NYMC Faculty Publications

Epigenetic Modulation of Human Podocyte Vitamin D Receptor in HIV Milieu

Author Type(s)

Faculty

DOI

10.1016/j.jmb.2015.07.011

Journal Title

Journal of Molecular Biology

First Page

3201

Last Page

3215

Document Type

Article

Publication Date

10-9-2015

Department

Medicine

Keywords

Animals, Cell Line, Chromatin Immunoprecipitation, DNA (Cytosine-5-)-Methyltransferase 1, DNA (Cytosine-5-)-Methyltransferases, DNA Methylation, Enzyme Activation, HEK293 Cells, HIV, HIV Infections, Histone Deacetylase 1, Histones, Humans, Kidney, Mice, Mice, Transgenic, Podocytes, Promoter Regions, Genetic, RNA Interference, RNA, Small Interfering, Receptors, Calcitriol, Renin-Angiotensin System, Repressor Proteins, Sin3 Histone Deacetylase and Corepressor Complex, Snail Family Transcription Factors, Transcription Factors, DNA Methyltransferase 3B

Disciplines

Medicine and Health Sciences

Abstract

HIV (human immunodeficiency virus) has been reported to induce podocyte injury through down regulation of vitamin D receptor (VDR) and activation of renin angiotensin system; however, the involved mechanism is not clear. Since HIV has been reported to modulate gene expression via epigenetic phenomena, we asked whether epigenetic factors contribute to down regulation of VDR. Kidney cells in HIV transgenic mice and HIV-infected podocytes (HIV/HPs) displayed enhanced expression of SNAIL, a repressor of VDR. To elucidate the mechanism, we studied the effect of HIV on expression of molecules involved in SNAIL repressor complex formation and demonstrated that HIV enhances expression of the histone deacetylase HDAC1 and DNA methyl transferases DNMT3b and DNMT1. 293T cells, when stably transfected with SNAIL (SNAIL/293T), displayed suppressed transcription and translation of VDR. In SNAIL/293T cells, co-immunoprecipitation studies revealed the association of HDAC1, DNMT3b, DNMT1, and mSin3A with SNAIL. Chromatin immunoprecipitation experiments confirmed the presence of the SNAIL repressor complex at the VDR promoter. Consistent with the enhanced DNA methyl transferase expression in HIV/HPs, there was an increased CpG methylation at the VDR promoter. Chromatin immunoprecipitation assay confirmed occurrence of H3K4 trimethylation on SNAIL promoter. Neither a VDR agonist (VDA) nor an HDAC inhibitor (HDACI) nor a demethylating agent (DAC) individually could optimally up regulate VDR in HIV milieu. However, VDA and HDACI when combined were successful in de-repressing VDR expression. Our findings demonstrate that SNAIL recruits multiple chromatin enzymes to form a repressor complex in HIV milieu that down regulates VDR expression.

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