title: RFXB and its splice variant RFXBSV mediate the antagonism between IFNgamma and TGFbeta on COL1A2 transcription in vascular smooth muscle cells.
abstract: Cytokines secreted by infiltrating immune cells during atherogenesis modulate vascular remodeling. One exemplary event is the antagonism between transformed growth factor (TGF-beta) and interferon gamma (IFN-gamma) on the transcriptional control of type I collagen gene (COL1A2). Previously we have reported that IFN-gamma up-regulates regulatory factor for X-box B (RFXB) to repress collagen transcription while down-regulates the expression of RFXBSV, a splice variant of RFXB that blocks collagen repression in fibroblasts. Here we demonstrate that TGF-beta abrogated COL1A2 repression by IFN-gamma through altering the relative expression of RFXB and RFXBSV. Unlike RFXB, RFXBSV did not bind to the collagen promoter and competed with RFXB for the co-repressor histone deacetylase 2 (HDAC2), limiting HDAC2 recruitment to the collagen transcription start site as evidenced by chromatin immunoprecipitation assays. Over-expression of RFXB by lentiviral infection in HASMCs enhanced HDAC2 enlistment, promoted histone deacetylation surrounding the collagen site by IFN-gamma, and blocked the TGF-beta antagonism, a pattern reversed by RFXBSV infection. On the contrary, silencing of RFXB, but not both RFXB and RFXBSV, expression promoted the TGF-beta antagonism. Thus, we have identified a novel mechanism whereby TGF-beta antagonizes the IFN-gamma repression of collagen transcription in HASMCs and as such provided new insights into antiatherogenic strategies.
authors.affiliation: Department of Pathophysiology, Key Laboratory of Human Functional Genomics, Atherosclerosis Research Center, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Mingming
authors.initials: M
authors.lastname: Fang
authors.forename: Xiaocen
authors.initials: X
authors.lastname: Kong
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.forename: Fei
authors.initials: F
authors.lastname: Fang
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wu
authors.forename: Hui
authors.initials: H
authors.lastname: Bai
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Qi
authors.forename: Qi
authors.initials: Q
authors.lastname: Chen
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
mesh_terms: D001667:Binding, Competitive; D002478:Cells, Cultured; D003094:Collagen / Q000235:genetics*; D024042:Collagen Type I; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000037:antagonists & inhibitors*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D034622:RNA Interference; D012326:RNA Splicing; D012097:Repressor Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D024363:Transcription Initiation Site; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
chemical_list: D024042:Collagen Type I; D004268:DNA-Binding Proteins; D006657:Histones; C117892:RFXANK protein, human; D012097:Repressor Proteins; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D007371:Interferon-gamma; D003094:Collagen; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases