TET2-mediated Cdkn2A DNA hydroxymethylation in midbrain dopaminergic neurons injury of Parkinson's disease
TET2-mediated Cdkn2A DNA hydroxymethylation in midbrain dopaminergic neurons injury of Parkinson's disease
复制标题
TET2介导的Cdkn2A DNA羟甲基化在帕金森病中脑多巴胺能神经元损伤中的作用
DOI：
10.1093/hmg/ddaa022
复制
发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Wu YC
中科院分区：
文献类型：
--
作者：
Wu TT;Liu T;Li X;Chen YJ;Chen TJ;Zhu XY;Chen JL;Li Q;Liu Y;Feng Y;Wu YC
据报道，表观遗传修饰异常与帕金森病（PD）的发生有关。在这里，我们发现 DNA 羟化酶家族的成员之一 10-11 易位 2 (TET2) 在体外和体内的多巴胺能神经元中增加。 DNA 5-羟甲基胞嘧啶 (5-hmC) 测序的全基因组图谱揭示了 1-甲基-4-苯基碘化吡啶 (MPP+) 诱导的 SH-SY5Y 细胞中异常的表观基因组 5-hmC 景观。 DNA 羟化酶的 TET 家族可以通过将 5-甲基胞嘧啶 (5-mC) 氧化为 5-hmC 来逆转 DNA 甲基化。然而，DNA羟甲基化修饰与PD发病机制之间的关系尚不清楚。根据5-hmC测序研究结果，5-hmC与细胞周期相关基因组中基因丰富的区域相关，特别是基因周期蛋白依赖性激酶抑制剂2A（Cdkn2A）。 TET2表达下调可以显着挽救MPP+刺激的SH-SY5Y细胞损伤和细胞周期停滞。同时，敲低 MPTP 诱导的 PD 小鼠黑质致密部中的 Tet2 表达，可通过 p16 抑制减轻 MPTP 诱导的运动缺陷和多巴胺能神经元损伤。在这项研究中，我们通过CDKN2A活性依赖性表观遗传途径证明了TET2在PD发展中的关键功能，这提出了表观遗传治疗的潜在新策略。
It has been reported that abnormal epigenetic modification is associated with the occurrence of Parkinson’s disease (PD). Here, we found that a ten-eleven translocation 2 (TET2), a staff of the DNA hydroxylases family, was increased in dopaminergic neuronsin vitroandin vivo. Genome-wide mapping of DNA 5-hydroxymethylcytosine (5-hmC)-sequencing has revealed an aberrant epigenome 5-hmC landscape in 1-methyl-4-phenylpyridinium iodide (MPP+)-induced SH-SY5Y cells. The TET family of DNA hydroxylases could reverse DNA methylation by oxidization of 5-methylcytosine (5-mC) to 5-hmC. However, the relationship between modification of DNA hydroxymethylation and the pathogenesis of PD is not clear. According to the results of 5-hmC-sequencing studies, 5-hmC was associated with gene-rich regions in the genomes related to cell cycle, especially gene-cyclin-dependent kinase inhibitor 2A (Cdkn2A). Downregulation of TET2 expression could significantly rescue MPP+-stimulated SH-SY5Y cell damage and cell cycle arrest. Meanwhile, knockdown ofTet2expression in the substantia nigra pars compacta of MPTP-induced PD mice resulted in attenuated MPTP-induced motor deficits and dopaminergic neuronal injury via p16 suppression. In this study, we demonstrated a critical function of TET2 in PD development via the CDKN2A activity-dependent epigenetic pathway, suggesting a potential new strategy for epigenetic therapy.