Ligand-dependent activation of the farnesoid X-receptor directs arginine methylation of histone H3 by CARM1.

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Citation

Ananthanarayanan M, Li S, Balasubramaniyan N, Suchy FJ, Walsh MJ

Ligand-dependent activation of the farnesoid X-receptor directs arginine methylation of histone H3 by CARM1.

J Biol Chem. 2004 Dec 24;279(52):54348-57. Epub 2004 Oct 6.

PubMed ID
15471871 [ View in PubMed
]
Abstract

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.

DrugBank Data that Cites this Article

Polypeptides
NameUniProt ID
Bile acid receptorQ96RI1Details