DNA methylation and demethylation at CpG di-nucleotide sites plays important roles in cell fate specification of neural stem cells (NSCs). We have previously reported that DNA methyltransferases, Dnmt1and Dnmt3a, serve to suppress precocious astrocyte differentiation from NSCs via methylation of astroglial lineage genes. However, whether active DNA demethylase also participates in astrogliogenesis remains undetermined. In this study, we discovered that a Ten-eleven translocation (Tet) protein, Tet2, which was critically involved in active DNA demethylation through oxidation of 5-Methylcytosine (5mC), drove astrocyte differentiation from NSCs by demethylation of astroglial lineage genes including Gfap. Moreover, we found that an NSC-specific bHLH transcription factor Olig2 was an upstream inhibitor for Tet2 expression through direct association with the Tet2 promoter, and indirectly inhibited astrocyte differentiation. Our research not only revealed a brand-new function of Tet2 to promote NSC differentiation into astrocytes, but also a novel mechanism for Olig2 to inhibit astrocyte formation.

中文翻译：

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Tet2介导的表观遗传驱动星形胶质细胞从胚胎神经干细胞分化。

CpG 二核苷酸位点的 DNA 甲基化和去甲基化在神经干细胞 (NSC) 的细胞命运规范中发挥着重要作用。我们之前报道过 DNA 甲基转移酶 Dnmt1 和 Dnmt3a 通过星形胶质细胞谱系基因的甲基化来抑制早熟星形胶质细胞从 NSC 分化。然而，活性 DNA 去甲基酶是否也参与星形胶质细胞生成仍不清楚。在这项研究中，我们发现一种 11-11 易位 (Tet) 蛋白 Tet2 通过 5-甲基胞嘧啶 (5mC) 的氧化参与主动 DNA 去甲基化，通过星形胶质细胞谱系基因（包括 Gfap）的去甲基化驱动星形胶质细胞从 NSC 分化。 。此外，我们发现 NSC 特异性 bHLH 转录因子 Olig2 通过与 Tet2 启动子直接关联，成为 Tet2 表达的上游抑制剂，并间接抑制星形胶质细胞分化。我们的研究不仅揭示了Tet2促进NSC分化为星形胶质细胞的全新功能，而且揭示了Olig2抑制星形胶质细胞形成的新机制。