Abstract
Background: CYP24A1 is the principal enzyme involved in the catabolism of 1,25(OH)(2)D-3. Results: The SWI/SNF complex and PRMT5 converge at the transcriptional level to control 1,25(OH)(2)D-3-induced Cyp24a1 gene expression. Conclusion: PRMT5-mediated repression represents a novel mechanism of negative regulation of Cyp24a1. Significance: Our study reveals key factors involved in the regulation of 1,25(OH)(2)D-3 catabolism and therefore in the control of calcium homeostasis.
The SWI/SNF chromatin remodeling complex facilitates gene transcription by remodeling chromatin using the energy of ATP hydrolysis. Recent studies have indicated an interplay between the SWI/SNF complex and protein-arginine methyltransferases (PRMTs). Little is known, however, about the role of SWI/SNF and PRMTs in vitamin D receptor (VDR)-mediated transcription. Using SWI/SNF-defective cells, we demonstrated that Brahma-related gene 1 (BRG1), an ATPase that is a component of the SWI/SNF complex, plays a fundamental role in induction by 1,25-dihydroxyvitamin D-3 (1,25(OH)(2)D-3) of the transcription of Cyp24a1 encoding the enzyme 25-hydroxyvitamin D-3 24-hydroxylase involved in the catabolism of 1,25(OH)(2)D-3. BRG1 was found to associate with CCAAT-enhancer-binding protein (C/EBP) and cooperate with VDR and C/EBP in regulating Cyp24a1 transcription. PRMT5, a type II PRMT that interacts with BRG1, repressed Cyp24a1 transcription and mRNA expression. Our findings indicate the requirement of the C/EBP site for the inhibitory effect of PRMT5 via its methylation of H3R8 and H4R3. These findings indicate that the SWI/SNF complex and PRMT5 may be key factors involved in regulation of 1,25(OH)(2)D-3 catabolism and therefore in the maintenance of calcium homeostasis by vitamin D. These studies also define epigenetic events linked to a novel mechanism of negative regulation of VDR-mediated transcription.