Epigenetic Regulation of Transcriptional Activity of Pregnane X Receptor by Protein Arginine Methyltransferase 1*
- ‡Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas 77843, the §Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, and the ¶Department of Carcinogenesis, University of Texas M. D. Anderson Cancer Center, Smithville, Texas 78957
- 1 To whom correspondence should be addressed: Dept. of Veterinary Physiology and Pharmacology, Mail Stop 4466, Texas A&M University, College Station, TX 77843. Tel.: 979-458-3599; Fax: 979-862-4929; E-mail: ytian{at}cvm.tamu.edu.
Abstract
Pregnane X receptor (PXR) is a ligand-dependent transcription factor, regulating gene expression of enzymes and transporters involved in xenobiotic/drug metabolism. Here, we report that protein arginine methyltransferase 1 (PRMT1) is required for the transcriptional activity of PXR. PRMT1 regulates expression of numerous genes, including nuclear receptor-regulated transcription, through methylating histone and non-histone proteins. Co-immunoprecipitation and histone methyltransferase assays revealed that PRMT1 is a major histone methyltransferase associated with PXR. The PXR ligand-binding domain is responsible for PXR-PRMT1 interaction as determined by mammalian two-hybrid and glutathione S-transferase (GST) pull-down assays. The chromatin immunoprecipitation (ChIP) assay showed that PRMT1 was recruited to the regulatory region of the PXR target gene cytochrome P450 3A4 (CYP3A4), with a concomitant methylation of arginine 3 of histone H4, in response to the PXR agonist rifampicin. In mammalian cells, small interfering RNA (siRNA) knockdown and gene deletion of PRMT1 greatly diminished the transcriptional activity of PXR, suggesting an indispensable role of PRMT1 in PXR-regulated gene expression. Interestingly, PXR appears to have a reciprocal effect on the PRMT1 functions by regulating its cellular compartmentalization as well as its substrate specificity. Taken together, these results demonstrated mutual interactions and functional interplays between PXR and PRMT1, and this interaction may be important for the epigenetics of PXR-regulated gene expression.
Footnotes
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↵2 The abbreviations used are: PXR, pregnane X receptor; PRMT, protein arginine methyltransferase; CARM1, coactivator-associated arginine methyltransferase 1; CYP3A4, cytochrome P450 3A4; HMT, histone methyltransferase; Co-IP, co-immunoprecipitation; GST, glutathione S-transferase; XREM, xenobiotic response enhancer module; ChIP, chromatin immunoprecipitation; RIF, rifampicin; PCN, pregnenolone-16-α-carbonitrile; DMSO, dimethyl sulfoxide; PBS, phosphate-buffered saline.
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↵* This work was supported, in whole or in part, by NIEHS, National Institutes of Health Grants ES 09859 and ES 09106. This work was also supported by American Heart Association Grant 0355131Y. 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.
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- Received August 11, 2008.
- Revision received January 13, 2009.
- The American Society for Biochemistry and Molecular Biology, Inc.
