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PMID: 29507755 Published · epublish English Journal Article

VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation.

Cell discovery ·Vol. 4 ·2018-00-00 ·Pages 10

Yue Y, Liu J, Cui X, Cao J, Luo G, Zhang Z, Cheng T, Gao M, Shu X, Ma H, Wang F, Wang X, Shen B, Wang Y, Feng X, He C, Liu J

Abstract

N6-methyladenosine (m6A) is enriched in 3'untranslated region (3'UTR) and near stop codon of mature polyadenylated mRNAs in mammalian systems and has regulatory roles in eukaryotic mRNA transcriptome switch. Significantly, the mechanism for this modification preference remains unknown, however. Herein we report a characterization of the full m6A methyltransferase complex in HeLa cells identifying METTL3/METTL14/WTAP/VIRMA/HAKAI/ZC3H13 as the key components, and we show that VIRMA mediates preferential mRNA methylation in 3'UTR and near stop codon. Biochemical studies reveal that VIRMA recruits the catalytic core components METTL3/METTL14/WTAP to guide region-selective methylations. Around 60% of VIRMA mRNA immunoprecipitation targets manifest strong m6A enrichment in 3'UTR. Depletions of VIRMA and METTL3 induce 3'UTR lengthening of several hundred mRNAs with over 50% targets in common. VIRMA associates with polyadenylation cleavage factors CPSF5 and CPSF6 in an RNA-dependent manner. Depletion of CPSF5 leads to significant shortening of 3'UTR of over 2800 mRNAs, 84% of which are modified with m6A and have increased m6A peak density in 3'UTR and near stop codon after CPSF5 knockdown. Together, our studies provide insights into m6A deposition specificity in 3'UTR and its correlation with alternative polyadenylation.

Authors & Affiliations
17 authors, click to expand affiliations / ORCID
Yue Yanan
1MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, Zhejiang 310027 China.
Liu Jun
2Department of Chemistry, Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, Howard Hughes Medical Institute, The University of Chicago, Chicago, IL 60637 USA.
Cui Xiaolong
2Department of Chemistry, Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, Howard Hughes Medical Institute, The University of Chicago, Chicago, IL 60637 USA.
Cao Jie
1MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, Zhejiang 310027 China.
Luo Guanzheng ORCID
2Department of Chemistry, Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, Howard Hughes Medical Institute, The University of Chicago, Chicago, IL 60637 USA.
Zhang Zezhou
1MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, Zhejiang 310027 China.
Cheng Tao
1MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, Zhejiang 310027 China.
Gao Minsong
1MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, Zhejiang 310027 China.
Shu Xiao
1MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, Zhejiang 310027 China.
Ma Honghui
2Department of Chemistry, Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, Howard Hughes Medical Institute, The University of Chicago, Chicago, IL 60637 USA.
Wang Fengqin
3College of Animal Sciences, Key Laboratory of Molecular Nutrition, Ministry of Education, Zhejiang University, Hangzhou, Zhejiang 310058 China.
Wang Xinxia
3College of Animal Sciences, Key Laboratory of Molecular Nutrition, Ministry of Education, Zhejiang University, Hangzhou, Zhejiang 310058 China.
Shen Bin
4State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing, Jiangsu 210029 China.
Wang Yizhen
3College of Animal Sciences, Key Laboratory of Molecular Nutrition, Ministry of Education, Zhejiang University, Hangzhou, Zhejiang 310058 China.
Feng Xinhua
5Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058 China.
He Chuan ORCID
2Department of Chemistry, Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, Howard Hughes Medical Institute, The University of Chicago, Chicago, IL 60637 USA.
Liu Jianzhao ORCID
1MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, Zhejiang 310027 China. | 5Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058 China.
Conflict of Interest

C.H. is a scientific founder of the Accent Therapeutics and a member of the Scientific Advisory Committee. The remaining authors declare that they have no conflict of interest.

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Article Info
Journal
Cell discovery
Abbr.
Cell Discov
ISSN
2056-5968
DOI
10.1038/s41421-018-0019-0
Published
2018-00-00
Epub
2018-00-27
Pages
10
Language
English
Region
England
NLM ID
101661034
PMCID
PMC5826926
Grants
NHGRI NIH HHS · R01 HG008688 · United States
External Links
PubMed source DOI: 10.1038/s41421-018-0019-0 PMC Full Text View journal details
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