This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplemental material
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Google Scholar
Right arrow Articles by Miao, J.
Right arrow Articles by Kemper, J. K.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Miao, J.
Right arrow Articles by Kemper, J. K.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, December 2009, p. 6170-6181, Vol. 29, No. 23
0270-7306/09/$08.00+0     doi:10.1128/MCB.00825-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Functional Specificities of Brm and Brg-1 Swi/Snf ATPases in the Feedback Regulation of Hepatic Bile Acid Biosynthesis{triangledown} ,{dagger}

Ji Miao,1 Sungsoon Fang,1 Jiyoung Lee,1 Clay Comstock,2 Karen E. Knudsen,2,3 and Jongsook Kim Kemper1*

Department of Molecular and Integrative Physiology, University of Illinois, Urbana, Illinois 61801,1 Department of Cancer Biology,2 Department of Urology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 191073

Received 24 June 2009/ Returned for modification 25 July 2009/ Accepted 19 September 2009

Bile acid homeostasis is critical in maintaining health and is primarily regulated by the nuclear receptors farnesoid X receptor (FXR) and small heterodimer partner (SHP). Bile acid-activated FXR indirectly inhibits expression of cholesterol 7{alpha} hydroxylase (CYP7A1), a key enzyme in conversion of cholesterol to bile acids, by induction of SHP. We recently demonstrated that SHP inhibits CYP7A1 transcription by recruiting chromatin-modifying cofactors, including Brm-Swi/Snf. Swi/Snf complexes contain either Brm or Brg-1 ATPases, and whether these subunits have distinct functions remains unclear. We have examined the role of these subunits in regulation of bile acid metabolism under physiological conditions by FXR and SHP. Brg-1 interacted with FXR and enhanced FXR-mediated transactivation of SHP, whereas Brm interacted with SHP and enhanced SHP-mediated repression of CYP7A1 and, interestingly, auto-repression of SHP. Chromatin immunoprecipitation and remodeling studies revealed that after treatment with FXR agonists, Brg-1 was recruited to the SHP promoter, resulting in transcriptionally active accessible chromatin, whereas Brm was recruited to both CYP7A1 and SHP promoters, resulting in inactive inaccessible chromatin. Our studies demonstrate that Brm and Brg-1 have distinct functions in the regulation of two key genes, CYP7A1 and SHP, within a single physiological pathway, feedback inhibition of bile acid biosynthesis, by differentially targeting SHP and FXR.

* Corresponding author. Mailing address: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, 524 Burrill Hall, 407 S. Goodwin Ave., Urbana, IL 61801. Phone: (217) 333-6317. Fax: (217) 333-1133. E-mail: jongsook{at}uiuc.edu

{triangledown} Published ahead of print on 5 October 2009.

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

Molecular and Cellular Biology, December 2009, p. 6170-6181, Vol. 29, No. 23
0270-7306/09/$08.00+0     doi:10.1128/MCB.00825-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»