Ligand-dependent activation of the farnesoid X-receptor directs arginine methylation of histone H3 by CARM1.
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.
Department of Pediatrics, Mount Sinai School of Medicine, New York, New York 10029, USA. meena.ananth@mssm.edu
Meenakshisundaram
M
Ananthanarayanan
SiDe
S
Li
Natarajan
N
Balasubramaniyan
Frederick J
FJ
Suchy
Martin J
MJ
Walsh
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000107:Acetylation; D001120:Arginine / Q000378:metabolism*; D001665:Binding Sites; D015153:Blotting, Western; D002460:Cell Line; D002843:Chromatin / Q000737:chemistry; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins; D004357:Drug Synergism; D004591:Electrophoresis, Polyacrylamide Gel; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007163:Immunosorbent Techniques; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D014157:Transcription Factors; D014162:Transfection; D000099150:Receptor, Farnesoid X-Activated
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D001120:Arginine; D002843:Chromatin; D004247:DNA; D004268:DNA-Binding Proteins; D006657:Histones; D008239:Lysine; D011484:Protein-Arginine N-Methyltransferases; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C093491:ABCB11 protein, human; C119966:coactivator-associated arginine methyltransferase 1