RNA modifications represent a novel layer of regulation of gene expression. Functional experiments revealed that N⁶‐methyladenosine (m⁶A) on messenger RNA (mRNA) plays critical roles in cell fate determination and development. m⁶A mark also resides in the decoding center of 18S ribosomal RNA (rRNA); however, the biological function of m⁶A on 18S rRNA is still poorly understood. Here, we report that methyltransferase‐like 5 (METTL5) methylates 18S rRNA both in vivo and in vitro, which is consistent with previous reports. Deletion of Mettl5 causes a dramatic differentiation defect in mouse embryonic stem cells (mESCs). Mechanistically, the m⁶A deposited by METTL5 is involved in regulating the efficient translation of F‐box and WD repeat domain‐containing 7 (FBXW7), a key regulator of cell differentiation. Deficiency of METTL5 reduces FBXW7 levels and leads to the accumulation of its substrate c‐MYC, thereby delaying the onset of mESC differentiation. Our study uncovers an important role of METTL5‐mediated 18S m⁶A in mESC differentiation through translation regulation and provides new insight into the functional significance of rRNA m⁶A.

中文翻译：

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18S rRNA m6 A 甲基转移酶 METTL5 促进小鼠胚胎干细胞分化。

RNA 修饰代表了一个新的基因表达调控层。功能实验表明，信使 RNA (mRNA) 上的 N ^6-甲基腺苷 (m ⁶ A) 在细胞命运决定和发育中起关键作用。m ⁶ A 标记也位于 18S 核糖体 RNA (rRNA) 的解码中心；然而，对 18S rRNA 上 m ⁶ A 的生物学功能仍然知之甚少。在这里，我们报告了甲基转移酶样 5 (METTL5)在体内和体外都将 18S rRNA 甲基化，这与之前的报道一致。Mettl5的缺失导致小鼠胚胎干细胞 (mESCs) 的显着分化缺陷。从机械上讲，m ⁶METTL5 保藏的 A 参与调节 F-box 和 WD 重复结构域 7 (FBXW7) 的有效翻译，FBXW7 是细胞分化的关键调节因子。METTL5 的缺乏会降低 FBXW7 的水平并导致其底物 c-MYC 的积累，从而延迟 mESC 分化的开始。^{我们的研究揭示了 METTL5 介导的 18S m 6} A 通过翻译调控在 mESC 分化中的重要作用，并为 rRNA m ⁶ A的功能意义提供了新的见解。