Epigenetic regulator CXXC5 recruits DNA demethylase Tet2 to regulate TLR7/9-elicited IFN response in pDCs

被引：90

作者：

Ma, Shixin ^{[1
,2
,3
,4
]}

Wan, Xiaoling ^{[1
]}

Deng, Zihou ^{[1
,2
,3
]}

Shi, Lei ^{[1
,2
,3
]}

Hao, Congfang ^{[1
,2
,3
]}

Zhou, Zhenyuan

Zhou, Chun ^{[1
,2
,3
]}

Fang, Yiyuan ^{[1
]}

Liu, Jinghua ^{[1
,2
,3
]}

Yang, Jing ^{[1
,3
]}

Chen, Xia ^{[1
,2
,3
]}

Li, Tiantian ^{[1
,2
,3
]}

Zang, Aiping ^{[1
,2
]}

Yin, Shigang ^{[1
]}

Li, Bin ^{[1
,2
,3
]}

Plumas, Joel ^{[7
]}

Chaperot, Laurence ^{[7
]}

Zhang, Xiaoming ^{[1
]}

Xu, Guoliang ^{[5
]}

Jiang, Lubin ^{[1
]}

Shen, Nan ^{[6
]}

Xiong, Sidong ^{[4
]}

Gao, Xiaoming

Zhang, Yan ^{[1
,3
]}

Xiao, Hui ^{[1
,2
]}

机构：

[1] Chinese Acad Sci, Inst Pasteur Shanghai, CAS Key Lab Mol Virol & Immunol, Shanghai 200031, Peoples R China

[2] Chinese Acad Sci, CAS Ctr Excellence Mol Cell Sci, Shanghai 200031, Peoples R China

[3] Univ Chinese Acad Sci, Chinese Acad Sci, Shanghai 200031, Peoples R China

[4] Soochow Univ, Inst Biol & Med Sci, Suzhou 215006, Jiangsu, Peoples R China

[5] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, CAS Excellence Ctr Mol Cell Sci,State Key Lab Mol, Shanghai 200031, Peoples R China

[6] Shanghai Jiao Tong Univ, Renji Hosp, Sch Med, Shanghai Inst Rheumatol, Shanghai 200240, Peoples R China

[7] Univ Grenoble Alpes Etab Francais Sang Rhone Alpe, IAB, Inst Natl Sante & Rech Med U1209, Ctr Natl Rech Sci UMR5309,Team Immunobiol & Immun, F-38700 Grenoble, France

来源：

JOURNAL OF EXPERIMENTAL MEDICINE | 2017年 / 214卷 / 05期

基金：

中国国家自然科学基金;

关键词：

PLASMACYTOID DENDRITIC CELLS; VIRAL-INFECTION; I INTERFERON; 5-METHYLCYTOSINE OXIDATION; ANTIMICROBIAL PEPTIDE; IMMUNE-SYSTEM; CPG ISLANDS; TRANSCRIPTION; EXPRESSION; ACTIVATION;

D O I：

10.1084/jem.20161149

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

TLR7/9 signals are capable of mounting massive interferon (IFN) response in plasmacytoid dendritic cells (pDCs) immediately after viral infection, yet the involvement of epigenetic regulation in this process has not been documented. Here, we report that zinc finger CXXC family epigenetic regulator CXXC5 is highly expressed in pDCs, where it plays a crucial role in TLR7/9- and virus-induced IFN response. Notably, genetic ablation of CXXC5 resulted in aberrant methylation of the CpG-containing island (CGI) within the Irf7 gene and impaired IRF7 expression in steady-state pDCs. Mechanistically, CXXC5 is responsible for the recruitment of DNA demethylase Tet2 to maintain the hypomethylation of a subset of CGIs, a process coincident with active histone modifications and constitutive transcription of these CGI-containing genes. Consequently, CXXC5-deficient mice had compromised early IFN response and became highly vulnerable to infection by herpes simplex virus and vesicular stomatitis virus. Together, our results identify CXXC5 as a novel epigenetic regulator for pDC-mediated antiviral response.

引用

页码：1471 / 1491

页数：21

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