Glucocorticoid Receptor:MegaTrans Switching Mediates the Repression of an ERα-Regulated Transcriptional Program

Feng Yang, Qi Ma, Zhijie Liu, Wenbo Li, Yuliang Tan, Chunyu Jin, Wubin Ma, Yiren Hu, Jia Shen, Kenneth A. Ohgi, Francesca Telese, Wen Liu, Michael G. Rosenfeld

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

The molecular mechanisms underlying the opposing functions of glucocorticoid receptors (GRs) and estrogen receptor α (ERα) in breast cancer development remain poorly understood. Here we report that, in breast cancer cells, liganded GR represses a large ERα-activated transcriptional program by binding, in trans, to ERα-occupied enhancers. This abolishes effective activation of these enhancers and their cognate target genes, and it leads to the inhibition of ERα-dependent binding of components of the MegaTrans complex. Consistent with the effects of SUMOylation on other classes of nuclear receptors, dexamethasone (Dex)-induced trans-repression of the estrogen E2 program appears to depend on GR SUMOylation, which leads to stable trans-recruitment of the GR-N-CoR/SMRT-HDAC3 corepressor complex on these enhancers. Together, these results uncover a mechanism by which competitive recruitment of DNA-binding nuclear receptors/transcription factors in trans to hot spot enhancers serves as an effective biological strategy for trans-repression, with clear implications for breast cancer and other diseases.

Original languageEnglish (US)
Pages (from-to)321-331.e6
JournalMolecular Cell
Volume66
Issue number3
DOIs
StatePublished - May 4 2017

Keywords

  • enhancers
  • nuclear receptors
  • transcriptional regulation
  • transrepression

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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