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

Nat Commun. 2018 Jun 28;9(1):2526. doi: 10.1038/s41467-018-04931-0.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actinin / genetics*
  • Actinin / metabolism
  • Calpain / genetics*
  • Calpain / metabolism
  • Cell Differentiation
  • Cell Line
  • Enhancer Elements, Genetic
  • Gene Regulatory Networks*
  • Genome, Human
  • Genome-Wide Association Study
  • Heart Conduction System / cytology
  • Heart Conduction System / metabolism
  • Heart Rate / physiology
  • Heart Ventricles / cytology
  • Heart Ventricles / metabolism
  • Histones / genetics
  • Histones / metabolism
  • Human Embryonic Stem Cells / cytology
  • Human Embryonic Stem Cells / metabolism*
  • Humans
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / metabolism*
  • Promoter Regions, Genetic*
  • Protein Interaction Mapping
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Quantitative Trait Loci

Substances

  • ACTN4 protein, human
  • Histones
  • Protein Isoforms
  • Actinin
  • CAPN12 protein, human
  • Calpain