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Molecular and Cellular Biology, June 2009, p. 3413-3423, Vol. 29, No. 12
0270-7306/09/$08.00+0     doi:10.1128/MCB.00020-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Coactivator Function Defines the Active Estrogen Receptor Alpha Cistrome ^,

Mathieu Lupien,^1, Jérôme Eeckhoute,^1, Clifford A. Meyer,² Susan A. Krum,^1,|| Daniel R. Rhodes,³ X. Shirley Liu,² and Myles Brown^1*

Division of Molecular and Cellular Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115,¹ Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, Massachusetts 02115,² Compendia Bioscience, Inc., Ann Arbor, Michigan 48104³

Received 6 January 2009/ Returned for modification 16 February 2009/ Accepted 29 March 2009

Proper activation of transcriptional networks in complex organisms is central to the response to stimuli. We demonstrate that the selective activation of a subset of the estrogen receptor alpha (ER) cistrome in MCF7 breast cancer cells provides specificity to the estradiol (E2) response. ER-specific enhancers that are subject to E2-induced coactivator-associated arginine methyltransferase 1 (CARM1) action are critical to E2-stimulated gene expression. This is true for both FoxA1-dependent and independent enhancers. In contrast, a subset of E2-suppressed genes are controlled by FoxA1-independent ER binding sites. Nonetheless, these are sites of E2-induced CARM1 activity. In addition, the MCF7 RNA polymerase II cistrome reveals preferential occupancy of E2-regulated promoters prior to stimulation. Interestingly, E2-suppressed genes tend to lie in otherwise silent genomic regions. Together, our results suggest that the transcriptional response to E2 in breast cancer cells is dependent on the interplay between polymerase II pre-occupied promoters and the subset of the ER cistrome associated with coactivation.

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* Corresponding author. Mailing address: Dana-Farber Cancer Institute, Division of Molecular and Cellular Oncology, 44 Binney St., Boston, MA 02115. Phone: (617) 632-3948. Fax: (617) 632-5417. E-mail: myles_brown{at}dfci.harvard.edu

Published ahead of print on 13 April 2009.

Supplemental material for this article may be found at http://mcb.asm.org/.

Present address: Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, NH 03756.

Present address: UMR CNRS 6026, Université de Rennes 1, Campus de Beaulieu, 35042 Rennes, France.

^|| Present address: Biomedical Sciences Research Building, UCLA, Los Angeles, CA 90095.

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Molecular and Cellular Biology, June 2009, p. 3413-3423, Vol. 29, No. 12
0270-7306/09/$08.00+0     doi:10.1128/MCB.00020-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

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