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Molecular and Cellular Biology, September 2004, p. 7707-7719, Vol. 24, No. 17
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.17.7707-7719.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Role of an mSin3A-Swi/Snf Chromatin Remodeling Complex in the Feedback Repression of Bile Acid Biosynthesis by SHP

Jongsook Kim Kemper,1,{dagger}* Hwajin Kim,1,{dagger} Ji Miao,2 Sonali Bhalla,1 and Yangjin Bae1

Department of Molecular and Integrative Physiology,1 Department of Cell and Structural Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois2

Received 10 March 2004/ Returned for modification 9 April 2004/ Accepted 1 June 2004

The orphan receptor SHP interacts with many nuclear receptors and inhibits their transcriptional activities. SHP is central to feedback repression of cholesterol 7{alpha} hydroxylase gene (CYP7A1) expression by bile acids, which is critical for maintaining cholesterol homeostasis. Using CYP7A1 as a model system, we studied the molecular mechanisms of SHP repression at the level of native chromatin. Chromatin immunoprecipitation studies showed that mSin3A and a Swi/Snf complex containing Brm as a central ATPase were recruited to the promoter. This recruitment was associated with chromatin remodeling after bile acid treatment that was blunted by inhibition of the endogenous Swi/Snf function by dominant-negative ATPase mutants. Biochemical studies indicated that SHP was associated with the mSin3A-Swi/Snf complex by direct interaction with Brm and mSin3A through its repression domain. Expression of Brm, but not an ATPase mutant, inhibited CYP7A1 promoter activity and further enhanced SHP-mediated repression. Bile acid-induced recruitment of mSin3A/Brm, chromatin remodeling, and concomitant repression of endogenous CYP7A1 expression were impaired when SHP expression was inhibited by SHP small interfering RNA. Our results suggest that SHP mediates recruitment of mSin3A-Swi/Snf to the CYP7A1 promoter, resulting in chromatin remodeling and gene repression, which may also be a mechanism for the repression by SHP of genes activated by many nuclear receptors. Our study establishes the first link between a Swi/Snf complex and regulation of cholesterol metabolism.

* Corresponding author. Mailing address: Department of Molecular and Integrative Physiology, University of Illinois, Urbana, IL 61801. Phone: (217) 333-6317. Fax: (217) 333-1133. E-mail: jongsook{at}uiuc.edu.

{dagger} J.K.K. and H.K. contributed equally to this study.

Molecular and Cellular Biology, September 2004, p. 7707-7719, Vol. 24, No. 17
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.17.7707-7719.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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