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J. Biol. Chem. 285 (29): 22059-22066

© 2010 by The American Society for Biochemistry and Molecular Biology, Inc.

Estrogen Receptor β Binds to and Regulates Three Distinct Classes of Target Genes*Formula

Omar I. Vivar{ddagger}1, Xiaoyue Zhao§1, Elise F. Saunier§, Chandi Griffin§, Oleg S. Mayba, Mary Tagliaferri§, Isaac Cohen§, Terence P. Speed||2, , and Dale C. Leitman{ddagger}23

From the {ddagger}Department of Nutritional Science and Toxicology, University of California, Berkeley, California 94720,
§Bionovo, Inc., Emeryville, California 94608,
the Department of Statistics, University of California, Berkeley, California 94720, and
the ||Division of Bioinformatics, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia

ABSTRACT Back to Top

Abstract: Estrogen receptor β (ERβ) has potent antiproliferative and anti-inflammatory properties, suggesting that ERβ-selective agonists might be a new class of therapeutic and chemopreventative agents. To understand how ERβ regulates genes, we identified genes regulated by the unliganded and liganded forms of ER{alpha} and ERβ in U2OS cells. Microarray data demonstrated that virtually no gene regulation occurred with unliganded ER{alpha}, whereas many genes were regulated by estradiol (E2). These results demonstrated that ER{alpha} requires a ligand to regulate a single class of genes. In contrast, ERβ regulated three classes of genes. Class I genes were regulated primarily by unliganded ERβ. Class II genes were regulated only with E2, whereas class III genes were regulated by both unliganded ERβ and E2. There were 453 class I genes, 258 class II genes, and 83 class III genes. To explore the mechanism whereby ERβ regulates different classes of genes, chromatin immunoprecipitation-sequencing was performed to identify ERβ binding sites and adjacent transcription factor motifs in regulated genes. AP1 binding sites were more enriched in class I genes, whereas ERE, NF{kappa}B1, and SP1 sites were more enriched in class II genes. ERβ bound to all three classes of genes, demonstrating that ERβ binding is not responsible for differential regulation of genes by unliganded and liganded ERβ. The coactivator NCOA2 was differentially recruited to several target genes. Our findings indicate that the unliganded and liganded forms of ERβ regulate three classes of genes by interacting with different transcription factors and coactivators.

Key Words: Chromatin Immunoprecipitation (ChiP) • Estrogen • Gene Regulation • Gene Transcription • Microarray • Nuclear Receptors • Steroid Hormone Receptor

Received for publication February 14, 2010. Revision received April 14, 2010.


1 Both authors contributed equally to this work.

2 Members of the Scientific Advisory Board of Bionovo, Inc.

3 Recipient of a gift of financial support for research from Bionovo, Inc. To whom correspondence should be addressed: University of California, Dept. of Nutritional Science and Toxicology, 44 Morgan Hall, Berkeley, CA 94720. Tel.: 510-642-0862; E-mail: dale{at}

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