N6-methyladenosine (m6A), catalyzed by the methyltransferase complex consisting of Mettl3 and Mettl14, is the most abundant RNA modification in mRNAs and participates in diverse biological processes. However, the roles and precise mechanisms of m6A modification in regulating neuronal development and adult neurogenesis remain unclear. Here, we examined the function of Mettl3, the key component of the complex, in neuronal development and adult neurogenesis of mice. We found that the depletion of Mettl3 significantly reduced m6A levels in adult neural stem cells (aNSCs) and inhibited the proliferation of aNSCs. Mettl3 depletion not only inhibited neuronal development and skewed the differentiation of aNSCs more toward glial lineage, but also affected the morphological maturation of newborn neurons in the adult brain. m6A immunoprecipitation combined with deep sequencing (MeRIP-seq) revealed that m6A was predominantly enriched in transcripts related to neurogenesis and neuronal development. Mechanistically, m6A was present on the transcripts of histone methyltransferase Ezh2, and its reduction upon Mettl3 knockdown decreased both Ezh2 protein expression and consequent H3K27me3 levels. The defects of neurogenesis and neuronal development induced by Mettl3 depletion could be rescued by Ezh2 overexpression. Collectively, our results uncover a crosstalk between RNA and histone modifications and indicate that Mettl3-mediated m6A modification plays an important role in regulating neurogenesis and neuronal development through modulating Ezh2.

中文翻译：

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m6A 通过调节组蛋白甲基转移酶 Ezh2 调节神经发生和神经元发育。

N6-甲基腺苷 (m6A) 由 Mettl3 和 Mettl14 组成的甲基转移酶复合物催化，是 mRNA 中最丰富的 RNA 修饰，参与多种生物过程。然而，m6A 修饰在调节神经元发育和成体神经发生中的作用和精确机制仍不清楚。在这里，我们检查了 Mettl3（复合物的关键成分）在小鼠神经元发育和成年神经发生中的功能。我们发现 Mettl3 的消耗显着降低了成体神经干细胞 (aNSCs) 中的 m6A 水平并抑制了 aNSCs 的增殖。Mettl3 耗竭不仅抑制神经元发育并使 aNSCs 的分化更倾向于神经胶质谱系，而且还影响成人大脑中新生神经元的形态成熟。m6A 免疫沉淀结合深度测序 (MeRIP-seq) 表明 m6A 主要富含与神经发生和神经元发育相关的转录本。从机制上讲，m6A 存在于组蛋白甲基转移酶 Ezh2 的转录本上，并且它在 Mettl3 敲低时的减少降低了 Ezh2 蛋白表达和随后的 H3K27me3 水平。Ezh2 过表达可以挽救 Mettl3 耗竭引起的神经发生和神经元发育缺陷。总的来说，我们的结果揭示了 RNA 和组蛋白修饰之间的串扰，并表明 Mettl3 介导的 m6A 修饰通过调节 Ezh2 在调节神经发生和神经元发育中发挥重要作用。