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.

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Rizzo G, Renga B, Antonelli E, Passeri D, Pellicciari R, Fiorucci S

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.

Mol Pharmacol. 2005 Aug;68(2):551-8. Epub 2005 May 23.

PubMed ID

15911693 [ View in PubMed

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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 7alpha-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.

DrugBank Data that Cites this Article

Pharmaco-transcriptomics

Drug	Drug Groups	Gene	Gene ID	Change	Interaction	Chromosome
Obeticholic acid	Approved	ABCB11	8647	upregulated	6-ethylchenodeoxycholic acid results in increased expression of ABCB11 mRNA	2q31.1
Obeticholic acid	Approved	CYP7A1	1581	downregulated	6-ethylchenodeoxycholic acid results in decreased expression of CYP7A1 mRNA	8q12.1
Obeticholic acid	Approved	NR0B2	8431	upregulated	6-ethylchenodeoxycholic acid results in increased expression of NR0B2 mRNA	1p36.11
Obeticholic acid	Approved	SLC10A1	6554	downregulated	6-ethylchenodeoxycholic acid results in decreased expression of SLC10A1 mRNA	14q24.1