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.
与DNA相比，RNA的修饰形式更加丰富和多样化，其中研究最为深入、含量最高的是N6-甲基腺嘌呤（N6-methyladenosine ，m6A）。甲基转移酶Mettl3和Mettl14催化甲基转移到腺嘌呤而产生m6A，后者又可以在去甲基化转移酶FTO和ALKBH5的作用下实现去甲基化。研究发现m6A修饰参与了多种生物学过程，与多种疾病密切相关。我们实验室和其他研究团队之前的工作都揭示了m6A修饰与神经发育和神经系统功能密切相关，但是关于Mettl3介导的m6A修饰在成体神经发生中的功能和机制尚不明确。基于此，我们采用分离培养的小鼠成体神经干细胞进行了本研究。我们的研究发现，Mettl3敲低可以显著降低神经干细胞中m6A修饰的水平，抑制神经干细胞的增殖，使得神经干细胞在分化时更倾向于进入胶质细胞谱系。Mettl3敲低后显著改变了与细胞增殖、神经发育等基因的表达，特别是组蛋白甲基化转移酶Ezh2的表达，而过表达Ezh2可以拯救Mettl3缺失而导致的神经干细胞增殖和分化能力的异常。我们的研究结果揭示了RNA修饰和组蛋白修饰相互作用，从而精细调控成体神经发生，为表观遗传修饰在成体神经发生的调控作用提供了新的证据。





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