Interferon-γ-induced chromatin remodeling at the CIITA locus is BRG1 dependent
Interferon-γ-induced chromatin remodeling at the CIITA locus is BRG1 dependent
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DOI：
10.1093/emboj/21.8.1978
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发表时间：
2002-04-15
期刊：
影响因子：
11.4
通讯作者：
Bremner, R
中科院分区：
文献类型：
--
作者：
Pattenden, SG;Klose, R;Bremner, R
SWI/SNF调节生长控制、分化和肿瘤抑制，然而在哺乳动物细胞中已经确定了这种染色质重塑复合物的一些直接靶点。我们报告说，SWI/SNF是所需的干扰素（IFN）-γ诱导CIITA，主要组织相容性复合体II类表达的主调节。尽管存在功能性STAT 1、IRF-1和USF-1（参与CIITA表达的激活剂），但IFN-γ在缺乏BRG 1和hBRM（SWI/SNF的ATP酶亚基）的细胞中不诱导CIITA。用BRG 1而不是该蛋白的ATP酶缺陷型（K798 R）重建，挽救了CIITA诱导，并提高了IFN-γ应答性GBP-1基因的诱导率。值得注意的是，BRG 1在瞬时转染试验中抑制CIITA启动子，强调了适当的染色体环境的重要性。染色质免疫沉淀显示，BRG 1直接与内源性CIITA启动子相互作用的IFN-γ诱导的方式，而在体内DNA酶I足迹和限制性酶的可及性分析表明，在这个位点的染色质重塑需要功能性BRG 1。这些数据提供了细胞因子途径和SWI/SNF之间的第一个联系，并表明这种染色质重塑复合物在免疫监视中的新作用。
SWI/SNF regulates growth control, differentiation and tumor suppression, yet few direct targets of this chromatin-remodeling complex have been identified in mammalian cells. We report that SWI/SNF is required for interferon (IFN)-gamma induction of CIITA, the master regulator of major histocompatibility complex class II expression. Despite the presence of functional STAT1, IRF-1 and USF-1, activators implicated in CIITA expression, IFN-gamma did not induce CIITA in cells lacking BRG1 and hBRM, the ATPase subunits of SWI/SNF. Reconstitution with BRG1, but not an ATPase-deficient version of this protein (K798R), rescued CIITA induction, and enhanced the rate of induction of the IFN-gamma-responsive GBP-1 gene. Notably, BRG1 inhibited the CIITA promoter in transient transfection assays, underscoring the importance of an appropriate chromosomal environment. Chromatin immunoprecipitation revealed that BRG1 interacts directly with the endogenous CIITA promoter in an IFN-gamma-inducible fashion, while in vivo DNase I footprinting and restriction enzyme accessibility assays showed that chromatin remodeling at this locus requires functional BRG1. These data provide the first link between a cytokine pathway and SWI/SNF, and suggest a novel role for this chromatin-remodeling complex in immune surveillance.