Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6.
Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6.
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Tet2 需要通过招募 Hdac2 来特异性抑制 IL-6 来解决炎症
DOI：
10.1038/nature15252
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发表时间：
2015-09-17
期刊：
影响因子：
64.8
通讯作者：
Cao X
中科院分区：
文献类型：
--
作者：
Zhang Q;Zhao K;Shen Q;Han Y;Gu Y;Li X;Zhao D;Liu Y;Wang C;Zhang X;Su X;Liu J;Ge W;Levine RL;Li N;Cao X
表观遗传修饰物通过建立和维持谱系特定的染色质和甲基化状态，在定义独特的细胞身份方面具有基础作用。一些DNA修饰，如5-羟甲基胞嘧啶(5hmC)，是由十个11位易位(Tet)甲基胞嘧啶双加氧酶家族成员催化的，Tet蛋白在调节染色质结构和基因转录方面的作用不依赖于DNA甲基化，已逐渐被发现。然而，Tet蛋白对免疫和炎症的调节作用与它们在调节DNA甲基化中的作用无关，在很大程度上仍不清楚。在这里，我们发现TET2选择性地介导了炎症消退过程中白介素6(IL-6)转录的主动抑制，包括树突状细胞和巨噬细胞。在内毒素刺激的反应后期，TET2的缺失导致包括IL-6在内的几种炎症介质的上调。与野生型小鼠相比，TET2缺陷小鼠对内毒素休克和葡聚糖硫酸钠诱导的结肠炎更敏感，表现出更严重的炎症表型和IL-6的产生。IL-6特异性转录因子IκBζ介导了TET2对IL 6启动子的特异性靶向，进一步表明IκBζ在炎症的初始阶段和消退阶段具有相反的调节作用。对于抑制机制，TET2不依赖于DNA甲基化和羟甲基化，而是通过组蛋白去乙酰化来招募HDAC2和抑制IL6的转录。我们通过组蛋白脱乙酰化为TET2的基因特异性转录抑制活性以及在染色质水平上阻止持续转录激活以消解炎症提供了机制证据。
Epigenetic modifiers have fundamental roles in defining unique cellular identity through the establishment and maintenance of lineage-specific chromatin and methylation status. Several DNA modifications such as 5-hydroxymethylcytosine (5hmC) are catalysed by the ten eleven translocation (Tet) methylcytosine dioxygenase family members, and the roles of Tet proteins in regulating chromatin architecture and gene transcription independently of DNA methylation have been gradually uncovered. However, the regulation of immunity and inflammation by Tet proteins independent of their role in modulating DNA methylation remains largely unknown. Here we show that Tet2 selectively mediates active repression of interleukin-6 (IL-6) transcription during inflammation resolution in innate myeloid cells, including dendritic cells and macrophages. Loss of Tet2 resulted in the upregulation of several inflammatory mediators, including IL-6, at late phase during the response to lipopolysaccharide challenge. Tet2-deficient mice were more susceptible to endotoxin shock and dextran-sulfate-sodium-induced colitis, displaying a more severe inflammatory phenotype and increased IL-6 production compared to wild-type mice. IκBζ, an IL-6-specific transcription factor, mediated specific targeting of Tet2 to theIl6promoter, further indicating opposite regulatory roles of IκBζ at initial and resolution phases of inflammation. For the repression mechanism, independent of DNA methylation and hydroxymethylation, Tet2 recruited Hdac2 and repressed transcription ofIl6via histone deacetylation. We provide mechanistic evidence for the gene-specific transcription repression activity of Tet2 via histone deacetylation and for the prevention of constant transcription activation at the chromatin level for resolving inflammation.