Promoter interactome of human embryonic stem cell-derived cardiomyocytes connects GWAS regions to cardiac gene networks

• DOI: 10.1038/s41467-018-04931-0
• Publication Date: 2018-06-22T11:53:24Z
• Authors: Mun-Kit Choy; Biola M. Javierre; Simon G. Williams; Stephanie L. Baross; Yingjuan Liu; Steven W. Wingett; Artur Akbarov; Chris Wallace; Paula Freire-Prit...; Peter J. Rugg-Gunn; Mikhail Spivakov; Peter Fraser; Bernard D. Keavney
• Keywords: 0303 health sciences; Calpain; Genome, Human; Science; Heart Ventricles; Q; Human Embryonic Stem Cells; Quantitative Trait Loci; Cell Differentiation; Article; Cell Line; Histones; 03 medical and health sciences; Enhancer Elements, Genetic; Heart Conduction System; Heart Rate; Protein Interaction Mapping; Humans; Protein Isoforms; Actinin; Gene Regulatory Networks; Myocytes, Cardiac; Promoter Regions, Genetic; Genome-Wide Association Study

AbstractLong-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.