Unliganded progesterone receptor-mediated targeting of an RNA-containing repressive complex silences a subset of hormone-inducible genes
- Guillermo Pablo Vicent1,2,3,
- A. Silvina Nacht1,2,
- Roser Zaurin1,2,
- Jofre Font-Mateu1,2,
- Daniel Soronellas1,2,
- Francois Le Dily1,2,
- Diana Reyes1,2 and
- Miguel Beato1,2
- 1Centre for Genomic Regulation (CRG), E-08003 Barcelona, Spain;
- 2Universitat Pompeu Fabra (UPF), E-08003 Barcelona, Spain
Abstract
A close chromatin conformation precludes gene expression in eukaryotic cells. Genes activated by external cues have to overcome this repressive state by locally changing chromatin structure to a more open state. Although much is known about hormonal gene activation, how basal repression of regulated genes is targeted to the correct sites throughout the genome is not well understood. Here we report that in breast cancer cells, the unliganded progesterone receptor (PR) binds genomic sites and targets a repressive complex containing HP1γ (heterochromatin protein 1γ), LSD1 (lysine-specific demethylase 1), HDAC1/2, CoREST (corepressor for REST [RE1 {neuronal repressor element 1} silencing transcription factor]), KDM5B, and the RNA SRA (steroid receptor RNA activator) to 20% of hormone-inducible genes, keeping these genes silenced prior to hormone treatment. The complex is anchored via binding of HP1γ to H3K9me3 (histone H3 tails trimethylated on Lys 9). SRA interacts with PR, HP1γ, and LSD1, and its depletion compromises the loading of the repressive complex to target chromatin-promoting aberrant gene derepression. Upon hormonal treatment, the HP1γ–LSD1 complex is displaced from these constitutively poorly expressed genes as a result of rapid phosphorylation of histone H3 at Ser 10 mediated by MSK1, which is recruited to the target sites by the activated PR. Displacement of the repressive complex enables the loading of coactivators needed for chromatin remodeling and activation of this set of genes, including genes involved in apoptosis and cell proliferation. These results highlight the importance of the unliganded PR in hormonal regulation of breast cancer cells.
Keywords
- basal repression
- RNA-containing repressive complex
- unliganded receptor
- cell proliferation
- progesterone gene regulation
Footnotes
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↵3 Corresponding author
E-mail guillermo.vicent{at}crg.es
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.215293.113.
- Received February 1, 2013.
- Accepted April 22, 2013.
- Copyright © 2013 by Cold Spring Harbor Laboratory Press