Epigenetic initiation of the T(H)17 differentiation program is promoted by Cxxc finger protein 1
Epigenetic initiation of the T(H)17 differentiation program is promoted by Cxxc finger protein 1
复制标题
Cxxc 指蛋白 1 促进 T(H)17 分化程序的表观遗传启动
DOI：
10.1126/sciadv.aax1608
复制
发表时间：
2019
期刊：
影响因子：
13.6
通讯作者：
Lie Wang
中科院分区：
文献类型：
--
作者：
Feng Lin;Xiaoyu Meng;Yixin Guo;Wenqiang Cao;Wanlu Liu;Qiming Xia;Zhaoyuan Hui;Jian Chen;Shenghui Hong;Xuliang Zhang;Chuan Wu;Di Wang;Jianli Wang;Linrong Lu;Wenbin Qian;Lai Wei;Lie Wang
已知IL-6/STAT 3信号传导启动TH 17分化程序，但上游调控机制仍然很少探索。在这里，我们表明，Cxxc指蛋白1（Cxxc 1）促进TH 17细胞作为表观遗传调节剂的产生，并阻止其分化为Treg细胞。具有T细胞特异性Cxxc 1缺失的小鼠可以免受实验性自身免疫性脑脊髓炎的影响，并且更容易受到啮齿类柠檬酸杆菌感染。Cxxc 1缺陷可降低IL-6 R α的表达，阻碍IL-6/STAT 3信号通路，而IL-6 R α过表达可部分逆转Cxxc 1缺陷的TH 17细胞的上述缺陷。全基因组占有率分析表明，Cxxc 1通过保持其启动子的适当H3 K4 me 3修饰而结合到Il 6 r α基因位点。因此，这些数据强调了Cxxc 1作为关键调节因子通过控制IL-6 R α的表达来控制TH 17和Treg细胞之间的平衡，IL-6 R α影响IL-6/STAT 3信号传导并对TH 17相关的自身免疫性疾病产生影响。
IL-6/STAT3 signaling is known to initiate the TH17 differentiation program, but the upstream regulatory mechanisms remain minimally explored. Here, we show that Cxxc finger protein 1 (Cxxc1) promoted the generation of TH17 cells as an epigenetic regulator and prevented their differentiation into Tregcells. Mice with a T cell–specific deletion of Cxxc1 were protected from experimental autoimmune encephalomyelitis and were more susceptible toCitrobacter rodentiuminfection. Cxxc1 deficiency decreased IL-6Rα expression and impeded IL-6/STAT3 signaling, whereas the overexpression of IL-6Rα could partially reverse the defects inCxxc1-deficient TH17 cells in vitro and in vivo. Genome-wide occupancy analysis revealed that Cxxc1 bound toIl6rα gene loci by maintaining the appropriate H3K4me3 modification of its promoter. Therefore, these data highlight that Cxxc1 as a key regulator governs the balance between TH17 and Tregcells by controlling the expression of IL-6Rα, which affects IL-6/STAT3 signaling and has an impact on TH17-related autoimmune diseases.