Genome-wide orchestration of cardiac functions by the orphan nuclear receptors ERRalpha and gamma

Cell Metab. 2007 May;5(5):345-56. doi: 10.1016/j.cmet.2007.03.007.

Abstract

Orphan nuclear receptor ERRalpha (NR3B1) is recognized as a key regulator of mitochondrial biogenesis, but it is not known whether ERRalpha and other ERR isoforms play a broader role in cardiac energetics and function. We used genome-wide location analysis and expression profiling to appraise the role of ERRalpha and gamma (NR3B3) in the adult heart. Our data indicate that the two receptors, acting as nonobligatory heterodimers, target a common set of promoters involved in the uptake of energy substrates, production and transport of ATP across the mitochondrial membranes, and intracellular fuel sensing, as well as Ca(2+) handling and contractile work. Motif-finding algorithms assisted by functional studies indicated that ERR target promoters are enriched for NRF-1, CREB, and STAT3 binding sites. Our study thus reveals that the ERRs orchestrate a comprehensive cardiac transcriptional program and further suggests that modulation of ERR activities could be used to manage cardiomyopathies.

Publication types

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

MeSH terms

  • Animals
  • Chromatin Immunoprecipitation
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation*
  • Genome / genetics*
  • Heart / physiology*
  • Male
  • Mice
  • Mice, Knockout
  • NF-E2-Related Factor 1 / metabolism
  • Promoter Regions, Genetic / genetics
  • Promoter Regions, Genetic / physiology*
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Receptors, Estrogen / metabolism*
  • STAT3 Transcription Factor / metabolism

Substances

  • Creb1 protein, mouse
  • Cyclic AMP Response Element-Binding Protein
  • ERRalpha estrogen-related receptor
  • ESRRG protein, human
  • NF-E2-Related Factor 1
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Estrogen
  • STAT3 Transcription Factor
  • Stat3 protein, mouse

Associated data

  • GEO/GSE7196