title: Estrogen receptor beta binds to and regulates three distinct classes of target genes.
abstract: Estrogen receptor beta (ERbeta) has potent antiproliferative and anti-inflammatory properties, suggesting that ERbeta-selective agonists might be a new class of therapeutic and chemopreventive agents. To understand how ERbeta regulates genes, we identified genes regulated by the unliganded and liganded forms of ERalpha and ERbeta in U2OS cells. Microarray data demonstrated that virtually no gene regulation occurred with unliganded ERalpha, whereas many genes were regulated by estradiol (E(2)). These results demonstrated that ERalpha requires a ligand to regulate a single class of genes. In contrast, ERbeta regulated three classes of genes. Class I genes were regulated primarily by unliganded ERbeta. Class II genes were regulated only with E(2), whereas class III genes were regulated by both unliganded ERbeta and E(2). There were 453 class I genes, 258 class II genes, and 83 class III genes. To explore the mechanism whereby ERbeta regulates different classes of genes, chromatin immunoprecipitation-sequencing was performed to identify ERbeta binding sites and adjacent transcription factor motifs in regulated genes. AP1 binding sites were more enriched in class I genes, whereas ERE, NFkappaB1, and SP1 sites were more enriched in class II genes. ERbeta bound to all three classes of genes, demonstrating that ERbeta binding is not responsible for differential regulation of genes by unliganded and liganded ERbeta. The coactivator NCOA2 was differentially recruited to several target genes. Our findings indicate that the unliganded and liganded forms of ERbeta regulate three classes of genes by interacting with different transcription factors and coactivators.
authors.affiliation: Department of Nutritional Science and Toxicology, University of California, Berkeley, California 94720, USA.
authors.forename: Omar I
authors.initials: OI
authors.lastname: Vivar
authors.forename: Xiaoyue
authors.initials: X
authors.lastname: Zhao
authors.forename: Elise F
authors.initials: EF
authors.lastname: Saunier
authors.forename: Chandi
authors.initials: C
authors.lastname: Griffin
authors.forename: Oleg S
authors.initials: OS
authors.lastname: Mayba
authors.forename: Mary
authors.initials: M
authors.lastname: Tagliaferri
authors.forename: Isaac
authors.initials: I
authors.lastname: Cohen
authors.forename: Terence P
authors.initials: TP
authors.lastname: Speed
authors.forename: Dale C
authors.initials: DC
authors.lastname: Leitman
mesh_terms: D020029:Base Pairing; D001665:Binding Sites; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D019295:Computational Biology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D008024:Ligands; D051958:Nuclear Receptor Coactivator 2 / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D008024:Ligands; C498001:NCOA2 protein, human; D051958:Nuclear Receptor Coactivator 2; D018808:Transcription Factor AP-1
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