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.
Highlights
RNA N6-methyladenosine (m6A), the most abundant internal modification of mRNAs, plays key roles in human development and health
N 6-methyladenosine (m6A) is the most abundant mRNA modification in mammals, and it has been widely explored following the development of the methylated RNA immunoprecipitation-sequencing (MeRIP-seq) method1,2. mRNA m6A is mostly found in stop codons, 3 ́untranslated regions (3 ́UTRs), and long exons that possess a consensus motif of RRACH (R means G or A, and H means A, C or U)1,3. m6A is a dynamically reversible modification, which is synergistically regulated by the methyltransferase complex METTL3-METTL14WTAP4 and demethylases FTO and ALKBH55–7. m6A plays important roles in RNA stability[8,9], splicing[10,11], translation[9,12], and other cellular processes[13,14,15,16]
We show that protein arginine N-methyltransferases 1 (PRMT1) contributes to R255 methylation, and loss of R255me affects the endoderm differentiation of mouse embryonic stem cells
Summary
RNA N6-methyladenosine (m6A), the most abundant internal modification of mRNAs, plays key roles in human development and health. 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. 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. Methylation of METTL14 at R255 regulates the activity of the m6A methyltransferase complex and enhances global RNA m6A modification. This study elucidates a critical role for arginine methylation in RNA m6A regulation and mESC differentiation, suggesting a direct link between protein methylation and RNA methylation
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