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"Novel Mechanism of Negative Regulation of CYP24A1 involving crosstalk between Protein Arginine Methyltransferase 5 and the SWI/SNF Complex"

by
TANYA SETH
B.Tech. 2009, GGS Indraprastha University
New Delhi, India


Thesis Advisor: Sylvia Christakos, Ph.D.
Professor
Department of Biochemistry and Molecular Biology

Wednesday, July 16, 2014
9:30 A.M., MSB E-609b


Abstract

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. In this study, we demonstrate that BRG1, an ATPase that is a component of the SWI/SNF complex, plays a fundamental role in induction by 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) of the transcription of 25-hydroxyvitamin D 24 hydroxylase (CYP24A1), the enzyme involved in the catabolism of 1,25(OH)2D3. BRG1 was found to associate with C/EBP and cooperate with VDR and C/EBP in regulating CYP24A1 transcription. PRMT5, a type II PRMT, which interacts with BRG1, represses CYP24A1 transcription and mRNA expression. My findings indicate the requirement of the C/EBP site for the inhibitory effect of PRMT5 via its methylation of H3R8 and H4R3. In addition, my work indicates that the SWI/SNF complex and PRMT5 may be key factors involved in regulation of 1,25(OH)2D3 catabolism and therefore in the maintenance of calcium homeostasis by vitamin D. My results define epigenetic events linked to a novel mechanism of negative regulation of VDR mediated transcription.


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