Arginine methylation of METTL14 promotes RNA N(6)-methyladenosine modification and endoderm differentiation of mouse embryonic stem cells.
Arginine methylation of METTL14 promotes RNA N(6)-methyladenosine modification and endoderm differentiation of mouse embryonic stem cells.
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METTL14精氨酸甲基化促进小鼠胚胎干细胞RNA N-6-甲基腺苷修饰和内胚层分化
DOI：
10.1038/s41467-021-24035-6
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发表时间：
2021-06-18
影响因子：
16.6
通讯作者：
Xiao S
中科院分区：
文献类型：
--
作者：
Liu X;Wang H;Zhao X;Luo Q;Wang Q;Tan K;Wang Z;Jiang J;Cui J;Du E;Xia L;Du W;Chen D;Xia L;Xiao S
RNA n6 -甲基腺苷（m6A）是最丰富的mrna内部修饰，在人类发育和健康中起着关键作用。蛋白质的翻译后甲基化通常对酶活性的动态调节至关重要。然而，核心甲基转移酶METTL3/METTL14的甲基化在m6A调控中的作用尚不明确。我们发现METTL14精氨酸255 （R255）被甲基化（R255me）。METTL14 R255K突变小鼠胚胎干细胞(mESCs)的mRNA m6A水平显著降低。我们进一步发现R255me极大地增强了METTL3/METTL14与WTAP的相互作用，促进了复合物与底物RNA的结合。我们发现蛋白精氨酸n -甲基转移酶1 （PRMT1）与R255位点的METTL14相互作用并使其甲基化，与此一致的是，PRMT1的缺失减少了mRNA m6A的整体修饰。最后，我们发现R255me的缺失优先影响mESCs的内胚层分化。总的来说，我们的研究结果表明，METTL14的精氨酸甲基化稳定了m6A甲基转移酶复合物与其底物RNA的结合，从而促进了m6A的整体修饰和mESC内胚层分化。这项工作强调了基因表达中蛋白质甲基化和RNA甲基化之间的串扰。METTL3-METTL14-WTAP的甲基转移酶复合物负责RNA上的m6A修饰。在这里，作者报道了METTL14精氨酸255 （R255）被PRMT1甲基化，这种修饰增加了METTL3/METTL14与WTAP和底物RNA的相互作用，促进了复合物的m6A甲基化活性。
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.
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赖氨酸 36 处的组蛋白 H3 三甲基化引导 m(6)A RNA 共转录修饰
影响因子：
64.8
作者：
Huang, Huilin;Weng, Hengyou;Chen, Jianjun
通讯作者：
Chen, Jianjun
影响因子：
23.9
作者：
Batista, Pedro J.;Molinie, Benoit;Wang, Jinkai;Qu, Kun;Zhang, Jiajing;Li, Lingjie;Bouley, Donna M.;Lujan, Ernesto;Haddad, Bahareh;Daneshvar, Kaveh;Carter, Ava C.;Flynn, Ryan A.;Zhou, Chan;Lim, Kok-Seong;Dedon, Peter;Wernig, Marius;Mullen, Alan C.;Xing, Yi;Giallourakis, Cosmas C.;Chang, Howard Y.
通讯作者：
Chang, Howard Y.
影响因子：
4.4
作者：
ESSMANN, U;PERERA, L;PEDERSEN, LG
通讯作者：
PEDERSEN, LG
影响因子：
64.8
作者：
Bertero A;Brown S;Madrigal P;Osnato A;Ortmann D;Yiangou L;Kadiwala J;Hubner NC;de Los Mozos IR;Sadée C;Lenaerts AS;Nakanoh S;Grandy R;Farnell E;Ule J;Stunnenberg HG;Mendjan S;Vallier L
通讯作者：
Vallier L
影响因子：
4.8
作者：
Feng, You;Maity, Ranjan;Clarke, Steven G.
通讯作者：
Clarke, Steven G.