Genome-wide compendium and functional assessment of in vivo heart enhancers

Nat Commun. 2016 Oct 5;7:12923. doi: 10.1038/ncomms12923.

Abstract

Whole-genome sequencing is identifying growing numbers of non-coding variants in human disease studies, but the lack of accurate functional annotations prevents their interpretation. We describe the genome-wide landscape of distant-acting enhancers active in the developing and adult human heart, an organ whose impairment is a predominant cause of mortality and morbidity. Using integrative analysis of >35 epigenomic data sets from mouse and human pre- and postnatal hearts we created a comprehensive reference of >80,000 putative human heart enhancers. To illustrate the importance of enhancers in the regulation of genes involved in heart disease, we deleted the mouse orthologs of two human enhancers near cardiac myosin genes. In both cases, we observe in vivo expression changes and cardiac phenotypes consistent with human heart disease. Our study provides a comprehensive catalogue of human heart enhancers for use in clinical whole-genome sequencing studies and highlights the importance of enhancers for cardiac function.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Echocardiography
  • Enhancer Elements, Genetic*
  • Epigenomics
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Gene Expression Regulation, Developmental
  • Genome, Human
  • Heart / physiology*
  • Histones / metabolism
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation
  • Phenotype

Substances

  • Histones