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      Dynamic transcriptomic m 6A decoration: writers, erasers, readers and functions in RNA metabolism

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          Abstract

          N 6-methyladenosine (m 6A) is a chemical modification present in multiple RNA species, being most abundant in mRNAs. Studies on enzymes or factors that catalyze, recognize, and remove m 6A have revealed its comprehensive roles in almost every aspect of mRNA metabolism, as well as in a variety of physiological processes. This review describes the current understanding of the m 6A modification, particularly the functions of its writers, erasers, readers in RNA metabolism, with an emphasis on its role in regulating the isoform dosage of mRNAs.

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          Most cited references66

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          The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase.

          Variants in the FTO (fat mass and obesity associated) gene are associated with increased body mass index in humans. Here, we show by bioinformatics analysis that FTO shares sequence motifs with Fe(II)- and 2-oxoglutarate-dependent oxygenases. We find that recombinant murine Fto catalyzes the Fe(II)- and 2OG-dependent demethylation of 3-methylthymine in single-stranded DNA, with concomitant production of succinate, formaldehyde, and carbon dioxide. Consistent with a potential role in nucleic acid demethylation, Fto localizes to the nucleus in transfected cells. Studies of wild-type mice indicate that Fto messenger RNA (mRNA) is most abundant in the brain, particularly in hypothalamic nuclei governing energy balance, and that Fto mRNA levels in the arcuate nucleus are regulated by feeding and fasting. Studies can now be directed toward determining the physiologically relevant FTO substrate and how nucleic acid methylation status is linked to increased fat mass.
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            Ythdc2 is an N6-methyladenosine binding protein that regulates mammalian spermatogenesis

            N 6 -methyladenosine (m 6 A) is the most common internal modification in eukaryotic mRNA. It is dynamically installed and removed, and acts as a new layer of mRNA metabolism, regulating biological processes including stem cell pluripotency, cell differentiation, and energy homeostasis. m 6 A is recognized by selective binding proteins; YTHDF1 and YTHDF3 work in concert to affect the translation of m 6 A-containing mRNAs, YTHDF2 expedites mRNA decay, and YTHDC1 affects the nuclear processing of its targets. The biological function of YTHDC2, the final member of the YTH protein family, remains unknown. We report that YTHDC2 selectively binds m 6 A at its consensus motif. YTHDC2 enhances the translation efficiency of its targets and also decreases their mRNA abundance. Ythdc2 knockout mice are infertile; males have significantly smaller testes and females have significantly smaller ovaries compared to those of littermates. The germ cells of Ythdc2 knockout mice do not develop past the zygotene stage and accordingly, Ythdc2 is upregulated in the testes as meiosis begins. Thus, YTHDC2 is an m 6 A-binding protein that plays critical roles during spermatogenesis.
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              VIRMA mediates preferential m 6 A mRNA methylation in 3′UTR and near stop codon and associates with alternative polyadenylation

              N 6-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.
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                Author and article information

                Contributors
                ygyang@big.ac.cn
                Journal
                Cell Res
                Cell Res
                Cell Research
                Nature Publishing Group UK (London )
                1001-0602
                1748-7838
                22 May 2018
                22 May 2018
                June 2018
                : 28
                : 6
                : 616-624
                Affiliations
                [1 ]ISNI 0000 0004 0644 6935, GRID grid.464209.d, CAS Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, , College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences, ; Beijing, 100101 China
                [2 ]ISNI 0000 0004 1797 8419, GRID grid.410726.6, University of Chinese Academy of Sciences, ; Beijing, 100049 China
                [3 ]ISNI 0000000119573309, GRID grid.9227.e, Institute of Stem Cell and Regeneration, Chinese Academy of Sciences, ; Beijing, 100101 China
                [4 ]ISNI 0000 0004 1936 7822, GRID grid.170205.1, Department of Chemistry and Institute for Biophysical Dynamics, Howard Hughes Medical Institute, , The University of Chicago, ; Chicago, IL 60637 USA
                [5 ]ISNI 0000 0004 1936 7822, GRID grid.170205.1, Medical Scientist Training Program/Committee on Immunology, , The University of Chicago, ; Chicago, IL 60637 USA
                Author information
                http://orcid.org/0000-0002-2821-8541
                Article
                40
                10.1038/s41422-018-0040-8
                5993786
                29789545
                96f99074-fea0-4506-b8f7-6cdb2f479f71
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 31 October 2017
                : 22 April 2018
                Categories
                Review Article
                Custom metadata
                © IBCB, SIBS, CAS 2018

                Cell biology
                Cell biology

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