m6A Regulates Neurogenesis and Neuronal Development by Modulating Histone Methyltransferase Ezh2

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.

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