title: Epigenetic Modulation of Human Podocyte Vitamin D Receptor in HIV Milieu.
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.
authors.affiliation: Center of Immunology and Inflammation, Feinstein Institute for Medical Research, Manhasset, NY 11030, USA; Hofstra North Shore LIJ Medical School, Hempstead, NY 11549-1000, USA.
authors.forename: Nirupama
authors.initials: N
authors.lastname: Chandel
authors.affiliation: Center of Immunology and Inflammation, Feinstein Institute for Medical Research, Manhasset, NY 11030, USA; Hofstra North Shore LIJ Medical School, Hempstead, NY 11549-1000, USA.
authors.forename: Kameshwar S
authors.initials: KS
authors.lastname: Ayasolla
authors.affiliation: Center of Immunology and Inflammation, Feinstein Institute for Medical Research, Manhasset, NY 11030, USA; Hofstra North Shore LIJ Medical School, Hempstead, NY 11549-1000, USA.
authors.forename: Xiqian
authors.initials: X
authors.lastname: Lan
authors.affiliation: Center of Immunology and Inflammation, Feinstein Institute for Medical Research, Manhasset, NY 11030, USA; Hofstra North Shore LIJ Medical School, Hempstead, NY 11549-1000, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Sultana-Syed
authors.affiliation: Center of Immunology and Inflammation, Feinstein Institute for Medical Research, Manhasset, NY 11030, USA; Hofstra North Shore LIJ Medical School, Hempstead, NY 11549-1000, USA.
authors.forename: Amrita
authors.initials: A
authors.lastname: Chawla
authors.affiliation: Center of Immunology and Inflammation, Feinstein Institute for Medical Research, Manhasset, NY 11030, USA; Hofstra North Shore LIJ Medical School, Hempstead, NY 11549-1000, USA.
authors.forename: Rivka
authors.initials: R
authors.lastname: Lederman
authors.affiliation: Center of Immunology and Inflammation, Feinstein Institute for Medical Research, Manhasset, NY 11030, USA; Hofstra North Shore LIJ Medical School, Hempstead, NY 11549-1000, USA.
authors.forename: Vasupradha
authors.initials: V
authors.lastname: Vethantham
authors.affiliation: Renal Academic Unit, University of Bristol, City of Bristol BS8 1TH, United Kingdom.
authors.forename: Moin A
authors.initials: MA
authors.lastname: Saleem
authors.affiliation: Department of Pathology, New York Medical College, Valhalla, NY 10595, USA.
authors.forename: Praveen N
authors.initials: PN
authors.lastname: Chander
authors.affiliation: Center of Immunology and Inflammation, Feinstein Institute for Medical Research, Manhasset, NY 11030, USA; Hofstra North Shore LIJ Medical School, Hempstead, NY 11549-1000, USA.
authors.forename: Ashwani
authors.initials: A
authors.lastname: Malhotra
authors.affiliation: Center of Immunology and Inflammation, Feinstein Institute for Medical Research, Manhasset, NY 11030, USA; Hofstra North Shore LIJ Medical School, Hempstead, NY 11549-1000, USA. Electronic address: psinghal@nshs.edu.
authors.forename: Pravin C
authors.initials: PC
authors.lastname: Singhal
mesh_terms: D000818:Animals; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000096:biosynthesis; D019175:DNA Methylation / Q000235:genetics*; D004789:Enzyme Activation; D057809:HEK293 Cells; D006678:HIV / Q000235:genetics; D015658:HIV Infections / Q000235:genetics; D056284:Histone Deacetylase 1 / Q000096:biosynthesis; D006657:Histones / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000166:cytology; D051379:Mice; D008822:Mice, Transgenic; D050199:Podocytes / Q000378:metabolism* / Q000821:virology; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering; D018167:Receptors, Calcitriol / Q000096:biosynthesis* / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000502:physiology; D012097:Repressor Proteins / Q000096:biosynthesis; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000097584:DNA Methyltransferase 3B
chemical_list: D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D056284:Histone Deacetylase 1; D006657:Histones; D034741:RNA, Small Interfering; D018167:Receptors, Calcitriol; D012097:Repressor Proteins; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D000097584:DNA Methyltransferase 3B; C099683:SIN3A transcription factor; C000619380:DNMT1 protein, human; C000619381:Dnmt1 protein, mouse; C484389:Hdac1 protein, mouse
keywords: HIV; SNAIL; epigenetics; kidney disease; podocyte