Coordinated regulation of IFITM1, 2 and 3 genes by an IFN-responsive enhancer through long-range chromatin interactions.
Coordinated regulation of IFITM1, 2 and 3 genes by an IFN-responsive enhancer through long-range chromatin interactions.
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IFN 响应增强子通过长程染色质相互作用协调调节 IFITM1、2 和 3 基因
DOI：
10.1016/j.bbagrm.2017.05.003
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发表时间：
2017-08
期刊：
影响因子：
--
通讯作者：
Zhao ZH
中科院分区：
文献类型：
--
作者：
Li P;Shi ML;Shen WL;Zhang Z;Xie DJ;Zhang XY;He C;Zhang Y;Zhao ZH
干扰素诱导的跨膜蛋白（IFITM）1、2和3基因编码干扰素（IFN）诱导的跨膜蛋白家族，其阻断广谱病原体的进入。然而，这些基因的转录调控，特别是是否存在任何增强子及其在IFN诱导过程中的作用仍然是难以捉摸的。在这里，通过公开数据挖掘、附加型荧光素酶报告基因测定和体内CRISPR-Cas9基因组编辑，我们鉴定了位于IFITM 3基因启动子上游35 kb的IFN应答增强子，其上调IFN诱导的IFITM 1、2和3基因的表达。染色质免疫沉淀（ChIP）、电泳迁移率变动分析（EMSA）和荧光素酶报告基因分析表明，信号转导和转录激活因子（STAT）1与IFN处理的增强子结合，是增强子活性所必需的。此外，我们使用染色体构象捕获技术，我们发现IFITM 1，2和3基因在HEK 293和A549细胞中物理聚集在一起，并通过长程相互作用组成性地环到远端增强子，为增强子协调调控IFITM 1，2和3提供了结构基础。最后，我们发现，在体内截断增强子削弱干扰素诱导的抗流感病毒A（IAV）感染。这些发现扩展了我们对IFITM 1，2和3表达的转录调控机制及其介导IFN信号传导的能力的理解。这是第一次报道增强子协同上调IFN诱导的IFITM基因表达。增强子通过IFN诱导的STAT 1结合和组成性长程相互作用发挥作用。增强子有助于IFN诱导的抗IAV感染。
Interferon-induced transmembrane protein (IFITM) 1, 2 and 3 genes encode a family of interferon (IFN)-induced transmembrane proteins that block entry of a broad spectrum of pathogens. However, the transcriptional regulation of these genes, especially whether there exist any enhancers and their roles during the IFN induction process remain elusive. Here, through public data mining, episomal luciferase reporter assay and in vivo CRISPR-Cas9 genome editing, we identified an IFN-responsive enhancer located 35 kb upstream of IFITM3 gene promoter upregulating the IFN-induced expression of IFITM1, 2 and 3 genes. Chromatin immunoprecipitation (ChIP), electrophoretic mobility shift assay (EMSA) and luciferase reporter assay demonstrated that signal transducers and activators of transcription (STAT) 1 bound to the enhancer with the treatment of IFN and was indispensable for the enhancer activity. Furthermore, using chromosome conformation capture technique, we revealed that the IFITM1, 2 and 3 genes physically clustered together and constitutively looped to the distal enhancer through long-range interactions in both HEK293 and A549 cells, providing structural basis for coordinated regulation of IFITM1, 2 and 3 by the enhancer. Finally, we showed that in vivo truncation of the enhancer impaired IFN-induced resistance to influenza A virus (IAV) infection. These findings expand our understanding of the mechanisms underlying the transcriptional regulation of IFITM1, 2 and 3 expression and its ability to mediate IFN signaling. This is the first report of an enhancer coordinately upregulating IFN-induced expression of IFITM genes The enhancer functions through IFN-induced STAT1 binding and constitutive long-range interactions The enhancer contributes to the IFN-induced resistance to IAV infection
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影响因子：
64.8
作者：
Jin, Fulai;Li, Yan;Dixon, Jesse R.;Selvaraj, Siddarth;Ye, Zhen;Lee, Ah Young;Yen, Chia-An;Schmitt, Anthony D.;Espinoza, Celso A.;Ren, Bing
通讯作者：
Ren, Bing
影响因子：
64.5
作者：
Phillips-Cremins JE;Sauria ME;Sanyal A;Gerasimova TI;Lajoie BR;Bell JS;Ong CT;Hookway TA;Guo C;Sun Y;Bland MJ;Wagstaff W;Dalton S;McDevitt TC;Sen R;Dekker J;Taylor J;Corces VG
通讯作者：
Corces VG
影响因子：
14.9
作者：
Banerjee AR;Kim YJ;Kim TH
通讯作者：
Kim TH
影响因子：
21.3
作者：
Huang, M;Qian, F;Wen, ZL
通讯作者：
Wen, ZL
影响因子：
32.4
作者：
Lee, GR;Fields, PE;Flavell, RA
通讯作者：
Flavell, RA