The histone H3 lysine-27 demethylase Jmjd3 plays a critical role in specific regulation of Th17 cell differentiation
The histone H3 lysine-27 demethylase Jmjd3 plays a critical role in specific regulation of Th17 cell differentiation
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组蛋白 H3 赖氨酸 27 去甲基化酶 Jmjd3 在 Th17 细胞分化的特异性调节中发挥关键作用
DOI：
10.1093/jmcb/mjv022
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发表时间：
2015-12-01
影响因子：
5.5
通讯作者：
Zhang, Xiaoren
中科院分区：
文献类型：
--
作者：
Liu, Zhi;Cao, Wei;Zhang, Xiaoren
产生白细胞介素（IL）17的辅助性T（Th 17）细胞在细胞外细菌和真菌的清除以及各种自身免疫性疾病（如多发性硬化症、银屑病和溃疡性结肠炎）的发病机制中起关键作用。虽然全球转录调控网络的Th 17细胞分化已被映射最近，参与分化过程中的表观遗传修饰尚未得到阐明。我们在这里证明，组蛋白H3赖氨酸-27（H3 K27）去甲基化，主要由H3 K27去甲基化酶Jmjd 3介导，关键调节Th 17细胞分化。初始CD 41 T细胞的活化立即诱导Jmjd 3的高表达。在体外和体内，CD 4 1 T细胞中Jmjd 3的遗传缺失特异性地损害Th 17细胞分化。Jmjd 3的异位表达在很大程度上挽救了Jmjd 3缺陷的CD 4（+）T细胞中Th 17细胞的体外分化受损。重要的是，Jmjd 3缺陷型小鼠对实验性自身免疫性脑脊髓炎（EAE）的诱导具有抗性。此外，用特异性抑制剂GSK-J 4抑制H3 K27脱甲基酶活性显著抑制了Th 17细胞的体外分化。在分子水平上，Jmjd 3直接结合并降低Rorc基因组位点处的H3 K27三甲基化（me 3）水平，Rorc编码主Th 17转录因子Ror γ t和Th 17细胞因子基因，如Il 17、Il 17 f和Il 22。因此，我们的研究确定了Jmjd 3介导的H3 K27去甲基化在Th 17细胞分化中的关键作用，并表明Jmjd 3可以成为抑制自身免疫反应的新的治疗靶点。
Interleukin (IL) 17-producing T helper (Th17) cells play critical roles in the clearance of extracellular bacteria and fungi as well as the pathogenesis of various autoimmune diseases, such as multiple sclerosis, psoriasis, and ulcerative colitis. Although a global transcriptional regulatory network of Th17 cell differentiation has been mapped recently, the participation of epigenetic modifications in the differentiation process has yet to be elucidated. We demonstrated here that histone H3 lysine-27 (H3K27) demethylation, predominantly mediated by the H3K27 demethylase Jmjd3, crucially regulated Th17 cell differentiation. Activation of naive CD4 1 T cells immediately induced high expression of Jmjd3. Genetic depletion of Jmjd3 in CD4 1 T cells specifically impaired Th17 cell differentiation both in vitro and in vivo. Ectopic expression of Jmjd3 largely rescued the impaired differentiation of Th17 cells in vitro in Jmjd3-deficientCD4(+) T cells. Importantly, Jmjd3-deficient mice were resistant to the induction of experimental autoimmune encephalomyelitis (EAE). Furthermore, inhibition of the H3K27 demethylase activity with the specific inhibitor GSK-J4 dramatically suppressed Th17 cell differentiation in vitro. At the molecular level, Jmjd3 directly bound to and reduced the level of H3K27 trimethylation (me3) at the genomic sites of Rorc, which encodes the master Th17 transcription factor Ror gamma t, and Th17 cytokine genes such as Il17, Il17f, and Il22. Therefore, our studies established a critical role of Jmjd3-mediated H3K27 demethylation in Th17 cell differentiation and suggest that Jmjd3 can be a novel therapeutic target for suppressing autoimmune responses.