CMs identified by our approach control gene expression involved in ventricular conduction and rhythm of the heart. The study of promoter interactions in other hESC-derived cell types may be of utility in functional investigation of GWAS-associated regions.
Highlights
Long-range chromosomal interactions bring distal regulatory elements and promoters together to regulate gene expression in biological processes
We show that the promoter interactome of hESC-CMs is associated with expression quantitative trait loci in cardiac left ventricular tissue; captures the dynamic process of genome reorganisation after hESC-CM differentiation; overlaps genome-wide association study (GWAS) regions associated with heart rate; and identifies new candidate genes in such regions
We demonstrate that the promoter interactome of cardiac genes is reorganised after cardiac differentiation and cardiac enhancers are enriched in the promoter-interacting regions (PIRs)
Summary
Long-range chromosomal interactions bring distal regulatory elements and promoters together to regulate gene expression in biological processes. By performing promoter capture Hi-C (PCHi-C) on human embryonic stem cell-derived cardiomyocytes (hESC-CMs), we show that such promoter interactions are a key mechanism by which enhancers contact their target genes after hESC-CM differentiation from hESCs. We show that the promoter interactome of hESC-CMs is associated with expression quantitative trait loci (eQTLs) in cardiac left ventricular tissue; captures the dynamic process of genome reorganisation after hESC-CM differentiation; overlaps genome-wide association study (GWAS) regions associated with heart rate; and identifies new candidate genes in such regions. Cardiomyocytes differentiated from human embryonic stem cells (hESC-CMs) have become a popular model to elucidate functional genomics of cardiac disease; there is little information supporting the notion that genomic regions associated with adult phenotypes (such as heart rate) play important roles in hESC-CMs, which have an immature phenotype It is essential, in the context of potential cardiac regenerative medicine approaches, to understand how promoters make specific interactions in hESC-CMs to regulate the gene expression patterns underlying the process of cardiomyocyte development. The PIRs share the same target genes with expression quantitative trait loci (eQTLs) of cardiac left ventricles and overlap genetic variants associated with conduction and rhythm of the heart
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