Editors' ChoiceNuclear Receptors

Repress, Derepress, Activate

Science Signaling  04 Jun 2013:
Vol. 6, Issue 278, pp. ec128
DOI: 10.1126/scisignal.2004393

Upon ligand binding, nuclear hormone receptors directly promote the expression of target genes, but many of these receptors also repress gene transcription in the absence of ligand. Vicent et al. report that the unliganded form of the progesterone receptor (PR) repressed gene transcription in breast cancer cells by recruiting to target promoters a multiprotein complex that prevents the chromatin remodeling events necessary for gene transcription. The authors used human T47D breast cancer cells carrying a genomically integrated luciferase reporter under control of the mouse mammary tumor virus (MMTV) promoter, which is induced by steroid hormones like progesterone and repressed in the absence of hormones. Without progesterone treatment, the MMTV promoter was associated with unliganded PR (uPR) and a multiprotein complex containing heterochromatin protein 1γ (HP1γ), the silencing factor CoREST, the DNA binding protein BRAF35, histone deacetylase 1, and the lysine-specific histone H3 demethylase LSD1. This complex repressed the MMTV promoter in the absence of hormone and dissociated from the promoter upon stimulation with a progestin analog. Components of the HP1γ-containing repressor complex and uPR were also found at endogenous progesterone-responsive promoters. Displacement of the HP1γ-containing repressor complex from the MMTV promoter required phosphorylation of histone H3 at Ser10 by the kinase MSK1, which is activated by hormone treatment and recruited to target promoters with ligand-bound PR. In coimmunoprecipitation assays, PR associated with components of the HP1γ-containing repressor complex in both the absence and presence of hormone. The complex was present at a subset of endogenous PR-responsive genes, and chromatin immunoprecipitation experiments indicated that uPR recruited the complex to these sites. RNase treatment of permeabilized cells reduced targeting of the repressor complex to the MMTV and endogenous promoters, and the repressor complex contained the RNA steroid receptor RNA activator (SRA), which was required for stable targeting of the complex to uPR-responsive promoters. These findings suggest a model in which uPR recruits a repressive complex to a subset of PR-responsive promoters to repress basal transcription of these genes. Hormone stimulation derepresses these by activating and recruiting MSK1, which phosphorylates histone H3 to displace the repressive complex. Subsequent trimethylation and acetylation of histone H3 mediate chromatin remodeling that enables ligand-bound PR-coactivator complexes to promote target gene transcription.

G. P. Vicent, A. S. Nacht, R. Zaurin, J. Font-Mateu, D. Soronellas, F. Le Dily, D. Reyes, M. Beato, Unliganded progesterone receptor-mediated targeting of an RNA-containing repressive complex silences a subset of hormone-inducible genes. Genes Dev. 27, 1179–1197 (2013). [Abstract] [Full Text]