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Systems Biology of Metabolic Regulation by Estrogen Receptor Signaling in Breast Cancer
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Estrogen receptor beta binds to and regulates three distinct classes of target genes

Omar I Vivar1, Xiaoyue Zhao, Elise F Saunier

  • 1Department of Nutritional Science and Toxicology, University of California, Berkeley, California 94720, USA.

The Journal of Biological Chemistry
|April 21, 2010
PubMed

Insights

Estrogen receptor beta (ERbeta) regulates genes differently depending on whether it is bound to a ligand. Unliganded ERbeta controls one gene class, while liganded ERbeta controls another, and both forms regulate a third class.

Area of Science:

  • Molecular Endocrinology
  • Gene Regulation
  • Estrogen Receptor Signaling

Background:

  • Estrogen receptor beta (ERbeta) exhibits significant antiproliferative and anti-inflammatory effects.
  • ERbeta-selective agonists are potential therapeutic and chemopreventive agents.
  • Understanding ERbeta's gene regulation mechanisms is crucial for therapeutic development.

Purpose of the Study:

  • To identify genes regulated by unliganded and liganded forms of ERalpha and ERbeta.
  • To elucidate the mechanisms by which ERbeta differentially regulates gene expression.
  • To investigate the role of transcription factors and coactivators in ERbeta-mediated gene regulation.

Main Methods:

  • Gene expression profiling using microarrays in U2OS cells.
  • Chromatin immunoprecipitation-sequencing (ChIP-seq) to identify ERbeta binding sites.
  • Analysis of transcription factor motifs and coactivator recruitment.

Main Results:

  • ERalpha primarily requires a ligand (estradiol, E(2)) to regulate genes.
  • ERbeta regulates three distinct classes of genes: unliganded (Class I, 453 genes), liganded (Class II, 258 genes), and both (Class III, 83 genes).
  • ERbeta binding is consistent across all gene classes; differential regulation is mediated by distinct transcription factor interactions (AP1 for Class I, ERE/NFkappaB1/SP1 for Class II) and differential coactivator (NCOA2) recruitment.

Conclusions:

  • Unliganded and liganded ERbeta regulate distinct gene sets through differential interactions with transcription factors and coactivators.
  • ERbeta's ability to regulate genes in both liganded and unliganded states offers diverse therapeutic potential.
  • The findings provide insights into the complex mechanisms of ERbeta-mediated gene transcription.

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