Epigenetic regulator CXXC5 recruits DNA demethylase Tet2 to regulate TLR7/9-elicited IFN response in pDCs.
Epigenetic regulator CXXC5 recruits DNA demethylase Tet2 to regulate TLR7/9-elicited IFN response in pDCs.
复制标题
表观遗传调节因子 CXXC5 招募 DNA 去甲基酶 Tet2 来调节 pDC 中 TLR7/9 引发的 IFN 反应
DOI：
10.1084/jem.20161149
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发表时间：
2017-05-01
期刊：
影响因子：
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通讯作者：
Xiao H
中科院分区：
文献类型：
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作者：
Ma S;Wan X;Deng Z;Shi L;Hao C;Zhou Z;Zhou C;Fang Y;Liu J;Yang J;Chen X;Li T;Zang A;Yin S;Li B;Plumas J;Chaperot L;Zhang X;Xu G;Jiang L;Shen N;Xiong S;Gao X;Zhang Y;Xiao H
Ma及其同事将CXXC 5鉴定为维持CGIs亚群低甲基化所需的表观遗传调节因子，从而促进pDC中转录因子如IRF 7的表达，以使IFN对病毒感染产生强有力的应答。TLR 7/9信号能够在病毒感染后立即在浆细胞样树突状细胞（pDC）中产生大量干扰素（IFN）应答，但尚未记录表观遗传调控在此过程中的参与。在这里，我们报告说，锌指CXXC家族表观遗传调节CXXC 5是高度表达的pDC，它在TLR 7/9和病毒诱导的IFN反应中起着至关重要的作用。值得注意的是，CXXC 5的基因切除导致Irf 7基因内含CpG岛（CGI）的异常甲基化，并损害稳态pDC中的IRF 7表达。从机制上讲，CXXC 5负责招募DNA去甲基化酶Tet 2，以维持CGI亚组的低甲基化，这一过程与这些含CGI基因的活性组蛋白修饰和组成型转录一致。因此，CXXC 5缺陷小鼠早期干扰素反应受损，并变得非常容易受到单纯疱疹病毒和水泡性口炎病毒的感染。总之，我们的研究结果确定CXXC 5作为一种新的表观遗传调节pDC介导的抗病毒反应。
Ma and colleagues identify CXXC5 as an epigenetic regulator required for maintaining the hypomethylation of a subset of CGIs, thereby promoting the expression of transcriptional factors such as IRF7 in pDCs to enable robust IFN response to viral infection. 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.