Internal N⁶-methyladenosine (m⁶A) modification is widespread in messenger RNAs (mRNAs) and is catalyzed by heterodimers of methyltransferase-like protein 3 (Mettl3) and Mettl14. To understand the role of m⁶A in development, we deleted Mettl14 in embryonic neural stem cells (NSCs) in a mouse model. Phenotypically, NSCs lacking Mettl14 displayed markedly decreased proliferation and premature differentiation, suggesting that m⁶A modification enhances NSC self-renewal. Decreases in the NSC pool led to a decreased number of late-born neurons during cortical neurogenesis. Mechanistically, we discovered a genome-wide increase in specific histone modifications in Mettl14 knockout versus control NSCs. These changes correlated with altered gene expression and observed cellular phenotypes, suggesting functional significance of altered histone modifications in knockout cells. Finally, we found that m⁶A regulates histone modification in part by destabilizing transcripts that encode histone-modifying enzymes. Our results suggest an essential role for m⁶A in development and reveal m⁶A-regulated histone modifications as a previously unknown mechanism of gene regulation in mammalian cells.

中文翻译：

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N6-甲基腺苷RNA修饰通过组蛋白修饰调节胚胎神经干细胞的自我更新。

内部N ^6-甲基腺苷（m ⁶ A）修饰在信使RNA（mRNA）中很普遍，并且被甲基转移酶样蛋白3（Mettl3）和Mettl14的异二聚体催化。为了了解m ⁶ A在发育中的作用，我们在小鼠模型中的胚胎神经干细胞（NSCs）中删除了Mettl14。从表型上看，缺乏Mettl14的NSC表现出明显的增殖减少和过早分化，表明m ⁶修改可增强NSC的自我更新。NSC库的减少导致皮层神经发生过程中后期出生的神经元数量减少。从机理上讲，我们发现与对照NSC相比，Mettl14基因敲除中特定组蛋白修饰的全基因组增加。这些变化与基因表达的改变和观察到的细胞表型有关，表明敲除细胞中组蛋白修饰改变的功能意义。最后，我们发现m ⁶ A部分通过破坏编码组蛋白修饰酶的转录本来调节组蛋白修饰。我们的结果表明，m ⁶ A在发育中起着至关重要的作用，并揭示了m ⁶ A调节的组蛋白修饰，这是哺乳动物细胞中基因调节的一个未知机制。