A polymorphic autoregulatory hormone response element in the human estrogen-related receptor alpha (ERRalpha) promoter dictates peroxisome proliferator-activated receptor gamma coactivator-1alpha control of ERRalpha expression

J Biol Chem. 2004 Apr 30;279(18):18504-10. doi: 10.1074/jbc.M313543200. Epub 2004 Feb 20.

Abstract

The orphan nuclear estrogen-related receptor alpha (ERRalpha) and transcriptional cofactor peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) are involved in the regulation of energy metabolism. Recently, extensive cross-talk between PGC-1alpha and ERRalpha has been demonstrated. The presence of PGC-1alpha is associated with an elevated expression of ERRalpha, and the two proteins can influence the transcriptional activities of one another. Using a candidate gene approach to detect regulatory variants within genes encoding nuclear receptors, we have identified a 23-bp sequence (ESRRA23) containing two nuclear receptor recognition half-site motifs that is present in 1-4 copies within the promoter of the human ESRRA gene encoding ERRalpha. The ESRRA23 sequence contains a functional ERR response element that is specifically bound by ERRalpha, and chromatin immunoprecipitation shows that endogenous ERRalpha occupies its own promoter in vivo. Strikingly, introduction of PGC-1alpha in HeLa cells by transient transfection induces the activity of the ESRRA promoter in a manner that is dependent on the presence of the ESRRA23 element and on its dosage. Coexpression of ERRalpha and PGC-1alpha results in a synergistic activation of the ESRRA promoter. In experiments using ERRalpha null fibroblasts, the ability of PGC-1alpha to stimulate the ESRRA promoter is considerably reduced but can be restored by addition of ERRalpha. Taken together, these results demonstrate that an interdependent ERRalpha/PGC-1alpha-based transcriptional pathway targets the ESRRA23 element to dictate the level of ERRalpha expression. This study further suggests that this regulatory polymorphism may provide differential responses to ERRalpha/PGC-1alpha-mediated metabolic cues in the human population.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Canada / epidemiology
  • DNA Mutational Analysis
  • ERRalpha Estrogen-Related Receptor
  • Feedback, Physiological / genetics*
  • Female
  • Gene Dosage
  • Genetic Testing
  • Heat-Shock Proteins / physiology*
  • Hormones / physiology
  • Humans
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Polymorphism, Genetic*
  • Promoter Regions, Genetic / genetics*
  • Receptors, Cytoplasmic and Nuclear / biosynthesis
  • Receptors, Cytoplasmic and Nuclear / genetics*
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Receptors, Estrogen / biosynthesis
  • Receptors, Estrogen / genetics*
  • Receptors, Estrogen / metabolism
  • Response Elements / genetics*
  • Transcription Factors / metabolism
  • Transcription Factors / physiology*

Substances

  • Heat-Shock Proteins
  • Hormones
  • PPARGC1A protein, human
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Estrogen
  • Transcription Factors
  • peroxisome-proliferator-activated receptor-gamma coactivator-1