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on March 17, 2005

Arteriosclerosis, Thrombosis, and Vascular Biology. 2005
Published online before print March 17, 2005, doi: 10.1161/01.ATV.0000163186.58462.c5
A more recent version of this article appeared on June 1, 2005
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Submitted on November 30, 2004
Accepted on March 10, 2005

Activation of ATP-Binding Cassette Transporter A1 Transcription by Chromatin Remodeling Complex

Jarkko Huuskonen *; Meeta Vishnu ; Phoebe E. Fielding ; and Christopher J. Fielding

From the Cardiovascular Research Institute (J.H., M.V., P.E.F., C.J.F.) and Departments of Medicine (P.E.F) and Physiology (C.J.F.), University of California, San Francisco.

* To whom correspondence should be addressed. E-mail: jhuu6676{at}itsa.ucsf.edu.

Objective--Liver X receptor (LXR) regulates the transcription of ATP-binding cassette transporter A1 (ABCA1) by binding to the DR-4 promoter element as a heterodimer with retinoid X receptor (RXR). The role of chromatin remodeling complex in LXR or ABCA1 activation has not been established previously. In this study, we investigated the activation of ABCA1 by brahma-related gene 1 (BRG-1) and brahma, members of the SWI/SNF (mating type switching/sucrose nonfermenting) chromatin remodeling complex.

Methods and Results--Overexpression of wild-type BRG-1 in SW-13 cells, but not a catalytically inactive mutant, increased ABCA1 mRNA levels determined by RT-PCR. These effects were enhanced by LXR and RXR agonists. In 293T (epithelial kidney cell line) and Hep3B (hepatocyte cell line) cells, small interfering RNA against BRG-1/brm also affected ABCA1 mRNA levels. Synergistic activation of ABCA1 was obtained after coexpressing BRG-1 and SRC-1, a coactivator of LXR. Luciferase assays showed that this activation of ABCA1 was dependent on the promoter DR-4 element. Coimmunoprecipitation and chromatin immunoprecipitation studies indicated that the mechanism of BRG-1-mediated activation of ABCA1 involved interaction of LXR/RXR with BRG-1 and binding of this complex to ABCA1 promoter.

Conclusions--Catalytic subunits of SWI/SNF chromatin remodeling complex, BRG-1 and brahma, play significant roles in enhancing LXR/RXR-mediated transcription of ABCA1 via the promoter DR-4 element.
Key words: ABCA1 • HDL metabolism • LXR • chromatin remodeling • BRG-1




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