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Molecular and Cellular Biology, October 2000, p. 7541-7549, Vol. 20, No. 20
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

BRG-1 Is Recruited to Estrogen-Responsive Promoters and Cooperates with Factors Involved in Histone Acetylation

James DiRenzo,1 Yongfeng Shang,1 Michael Phelan,2,3 Säid Sif,2,3,dagger Molly Myers,1 Robert Kingston,2,3 and Myles Brown1,*

Department of Adult Oncology, Dana Farber Cancer Institute,1 and Department of Genetics,2 Harvard Medical School, Boston, Massachusetts 02115, and Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 021143

Received 25 May 2000/Returned for modification 28 June 2000/Accepted 21 July 2000

Several factors that mediate activation by nuclear receptors also modify the chemical and structural composition of chromatin. Prominent in this diverse group is the steroid receptor coactivator 1 (SRC-1) family, which interact with agonist-bound nuclear receptors, thereby coupling them to multifunctional transcriptional coregulators such as CREB-binding protein (CBP), p300, and PCAF, all of which have potent histone acetyltransferase activity. Additionally factors including the Brahma-related gene 1 (BRG-1) that are involved in the structural remodeling of chromatin also mediate hormone-dependent transcriptional activation by nuclear receptors. Here, we provide evidence that these two distinct mechanisms of coactivation may operate in a collaborative manner. We demonstrate that transcriptional activation by the estrogen receptor (ER) requires functional BRG-1 and that the coactivation of estrogen signaling by either SRC-1 or CBP is BRG-1 dependent. We find that in response to estrogen, ER recruits BRG-1, thereby targeting BRG-1 to the promoters of estrogen-responsive genes in a manner that occurs simultaneous to histone acetylation. Finally, we demonstrate that BRG-1-mediated coactivation of ER signaling is regulated by the state of histone acetylation within a cell. Inhibition of histone deacetylation by trichostatin A dramatically increases BRG-1-mediated coactivation of ER signaling, and this increase is reversed by overexpression of histone deacetylase 1. These studies support a critical role for BRG-1 in ER action in which estrogen stimulates an ER-BRG-1 association coupling BRG-1 to regions of chromatin at the sites of estrogen-responsive promoters and promotes the activity of other recruited factors that alter the acetylation state of chromatin.

* Corresponding author. Mailing address: D-730 Dana Farber Cancer Institute, 44 Binney St., Boston, MA 02115. Phone: (617) 632-3948. Fax: (617) 632-5417. E-mail: Myles_Brown{at}dfci.harvard.edu.

dagger Present address: Department of Molecular and Cellular Biochemistry, Ohio State University College of Medicine, Columbus, OH 43210.

Molecular and Cellular Biology, October 2000, p. 7541-7549, Vol. 20, No. 20
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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