Dataset Information

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

ABSTRACT: m6A is the most abundant modification of mRNA in mammals and plays an important role in human development and disease. METTL14 is a key component of m6A methyltransferase complex. The project showed that its post-translational arginine methylation can regulate the generation of m6A and the endoderm differentiation of mouse embryonic stem cells, indicating its essential function in the normal development of embryos.

ORGANISM(S): Homo Sapiens

SUBMITTER: Shan Xiao

PROVIDER: PXD018458 | iProX | Mon May 17 00:00:00 BST 2021

REPOSITORIES: iProX

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Publications

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

Liu Xiaona X Wang Hailong H Zhao Xueya X Luo Qizhi Q Wang Qingwen Q Tan Kaifen K Wang Zihan Z Jiang Jia J Cui Jinru J Du Enhui E Xia Linjian L Du Wenyi W Chen Dahua D Xia Laixin L Xiao Shan S

Nature communications 20210618 1

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 l ...[more]

PMID: 34145242

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Project description:Protein arginine methylation, catalyzed by the protein arginine methyltransferase (PRMT) family, is recognized as a widespread post-translational modification (PTM) with implications in a plethora of biological processes in eukaryotes. PRMT proteins were classified into three types, type I, II and III, according to the final methyl-arginine products generated. Despite that thousands of substrates have been identified for Type I and II PRMTs, a full scope of arginine methylation catalyzed by the only type III PRMT, PRMT7, as well as its connection with that of type I and II PRMTs remain unknown, limiting our understanding of the network of arginine methylation and its functions in cells. In this study, global profiling of PRMT4 (type I), PRMT5 (type II) and PRMT7 (type III) substrates (also referred as methylome) revealed that PRMT7 methylated a GAR (glycine and arginine) motif similar as PRMT5, while PRMT4 uniquely methylated a motif in which proline was highly enriched. PRMT4, 5 and 7-methylome were all enriched with proteins functioning in mRNA splicing, and knockdown of PRMT4, 5 or 7 led to a global change of alternative splicing events, among which a cohort with implications in cancer development was co-regulated by all three PRMTs. PRMT4, 5 and 7-mediated arginine methylation on splicing factors such as hnRNPA1, though at different status, were shown to enhance RNA binding in general and participate in the regulation of PRMT4, 5 and 7 co-regulated alternative splicing events.The clinical significance of PRMT4, 5 and 7-mediated arginine methylation was underscored by the fact that these three PRMTs as well as hnRNPA1 arginine methylation were over-represented in multiple types of cancers, which were associated with aberrant gene alternative splicing. Consistently, silencing or pharmacological inhibition of PRMT4, 5 and 7 altered gene alternative splicing and suppressed cancer cell growth, and co-treatment exhibited synergistic effects. Taken together, our study provided an integrative view of substrates for the three types of PRMTs, revealing the important function of arginine methylation in RNA splicing and cancer.

Dataset Information

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

Publications

Arginine methylation of METTL14 promotes RNA N<sup>6</sup>-methyladenosine modification and endoderm differentiation of mouse embryonic stem cells.

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