Howard Hughes Medical Institute, Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, United States.
Bioinformatics Resource Center, The Rockefeller University, New York, United States.
Elife. 2020 Aug 26;9:e56980. doi: 10.7554/eLife.56980.
N-methyladenosine is the most prominent RNA modification in mammals. Here, we study mouse skin embryogenesis to tackle m6A's functions and physiological importance. We first landscape the m6A modifications on skin epithelial progenitor mRNAs. Contrasting with in vivo ribosomal profiling, we unearth a correlation between m6A modification in coding sequences and enhanced translation, particularly of key morphogenetic signaling pathways. Tapping physiological relevance, we show that m6A loss profoundly alters these cues and perturbs cellular fate choices and tissue architecture in all skin lineages. By single-cell transcriptomics and bioinformatics, both signaling and canonical translation pathways show significant downregulation after m6A loss. Interestingly, however, many highly m6A-modified mRNAs are markedly upregulated upon m6A loss, and they encode RNA-methylation, RNA-processing and RNA-metabolism factors. Together, our findings suggest that m6A functions to enhance translation of key morphogenetic regulators, while also destabilizing sentinel mRNAs that are primed to activate rescue pathways when m6A levels drop.
N6-甲基腺苷是哺乳动物中最主要的 RNA 修饰。在这里，我们研究了小鼠皮肤胚胎发生，以解决 m6A 的功能和生理重要性。我们首先描绘了皮肤上皮祖细胞 mRNA 上的 m6A 修饰。与体内核糖体图谱分析相反，我们发现编码序列中的 m6A 修饰与增强的翻译之间存在相关性，特别是关键形态发生信号通路的翻译。利用生理相关性，我们表明 m6A 的缺失会严重改变这些信号，并扰乱所有皮肤谱系中的细胞命运选择和组织结构。通过单细胞转录组学和生物信息学分析，信号和经典翻译途径在 m6A 缺失后均显著下调。有趣的是，然而，许多高度 m6A 修饰的 mRNA 在 m6A 缺失后显著上调，它们编码 RNA 甲基化、RNA 处理和 RNA 代谢因子。总之，我们的研究结果表明 m6A 增强了关键形态发生调节剂的翻译，同时也使处于激活救援途径预备状态的信号 mRNA 不稳定，而当 m6A 水平下降时，这些信号 mRNA 就会被激活。
