title: Estrogen receptor alpha represses transcription of early target genes via p300 and CtBP1.
abstract: The regulation of gene expression by nuclear receptors controls the phenotypic properties and diverse biologies of target cells. In breast cancer cells, estrogen receptor alpha (ERalpha) is a master regulator of transcriptional stimulation and repression, yet the mechanisms by which agonist-bound ERalpha elicits repression are poorly understood. We analyzed early estrogen-repressed genes and found that ERalpha is recruited to ERalpha binding sites of these genes, albeit more transiently and less efficiently than for estrogen-stimulated genes. Of multiple cofactors studied, only p300 was recruited to ERalpha binding sites of repressed genes, and its knockdown prevented estrogen-mediated gene repression. Because p300 is involved in transcription initiation, we tested whether ERalpha might be trying to stimulate transcription at repressed genes, with ultimately failure and a shift to a repressive program. We found that estrogen increases transcription in a rapid but transient manner at early estrogen-repressed genes but that this is followed by recruitment of the corepressor CtBP1, a p300-interacting partner that plays an essential role in the repressive process. Thus, at early estrogen-repressed genes, ERalpha initiates transient stimulation of transcription but fails to maintain the transcriptional process observed at estrogen-stimulated genes; rather, it uses p300 to recruit CtBP1-containing complexes, eliciting chromatin modifications that lead to transcriptional repression.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801-3704, USA.
authors.forename: Fabio
authors.initials: F
authors.lastname: Stossi
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Madak-Erdogan
authors.forename: Benita S
authors.initials: BS
authors.lastname: Katzenellenbogen
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000429:Alcohol Oxidoreductases / Q000378:metabolism*; D001665:Binding Sites; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism*; D050881:E1A-Associated p300 Protein / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008957:Models, Genetic; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D004268:DNA-Binding Proteins; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D006657:Histones; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D004958:Estradiol; D000429:Alcohol Oxidoreductases; C096794:C-terminal binding protein; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D008239:Lysine