title: Unliganded progesterone receptor-mediated targeting of an RNA-containing repressive complex silences a subset of hormone-inducible genes.
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.
authors.affiliation: Centre for Genomic Regulation CRG, E-08003 Barcelona, Spain. guillermo.vicent@crg.es
authors.forename: Guillermo Pablo
authors.initials: GP
authors.lastname: Vicent
authors.forename: A Silvina
authors.initials: AS
authors.lastname: Nacht
authors.forename: Roser
authors.initials: R
authors.lastname: Zaurin
authors.forename: Jofre
authors.initials: J
authors.lastname: Font-Mateu
authors.forename: Daniel
authors.initials: D
authors.lastname: Soronellas
authors.forename: Francois
authors.initials: F
authors.lastname: Le Dily
authors.forename: Diana
authors.initials: D
authors.lastname: Reyes
authors.forename: Miguel
authors.initials: M
authors.lastname: Beato
mesh_terms: D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D020868:Gene Silencing / Q000187:drug effects; D015894:Genome, Human / Q000235:genetics; D056466:Histone Demethylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D046912:Multiprotein Complexes / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation; D011374:Progesterone / Q000378:metabolism* / Q000494:pharmacology; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000378:metabolism*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism
chemical_list: C518294:CBX3 protein, human; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D006657:Histones; D008024:Ligands; D046912:Multiprotein Complexes; D062085:RNA, Long Noncoding; D011980:Receptors, Progesterone; C405423:steroid receptor RNA activator; D011374:Progesterone; D056466:Histone Demethylases; C495195:KDM1A protein, human; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1
keywords: RNA-containing repressive complex; basal repression; cell proliferation; progesterone gene regulation; unliganded receptor