Inhibition of Ezh2 In Vitro and the Decline of Ezh2 in Developing Midbrain Promote Dopaminergic Neurons Differentiation Through Modifying H3K27me3
Inhibition of Ezh2 In Vitro and the Decline of Ezh2 in Developing Midbrain Promote Dopaminergic Neurons Differentiation Through Modifying H3K27me3
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DOI：
10.1089/scd.2018.0258
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发表时间：
2019-04-25
影响因子：
4
通讯作者：
Feng, Linyin
中科院分区：
文献类型：
--
作者：
Hong, Feng;Zhao, Mengxue;Feng, Linyin
表观遗传修饰在神经发育中起重要作用。赖氨酸27位的三甲基化组蛋白H3（H3 K27 me 3）是介导组织发育的抑制性表观遗传标记。在这项研究中，我们证明，H3 K27 me 3和组蛋白甲基转移酶Ezh 2调节多巴胺能（DA）神经元在体外和体内的发展。我们发现H3 K27 me 3在腹侧中脑源性神经干细胞（VM-NSCs）分化过程中增加。而组蛋白去甲基化酶选择性抑制剂GSK-J1则可增加H3 K27 me 3的表达，降低酪氨酸羟化酶的表达。用Ezh 2选择性抑制剂EPZ 005687处理VM-NSCs培养物，抑制H3 K27的三甲基化，并增强DA神经元的分化。此外，Ezh 2抑制通过修饰相关启动子区域的H3 K27三甲基化促进DA神经元发育相关因子的表达。此外，Ezh 2抑制介导的DA神经元分化的作用被Nurr 1特异性shRNA的表达所阻断。在体内，Ezh 2减少，并导致发育中的中脑中H3 K27 me 3的减少。Ezh 2基因的RNA干扰缺失促进了中脑发育过程中DA能神经元的分化。Ezh 2的过表达增强了细胞的自我更新，并没有影响DA神经元的分化。
Epigenetic modifications play an important role in neural development. Trimethylated histone H3 at lysine 27 (H3K27me3) is a repressive epigenetic marker that mediates tissue development. In this study, we demonstrate that H3K27me3 and histone methyl transferase Ezh2 regulated the development of dopaminergic (DA) neurons in vitro and in vivo. We found that H3K27me3 increased during differentiation of ventral midbrain-derived neural stem cells (VM-NSCs). However, histone demethylase selective inhibitor GSK-J1 increased H3K27me3 level and decreased the expression of tyrosine hydroxylase. Treated with Ezh2-selective inhibitor EPZ005687 repressed the trimethylation of H3K27 and enhanced differentiation of DA neurons in VM-NSCs cultures. Furthermore, Ezh2 inhibition promoted the expression of DA neurons developmental-related factors by modifying H3K27 trimethylation on the relevant promoter regions. Moreover, the effect of Ezh2 inhibition-mediated DA neurons differentiation was blocked by the expression of shRNA specific for Nurr1. In vivo, Ezh2 decreased and resulted in a reduction of H3K27me3 in developing midbrain. Deletion of Ezh2 by RNA interference approach promoted differentiation of DA neurons during midbrain development. Overexpression of Ezh2 enhanced cell self-renewal and did not affect differentiation of DA neurons.