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Widespread negative response elements mediate direct repression by agonist-liganded glucocorticoid receptor.

Milan Surjit1, Krishna Priya Ganti, Atish Mukherji

  • 1Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR7104, Inserm U964, Université de Strasbourg, Collège de France, Illkirch, 67404, France.

Cell
|April 19, 2011
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Summary

Glucocorticoid receptor (GR) directly represses genes by binding to novel DNA sequences (IR nGREs), independent of previously known mechanisms. This direct repression provides a new layer of gene regulation by fluctuating glucocorticoid levels.

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Area of Science:

  • Molecular Biology
  • Genetics
  • Endocrinology

Background:

  • Glucocorticoid receptor (GR) mediates gene transcription via direct binding to positive glucocorticoid response elements (+GREs).
  • GR-mediated repression was traditionally attributed to indirect interactions with other DNA-bound factors.
  • Direct GR binding to negative GREs (nGREs) has been reported for repression.

Purpose of the Study:

  • To investigate a novel mechanism of direct GR-mediated gene repression.
  • To identify the DNA binding sequences involved in this direct repression.
  • To determine the prevalence and biological relevance of this regulatory pathway.

Main Methods:

  • Analysis of GR binding to DNA sequences in vitro and in cellulo.
  • Identification of novel DNA binding sites (IR nGREs) for GR.
  • Gene expression analysis in response to glucocorticoid treatment.
  • Bioinformatic analysis of gene targets.

Main Results:

  • Glucocorticoid receptor directly represses transcription via binding to simple DNA binding sequences (IR nGREs) unrelated to +GREs.
  • These IR nGREs recruit repressor complexes (SMRT/NCoR) to agonist-liganded GR.
  • Over 1000 orthologous mouse and human genes containing IR nGREs are repressed by glucocorticoids in vivo.
  • This mechanism allows for coordinate gene regulation (activation and repression) by varying glucocorticoid levels.

Conclusions:

  • Direct GR binding to IR nGREs represents a novel mechanism for gene repression.
  • This pathway provides an additional layer of regulation in glucocorticoid signaling, responding to ligand fluctuations.
  • The identified IR nGREs are present in a significant number of genes, highlighting the broad impact of this regulatory mechanism.