MBD2 regulates TH17 differentiation and experimental autoimmune encephalomyelitis by controlling the homeostasis of T-bet/Hlx axis
MBD2 regulates TH17 differentiation and experimental autoimmune encephalomyelitis by controlling the homeostasis of T-bet/Hlx axis
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MBD2 通过控制 T-bet/Hlx 轴的稳态来调节 TH17 分化和实验性自身免疫性脑脊髓炎。
DOI：
10.1016/j.jaut.2014.05.006
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发表时间：
2014-09-01
影响因子：
12.8
通讯作者：
Wang, Cong-Yi
中科院分区：
文献类型：
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作者：
Zhong, Jixin;Yu, Qilin;Wang, Cong-Yi
与遗传改变不同，表观遗传修饰是可逆的，并且易于药物干预，这使它们成为临床治疗的有吸引力的目标。然而，人们对实验性自身免疫性脑脊髓炎（EAE）的表观遗传调控知之甚少。在这里，我们证明了表观遗传调节剂甲基 CpG 结合域蛋白 2 (MBD2) 通过 T-bet/Hlx 控制自身免疫和 EAE。 Tbx21 和 Hlx 在极化时经历了 DNA 甲基化转换，独特的甲基化模式对于 T(H)17 的发育至关重要。 Mbd2 的缺失会导致读取甲基化转换编码信息的缺陷，从而破坏 T-bet/Hlx 轴的稳态并抑制 T(H)17 分化。 DNA 去甲基化对辅助 T 细胞分化产生类似的影响。因此，Mbd2(-/-) 小鼠完全免受 EAE 侵害。从接受 MOG35-55 攻击的野生型小鼠中分离出的致病性脾细胞可以将疾病过继性转移至 Mbd2(-/-) 小鼠。此外，用未刺激的野生型脾细胞重建的Mbd2(-/-)小鼠与野生型小鼠一样出现EAE。这些数据将为 EAE 表观遗传调控提供新的见解。 (C) 2014 Elsevier Ltd. 保留所有权利。
Unlike genetic alterations, epigenetic modifications are reversible and amenable to pharmacological interventions, which make them appealing targets for clinical therapy. However, little is known about epigenetic regulation in experimental autoimmune encephalomyelitis (EAE). Here we demonstrated that methyl-CpG-binding domain protein 2 (MBD2), an epigenetic regulator, controls autoimmunity and EAE through T-bet/Hlx. Tbx21 and Hlx underwent a DNA methylation turnover upon polarizations and a unique methylation pattern was essential for T(H)17 development. Loss of Mbd2 resulted in a defect for reading the information encoded by this methylation turnover, which disrupted the homeostasis of T-bet/Hlx axis and suppressed T(H)17 differentiation. DNA demethylation induced similar effect on helper T cell differentiation. Therefore, Mbd2(-/-) mice were completely protected from EAE. Pathogenic splenocytes isolated from wild-type mice challenged with MOG35-55 could adoptively transfer disease to Mbd2(-/-) mice. In addition, Mbd2(-/-) mice reconstituted with unstimulated wild-type splenocytes developed EAE as wild-type mice did. These data would provide novel insights into epigenetic regulation of EAE. (C) 2014 Elsevier Ltd. All rights reserved.