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Publication

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

Molecular cell | 2017

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.

Pubmed ID: 28475868 RIS Download

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Associated grants

Agency: NIDDK NIH HHS, United States
Id: R37 DK039949
Agency: NCI NIH HHS, United States
Id: R01 CA213371
Agency: NIDDK NIH HHS, United States
Id: R01 DK018477
Agency: NIDDK NIH HHS, United States
Id: R01 DK039949
Agency: Howard Hughes Medical Institute, United States

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WEBLOGO (tool)

RRID:SCR_010236

Web application to generate sequence logos, graphical representations of patterns within multiple sequence alignment. Designed to make generation of sequence logos easy. Sequence logo generator.

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edgeR (tool)

RRID:SCR_012802

Bioconductor software package for Empirical analysis of Digital Gene Expression data in R. Used for differential expression analysis of RNA-seq and digital gene expression data with biological replication.

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Bowtie 2 (tool)

RRID:SCR_016368

Ultrafast and memory efficient tool for aligning sequencing reads to long reference sequences. Supports gapped, local, and paired end alignment modes. More suited to finding longer, gapped alignments in comparison with original Bowtie method.

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