1. Arginine methylation of METTL14 promotes RNA N6-methyladenosine modification and endoderm differentiation of mouse embryonic stem cells
- Author
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Jinru Cui, Xueya Zhao, Qizhi Luo, Shan Xiao, Zihan Wang, Wenyi Du, Xiaona Liu, Hailong Wang, Qingwen Wang, Laixin Xia, Dahua Chen, Linjian Xia, Kaifen Tan, Jia Jiang, and Enhui Du
- Subjects
Epigenomics ,0301 basic medicine ,Protein-Arginine N-Methyltransferases ,Adenosine ,RNA methylation ,Science ,General Physics and Astronomy ,Stem cells ,Arginine ,Methylation ,Article ,General Biochemistry, Genetics and Molecular Biology ,Mice ,03 medical and health sciences ,0302 clinical medicine ,RNA interference ,Gene expression ,Protein methylation ,Animals ,Humans ,RNA, Small Interfering ,Messenger RNA ,Multidisciplinary ,Methyltransferase complex ,Chemistry ,Endoderm ,RNA ,Cell Differentiation ,Mouse Embryonic Stem Cells ,Methyltransferases ,General Chemistry ,RNA modification ,Cell biology ,HEK293 Cells ,030104 developmental biology ,Gene Expression Regulation ,RNA Interference ,Protein Processing, Post-Translational ,030217 neurology & neurosurgery ,HeLa Cells - Abstract
RNA N6-methyladenosine (m6A), the most abundant internal modification of mRNAs, plays key roles in human development and health. Post-translational methylation of proteins is often critical for the dynamic regulation of enzymatic activity. However, the role of methylation of the core methyltransferase METTL3/METTL14 in m6A regulation remains elusive. We find by mass spectrometry that METTL14 arginine 255 (R255) is methylated (R255me). Global mRNA m6A levels are greatly decreased in METTL14 R255K mutant mouse embryonic stem cells (mESCs). We further find that R255me greatly enhances the interaction of METTL3/METTL14 with WTAP and promotes the binding of the complex to substrate RNA. We show that protein arginine N-methyltransferases 1 (PRMT1) interacts with and methylates METTL14 at R255, and consistent with this, loss of PRMT1 reduces mRNA m6A modification globally. Lastly, we find that loss of R255me preferentially affects endoderm differentiation in mESCs. Collectively, our findings show that arginine methylation of METTL14 stabilizes the binding of the m6A methyltransferase complex to its substrate RNA, thereby promoting global m6A modification and mESC endoderm differentiation. This work highlights the crosstalk between protein methylation and RNA methylation in gene expression., The methyltransferase complex of METTL3-METTL14-WTAP is responsible for m6A modification on RNA. Here the authors report that METTL14 arginine 255 (R255) is methylated by PRMT1 and this modification increases interaction of METTL3/METTL14 interaction with WTAP and substrate RNA, promoting m6A methylation activity of the complex.
- Published
- 2021