Arginine methylation of METTL14 promotes RNA N6-methyladenosine modification and endoderm differentiation of mouse embryonic stem cells

Xiaona Liu, Hailong Wang, Xueya Zhao, Qizhi Luo, Qingwen Wang, Kaifen Tan, Zihan Wang, Jia Jiang, Jinru Cui, Enhui Du, Linjian Xia, Wenyi Du, Dahua Chen (), Laixin Xia () and Shan Xiao ()
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Xiaona Liu: University of Science and Technology of China
Hailong Wang: Guangzhou Medical University
Xueya Zhao: Southern Medical University
Qizhi Luo: Southern Medical University
Qingwen Wang: Southern Medical University
Kaifen Tan: Southern Medical University
Zihan Wang: Southern Medical University
Jia Jiang: Southern Medical University
Jinru Cui: Southern Medical University
Enhui Du: Southern Medical University
Linjian Xia: Southern Medical University
Wenyi Du: Sichuan MoDe Technology Co., Ltd
Dahua Chen: Chinese Academy of Sciences
Laixin Xia: Southern Medical University
Shan Xiao: Southern Medical University

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-24035-6

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