title: BRG-1 is recruited to estrogen-responsive promoters and cooperates with factors involved in histone acetylation.
abstract: Several factors that mediate activation by nuclear receptors also modify the chemical and structural composition of chromatin. Prominent in this diverse group is the steroid receptor coactivator 1 (SRC-1) family, which interact with agonist-bound nuclear receptors, thereby coupling them to multifunctional transcriptional coregulators such as CREB-binding protein (CBP), p300, and PCAF, all of which have potent histone acetyltransferase activity. Additionally factors including the Brahma-related gene 1 (BRG-1) that are involved in the structural remodeling of chromatin also mediate hormone-dependent transcriptional activation by nuclear receptors. Here, we provide evidence that these two distinct mechanisms of coactivation may operate in a collaborative manner. We demonstrate that transcriptional activation by the estrogen receptor (ER) requires functional BRG-1 and that the coactivation of estrogen signaling by either SRC-1 or CBP is BRG-1 dependent. We find that in response to estrogen, ER recruits BRG-1, thereby targeting BRG-1 to the promoters of estrogen-responsive genes in a manner that occurs simultaneous to histone acetylation. Finally, we demonstrate that BRG-1-mediated coactivation of ER signaling is regulated by the state of histone acetylation within a cell. Inhibition of histone deacetylation by trichostatin A dramatically increases BRG-1-mediated coactivation of ER signaling, and this increase is reversed by overexpression of histone deacetylase 1. These studies support a critical role for BRG-1 in ER action in which estrogen stimulates an ER-BRG-1 association coupling BRG-1 to regions of chromatin at the sites of estrogen-responsive promoters and promotes the activity of other recruited factors that alter the acetylation state of chromatin.
authors.affiliation: Department of Adult Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: J
authors.initials: J
authors.lastname: DiRenzo
authors.forename: Y
authors.initials: Y
authors.lastname: Shang
authors.forename: M
authors.initials: M
authors.lastname: Phelan
authors.forename: S
authors.initials: S
authors.lastname: Sif
authors.forename: M
authors.initials: M
authors.lastname: Myers
authors.forename: R
authors.initials: R
authors.lastname: Kingston
authors.forename: M
authors.initials: M
authors.lastname: Brown
mesh_terms: D000107:Acetylation / Q000187:drug effects; D050882:CREB-Binding Protein; D002843:Chromatin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004265:DNA Helicases; D004268:DNA-Binding Proteins / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology*; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008024:Ligands; D009687:Nuclear Proteins / Q000378:metabolism*; D056920:Nuclear Receptor Coactivator 1; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding / Q000187:drug effects; D011960:Receptors, Estrogen / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; D004967:Estrogens; D006657:Histones; D006877:Hydroxamic Acids; D008024:Ligands; D009687:Nuclear Proteins; D011960:Receptors, Estrogen; D015534:Trans-Activators; D014157:Transcription Factors; C012589:trichostatin A; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1; D006655:Histone Deacetylases; C084108:SMARCA4 protein, human; D004265:DNA Helicases