The Methyl Transferase PRMT1 Functions as Co-Activator of Farnesoid X Receptor (FXR)/9-cis Retinoid X Receptor and Regulates Transcription of FXR Responsive Genes
- Giovanni Rizzo,
- Barbara Renga,
- Elisabetta Antonelli,
- Daniela Passeri,
- Roberto Pellicciari and
- Stefano Fiorucci
- Dipartimento di Medicina Clinica e Sperimentale, Clinica di Gastroenterologia ed Epatologia, Università degli Studi di Perugia, Policlinico Monteluce Via E. Dal Pozzo, Perugia, Italy (G.R., B.R., E.A., S.F.) Dipartimento di Medicina Clinica e Sperimentale, Lab Biologia Molecolare, Università degli Studi di Perugia, Policlinico Monteluce Via Brunamonti, Perugia, Italy (D.P.), and Dipartimento di Chimica e Tecnologia del Farmaco, Universita degli Studi di Perugia, Perugia, Italy (R.P.)
- Address correspondence to:
Dr. Stefano Fiorucci, Clinica di Gastroenterologia ed Endoscopia Digestiva, Policlinico Monteluce, 06100 Perugia, Italy. E-mail: fiorucci{at}unipg.it
Abstract
The farnesoid X receptor (FXR) is a nuclear receptor that functions as an endogenous sensor for bile acids (BAs). FXR is bound to and activated by bile acid, and chenodeoxycholic acid (CDCA) is the natural most active ligand. Upon activation, FXR heterodimerizes with the 9-cis retinoic X receptor (RXR) and regulates genes involved in cholesterol and BA homeostasis. 6-Ethyl CDCA (6-ECDCA) is a synthetic BA that binds FXR and induces gene transcription by recruiting coactivators, such as steroid receptor coactivator-1, with histone acetyltransferase activity. In addition to acetylation, histone methylation is critically involved in regulating eukaryotic gene expression. In the present study, we demonstrated that 6-ECDCA activates FXR to interacts with Protein Arginine Methyl-Transferase type I (PRMT1), which induces up-regulation of bile salt export pump (BSEP) and the small heterodimer partner (SHP) mRNA expression and causes a down-regulation of P450 cholesterol 7α-hydroxylase and Na+ taurocholate cotransport peptide genes. Chromatin immunoprecipitation assay suggests that 6-ECDCA induces both the recruitment of PRMT1 and the H4 methylation to the promoter of BSEP and SHP genes. We also provide evidence that a methyltransferase inhibitor blocks the activation of FXR-responsive genes. Our results indicate that histone methylation, similar to acetylation, regulates transcriptional activation of genes involved in cholesterol and BAs homeostasis.
Footnotes
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Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
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doi:10.1124/mol.105.012104.
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ABBREVIATIONS: BA, bile acid; FXR, farnesoid X receptor; CDCA, chenodeoxycholic acid; 6-ECDCA, 6α-ethyl-chenodeoxycholic acid; SHP, small heterodimer partner; BSEP, bile-salt export pump; 9-cis RA, 9-cis-retinoic acid; RXR, 9-cis-retinoic acid receptor; SRC-1, steroid receptor coactivator-1; CARM1, coactivator-associated arginine methyltransferase 1; HMT, histone methyltransferase; SAM, S-adenosylmethionine; PRMT, protein arginine methyltransferase; ChIP, chromatin immunoprecipitation assay; RT-PCR, reverse transcription-polymerase chain reaction; GST, glutathione S-transferase; HEK, human embryonic kidney; CMV, cytomegalovirus; βgal, β-galactosidase; GW-4064; DMSO, dimethyl sulfoxide; PBS, phosphate-buffered saline; PAGE, polyacrylamide gel electrophoresis; qRT, quantitative real-time; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; cyt c, cytochrome c; MTA, 5′-deoxy-5′-methylthioadenosine; NTCP, Na+ taurocholate cotransport peptide; FXRE, farnesoid X receptor response element.
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The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.
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- Received February 17, 2005.
- Accepted May 23, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
