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Molecular and Cellular Biology, September 2009, p. 4949-4958, Vol. 29, No. 18
0270-7306/09/$08.00+0     doi:10.1128/MCB.00383-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Repression of ESR1 through Actions of Estrogen Receptor Alpha and Sin3A at the Proximal Promoter{triangledown}

Stephanie J. Ellison-Zelski, Natalia M. Solodin, and Elaine T. Alarid*

Department of Oncology, University of Wisconsin—Madison, Madison, Wisconsin 53706

Received 24 March 2009/ Returned for modification 12 May 2009/ Accepted 13 July 2009

Gene expression results from the coordinated actions of transcription factor proteins and coregulators. Estrogen receptor alpha (ER{alpha}) is a ligand-activated transcription factor that can both activate and repress the expression of genes. Activation of transcription by estrogen-bound ER{alpha} has been studied in detail, as has antagonist-induced repression, such as that which occurs by tamoxifen. How estrogen-bound ER{alpha} represses gene transcription remains unclear. In this report, we identify a new mechanism of estrogen-induced transcriptional repression by using the ER{alpha} gene, ESR1. Upon estrogen treatment, ER{alpha} is recruited to two sites on ESR1, one distal (ENH1) and the other at the proximal (A) promoter. Coactivator proteins, namely, p300 and AIB1, are found at both ER{alpha}-binding sites. However, recruitment of the Sin3A repressor, loss of RNA polymerase II, and changes in histone modifications occur only at the A promoter. Reduction of Sin3A expression by RNA interference specifically inhibits estrogen-induced repression of ESR1. Furthermore, an estrogen-responsive interaction between Sin3A and ER{alpha} is identified. These data support a model of repression wherein actions of ER{alpha} and Sin3A at the proximal promoter can overcome activating signals at distal or proximal sites and ultimately decrease gene expression.

* Corresponding author. Mailing address: Department of Oncology, McArdle Laboratories for Cancer Research, University of Wisconsin—Madison, 6151 Wisconsin Institutes for Medical Research, 1111 Highland Avenue, Madison, WI 53706. Phone: (608) 265-9319. Fax: (608) 262-2824. E-mail: alarid{at}oncology.wisc.edu

{triangledown} Published ahead of print on 20 July 2009.

Molecular and Cellular Biology, September 2009, p. 4949-4958, Vol. 29, No. 18
0270-7306/09/$08.00+0     doi:10.1128/MCB.00383-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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