m6A Regulates Neurogenesis and Neuronal Development by Modulating Histone Methyltransferase Ezh2
m6A Regulates Neurogenesis and Neuronal Development by Modulating Histone Methyltransferase Ezh2
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m(6)A 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
DOI：
10.1016/j.gpb.2018.12.007
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发表时间：
2019-04-01
影响因子：
9.5
通讯作者：
Li, Xuekun
中科院分区：
文献类型：
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作者：
Chen, Junchen;Zhang, Yi-Chang;Li, Xuekun
N-6-甲基腺苷（N-6-methyladenosine，m（6）A）是由Mettl 3和Mettl 14组成的甲基转移酶复合物催化的，是mRNA中最丰富的RNA修饰，参与多种生物学过程。然而，m（6）A修饰在调节神经元发育和成体神经发生中的作用和确切机制尚不清楚。在这里，我们研究的功能Mettl 3，复合物的关键组成部分，在神经元发育和成年小鼠的神经发生。我们发现Mettl 3的缺失显著降低了成体神经干细胞（aNSCs）中的m（6）A水平并抑制了aNSCs的增殖。Mettl 3缺失不仅抑制神经元发育并使aNSCs的分化更偏向于胶质细胞谱系，而且还影响成年脑中新生神经元的形态成熟。m（6）A免疫沉淀结合深度测序（MeRIP-seq）显示m（6）A主要富集与神经发生和神经元发育相关的转录物。从机制上讲，m（6）A存在于组蛋白甲基转移酶Ezh 2的转录物上，并且在Mettl 3敲低时其减少降低了Ezh 2蛋白表达和随后的H3 K27 me 3水平。Ezh 2过表达可挽救Mettl 3缺失所导致的神经发生和神经发育缺陷。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Mettl 3介导的m（6）A修饰通过调节Ezh 2在调节神经发生和神经元发育中起重要作用。
N-6-methyladenosine (m(6)A), 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 m(6)A 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 m(6)A 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. m(6)A immunoprecipitation combined with deep sequencing (MeRIP-seq) revealed that m(6)A was predominantly enriched in transcripts related to neurogenesis and neuronal development. Mechanistically, m(6)A 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 m(6)A modification plays an important role in regulating neurogenesis and neuronal development through modulating Ezh2.