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J. Biol. Chem., Vol. 279, Issue 52, 54348-54357, December 24, 2004

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Ligand-dependent Activation of the Farnesoid X-receptor Directs Arginine Methylation of Histone H3 by CARM1^*

Meenakshisundaram Ananthanarayanan, SiDe Li, Natarajan Balasubramaniyan, Frederick J. Suchy, and Martin J. Walsh¶

From the Department of Pediatrics, Mount Sinai School of Medicine, New York, New York 10029

In this study we demonstrate that the class II nuclear hormone receptor, farnesoid X-receptor (FXR), incorporates histone methyltransferase activity within the gene locus for bile salt export pump (BSEP), a well established FXR target gene that functions as an ATP-dependent canalicular bile acid transporter. This methyltransferase activity is directed specifically to arginine 17 of histone H3. We demonstrate that FXR is directly associated with co-activator-associated arginine methyltransferase 1 (CARM1) activity. Furthermore, we show by chromatin immunoprecipitation that the ligand-dependent activation of the human BSEP locus is associated with a simultaneous increase of FXR and CARM1 occupation. The increased occupation of the BSEP locus by CARM1 also corresponds with the increased deposition of Arg-17 methylation and Lys-9 acetylation of histone H3 within the FXR DNA-binding element of BSEP. Consistent with these findings, CARM1 led to increased BSEP promoter activity with an intact FXR regulatory element, whereas CARM1 failed to transactivate the BSEP promoter with a mutated FXRE. Induction of endogenous BSEP mRNA and Arg-17 methylation by FXR regulatory element ligand, CDCA, requires CARM1 activity. Therefore, histone methylation at Arg-17 by CARM1 is a downstream target of signaling through ligand-mediated activation of FXR. Our studies provide evidence that FXR directly recruits specific chromatin modifying activity of CARM1 necessary for full potentiation of the BSEP locus in vivo.

Received for publication, August 31, 2004 , and in revised form, October 4, 2004.

^* This work was supported in part by United States Public Health Service Awards HL67099 (to M. J. W.) and HD20632 (to F. J. S.) from the National Institutes of Health and by a Cystic Fibrosis Foundation Research award (to M. J. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

To whom correspondence may be addressed: Dept. of Pediatrics, Box 1664, The Mount Sinai Medical Center, One Gustave L. Levy Place, New York, NY 10029. Tel.: 212-241-3029; Fax: 212-426-1972; E-mail: meena.ananth{at}mssm.edu. ¶ To whom correspondence may be addressed. Tel.: 212-241-9714; Fax: 212-426-1972; E-mail: martin.walsh{at}mssm.edu.

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