Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

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.

FOOTNOTES Back to Top

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}leitmanlab.com.


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Preferential Estrogen Receptor {beta} Ligands Reduce Bcl-2 Expression in Hormone-Resistant Breast Cancer Cells to Increase Autophagy.
S. C. Ruddy, R. Lau, M. A. Cabrita, C. McGregor, B. C. McKay, L. C. Murphy, J. S. Wright, T. Durst, and M. A. C. Pratt (2014)
Mol. Cancer Ther. 13, 1882-1893
   Abstract »    Full Text »    PDF »
Support of a bi-faceted role of estrogen receptor {beta} (ER{beta}) in ER{alpha}-positive breast cancer cells.
P. Jonsson, A. Katchy, and C. Williams (2014)
Endocr. Relat. Cancer 21, 143-160
   Abstract »    Full Text »    PDF »
Post-transcriptional Regulation of Human Breast Cancer Cell Proteome by Unliganded Estrogen Receptor {beta} via microRNAs.
G. Nassa, R. Tarallo, G. Giurato, M. R. De Filippo, M. Ravo, F. Rizzo, C. Stellato, C. Ambrosino, M. Baumann, N. Lietzen, et al. (2014)
Mol. Cell. Proteomics 13, 1076-1090
   Abstract »    Full Text »    PDF »
Large-Scale Quality Analysis of Published ChIP-seq Data.
G. K. Marinov, A. Kundaje, P. J. Park, and B. J. Wold (2014)
g3 4, 209-223
   Abstract »    Full Text »    PDF »
ER{beta}-dependent effects on uterine endothelial cells are cell specific and mediated via Sp1.
E. Greaves, F. Collins, H. O. D. Critchley, and P. T. K. Saunders (2013)
Hum. Reprod. 28, 2490-2501
   Abstract »    Full Text »    PDF »
Sp1 trans-activates and is required for maximal aldosterone induction of the {alpha}ENaC gene in collecting duct cells.
Z. Yu, Q. Kong, and B. C. Kone (2013)
Am J Physiol Renal Physiol 305, F653-F662
   Abstract »    Full Text »    PDF »
Estrogen Receptor {beta} (ER{beta}1) Transactivation Is Differentially Modulated by the Transcriptional Coregulator Tip60 in a cis-Acting Element-dependent Manner.
M.-T. Lee, Y.-K. Leung, I. Chung, P. Tarapore, and S.-M. Ho (2013)
J. Biol. Chem. 288, 25038-25052
   Abstract »    Full Text »    PDF »
MicroRNA-191, an estrogen-responsive microRNA, functions as an oncogenic regulator in human breast cancer.
N. Nagpal, H. M. Ahmad, B. Molparia, and R. Kulshreshtha (2013)
Carcinogenesis 34, 1889-1899
   Abstract »    Full Text »    PDF »
Repression of mammary adipogenesis by genistein limits mammosphere formation of human MCF-7 cells.
M. T. E. Montales, O. M. Rahal, H. Nakatani, T. Matsuda, and R. C. M. Simmen (2013)
J. Endocrinol. 218, 135-149
   Abstract »    Full Text »    PDF »
A bi-faceted role of estrogen receptor {beta} in breast cancer.
E. Leygue and L. C. Murphy (2013)
Endocr. Relat. Cancer 20, R127-R139
   Abstract »    Full Text »    PDF »
Estrogen receptor {beta} sustains epithelial differentiation by regulating prolyl hydroxylase 2 transcription.
P. Mak, C. Chang, B. Pursell, and A. M. Mercurio (2013)
PNAS 110, 4708-4713
   Abstract »    Full Text »    PDF »
ChIPBase: a database for decoding the transcriptional regulation of long non-coding RNA and microRNA genes from ChIP-Seq data.
J.-H. Yang, J.-H. Li, S. Jiang, H. Zhou, and L.-H. Qu (2013)
Nucleic Acids Res. 41, D177-D187
   Abstract »    Full Text »    PDF »
Estrogen Represses Hepatocellular Carcinoma (HCC) Growth via Inhibiting Alternative Activation of Tumor-associated Macrophages (TAMs).
W. Yang, Y. Lu, Y. Xu, L. Xu, W. Zheng, Y. Wu, L. Li, and P. Shen (2012)
J. Biol. Chem. 287, 40140-40149
   Abstract »    Full Text »    PDF »
17{beta}-Estradiol Represses Myogenic Differentiation by Increasing Ubiquitin-specific Peptidase 19 through Estrogen Receptor {alpha}.
M. Ogawa, R. Yamaji, Y. Higashimura, N. Harada, H. Ashida, Y. Nakano, and H. Inui (2011)
J. Biol. Chem. 286, 41455-41465
   Abstract »    Full Text »    PDF »
Sex hormone control of left ventricular structure/function: mechanistic insights using echocardiography, expression, and DNA methylation analyses in adult mice.
I. A. Sebag, M.-A. Gillis, A. Calderone, A. Kasneci, M. Meilleur, R. Haddad, W. Noiles, B. Patel, and L. E. Chalifour (2011)
Am J Physiol Heart Circ Physiol 301, H1706-H1715
   Abstract »    Full Text »    PDF »
A single nucleotide polymorphism-derived regulatory gene network underlying puberty in 2 tropical breeds of beef cattle.
M. R. S. Fortes, A. Reverter, S. H. Nagaraj, Y. Zhang, N. N. Jonsson, W. Barris, S. Lehnert, G. B. Boe-Hansen, and R. J. Hawken (2011)
J Anim Sci 89, 1669-1683
   Abstract »    Full Text »    PDF »
Tamoxifen increases nuclear respiratory factor 1 transcription by activating estrogen receptor {beta} and AP-1 recruitment to adjacent promoter binding sites.
M. M. Ivanova, K. H. Luken, A. S. Zimmer, F. L. Lenzo, R. J. Smith, M. W. Arteel, T. J. Kollenberg, K. A. Mattingly, and C. M. Klinge (2011)
FASEB J 25, 1402-1416
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882