Recruitment of multiple interferon regulatory factors and histone acetyltransferase to the transcriptionally active interferon a promoters.
Type I interferon (IFN) plays a critical role in the innate immunity against viral infection. Expression of IFNA genes in infected cells is cell type-dependent and is regulated at the transcriptional level. The present study is focused on the molecular mechanism underlying the differential expression of human IFNA1 and A2 genes. Two nucleotides, at positions -98 and -81 of IFNA1 and A2 promoter, were pivotal to the differential expression. The DNA pull-down and chromatin precipitation assays have shown that nuclear interferon regulatory factor (IRF)-3 and IRF-7 as well as IRF-1 bind to IFNA1 virus-responsive element (VRE). Interestingly, overexpression of IRF-7 increased the otherwise weak binding of both IRF-3 and IRF-7 to IFNA2 VRE. These data together with the results of two-step chromatin immunoprecipitation strongly suggest that the IRF-3 and IRF-7 bind to IFNA1 promoter as a dimer. Furthermore, binding of IRF-3 and IRF-7 to IFNA VRE is associated with the presence of acetylated histone H3, suggesting that histone acetyltransferase(s) is tethered together with virus-activated IRF-3 and IRF-7 to the IFNA1 promoter. In addition, the constitutively active IRF-3 (5D) and IRF-7 (2D) mutants activate the endogenous IFNA genes in uninfected cells; however, the expression profile of IFNA is not identical to that induced by viral infection.
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Oncology Center and Department of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
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D000123:Acetyltransferases / Q000378:metabolism*; D001483:Base Sequence; D001665:Binding Sites; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000502:physiology*; D019281:Dimerization; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation; D051548:Histone Acetyltransferases; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D016898:Interferon-alpha / Q000235:genetics*; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D020218:Response Elements; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors / Q000737:chemistry / Q000502:physiology*; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D016898:Interferon-alpha; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D000123:Acetyltransferases; D051548:Histone Acetyltransferases