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

• Published in: The Journal of biological chemistry Vol. 279; no. 52; pp. 54348 - 54357
• Main Authors: Ananthanarayanan, Meenakshisundaram, Li, SiDe, Balasubramaniyan, Natarajan, Suchy, Frederick J., Walsh, Martin J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 24.12.2004; American Society for Biochemistry and Molecular Biology
• Subjects: Acetylation; Arginine - metabolism; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters - genetics; Binding Sites; Blotting, Western; Cell Line; Chromatin - chemistry; DNA - metabolism; DNA-Binding Proteins; Drug Synergism; Electrophoresis, Polyacrylamide Gel; Histones - metabolism; Humans; Immunosorbent Techniques; Lysine - metabolism; Methylation; Promoter Regions, Genetic - genetics; Protein-Arginine N-Methyltransferases - genetics; Protein-Arginine N-Methyltransferases - metabolism; Protein-Arginine N-Methyltransferases - physiology; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - physiology; RNA, Messenger - analysis; Signal Transduction; Transcription Factors; Transfection
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M410021200

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.