RFXB and its splice variant RFXBSV mediate the antagonism between IFNgamma and TGFbeta on COL1A2 transcription in vascular smooth muscle cells.
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.
Fang
Mingming
M
Department of Pathophysiology, Key Laboratory of Human Functional Genomics, Atherosclerosis Research Center, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
Kong
Xiaocen
X
Li
Ping
P
Fang
Fei
F
Wu
Xiaoyan
X
Bai
Hui
H
Qi
Xiaohong
X
Chen
Qi
Q
Xu
Yong
Y
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*
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