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      The m 6A Dynamics of Profilin in Neurogenesis

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          Abstract

          Our understanding of the biological role of N 6-methyladenosine (m 6A), a ubiquitous non-editing RNA modification, has increased greatly since 2011. More recently, work from several labs revealed that m 6A methylation regulates several aspects of mRNA metabolism. The “writer” protein METTL3, known as MT-A70 in humans, DmIme4 in flies, and MTA in plants, has the catalytic site of the METTL3/14/16 subunit of the methyltransferase complex that includes many other proteins. METTL3 is evolutionarily conserved and essential for development in multicellular organisms. However, until recently, no study has been able to provide a mechanism that explains the essentiality of METTL3. The addition of m 6A to gene transcripts has been compared with the epigenetic code of histone modifications because of its effects on gene expression and its reversibility, giving birth to the field of epitranscriptomics, the study of the biological role of this and similar RNA modifications. Here, we focus on METTL3 and its likely conserved role in profilin regulation in neurogenesis. However, this and many other subunits of the methyltransferase complex are starting to be identified in several developmental processes and diseases. A recent plethora of studies about the biological role of METTL3 and other components of the methyltransferase complex that erase (FTO) or recognize (YTH proteins) this modification on transcripts revealed that this RNA modification plays a variety of roles in many biological processes like neurogenesis. Our work in Drosophila shows that the ancient and evolutionarily conserved gene profilin ( chic in Drosophila) is a target of the m 6A writer. Here, we discuss the implications of our study in Drosophila and how it unveils a conserved mechanism in support of the essential function of METTL3 in metazoan development. Profilin ( chic) is an essential gene of ancient evolutionary origins, present in sponges (Porifera), the oldest still extant metazoan phylum of the common metazoan ancestor Urmetazoa. We propose that the relationship between profilin and METTL3 is conserved in metazoans and it provides insights into possible regulatory roles of m 6A modification of profilin transcripts in processes such as neurogenesis.

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          MTA is an Arabidopsis messenger RNA adenosine methylase and interacts with a homolog of a sex-specific splicing factor.

          N6-Methyladenosine is a ubiquitous modification identified in the mRNA of numerous eukaryotes, where it is present within both coding and noncoding regions. However, this base modification does not alter the coding capacity, and its biological significance remains unclear. We show that Arabidopsis thaliana mRNA contains N6-methyladenosine at levels similar to those previously reported for animal cells. We further show that inactivation of the Arabidopsis ortholog of the yeast and human mRNA adenosine methylase (MTA) results in failure of the developing embryo to progress past the globular stage. We also demonstrate that the arrested seeds are deficient in mRNAs containing N6-methyladenosine. Expression of MTA is strongly associated with dividing tissues, particularly reproductive organs, shoot meristems, and emerging lateral roots. Finally, we show that MTA interacts in vitro and in vivo with At FIP37, a homolog of the Drosophila protein FEMALE LETHAL2D and of human WILMS' TUMOUR1-ASSOCIATING PROTEIN. The results reported here provide direct evidence for an essential function for N6-methyladenosine in a multicellular eukaryote, and the interaction with At FIP37 suggests possible RNA processing events that might be regulated or altered by this base modification.
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            Epitranscriptomic m 6 A Regulation of Axon Regeneration in the Adult Mammalian Nervous System

            N 6 -methyladenosine (m 6 A) affects multiple aspects of mRNA metabolism and regulates developmental transitions by promoting mRNA decay. Little is known about the role of m 6 A in the adult mammalian nervous system. Here we report that sciatic nerve lesion elevates levels of m 6 A-tagged transcripts encoding many regeneration-associated genes and protein translation machinery components in the adult mouse dorsal root ganglion (DRG). Single-base resolution m 6 A-CLIP mapping further reveals a dynamic m 6 A landscape in the adult DRG upon injury. Loss of either m 6 A methyltransferase complex component Mettl14, or m 6 A-binding protein Ythdf1, globally attenuates injury-induced protein translation in adult DRGs and reduces functional axon regeneration in the peripheral nervous system in vivo. Furthermore, Pten deletion-induced axon regeneration of retinal ganglion neurons in the adult central nervous system is attenuated upon Mettl14 knockdown. Our study reveals a critical epitranscriptomic mechanism in promoting injury-induced protein synthesis and axon regeneration in the adult mammalian nervous system. N 6 -methyladenosine (m 6 A) occurs in many mRNAs. Weng et al. uncovered an epitranscriptomic mechanism wherein axonal injury elevates m 6 A levels and signaling to promote protein translation, including regeneration-associated genes, which is essential for functional axon regeneration of peripheral sensory neurons.
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              Recent advances in dynamic m6A RNA modification

              The identification of m6A demethylases and high-throughput sequencing analysis of methylated transcriptome corroborated m6A RNA epigenetic modification as a dynamic regulation process, and reignited its investigation in the past few years. Many basic concepts of cytogenetics have been revolutionized by the growing understanding of the fundamental role of m6A in RNA splicing, degradation and translation. In this review, we summarize typical features of methylated transcriptome in mammals, and highlight the ‘writers’, ‘erasers’ and ‘readers’ of m6A RNA modification. Moreover, we emphasize recent advances of biological functions of m6A and conceive the possible roles of m6A in the regulation of immune response and related diseases.
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                Author and article information

                Contributors
                Journal
                Front Genet
                Front Genet
                Front. Genet.
                Frontiers in Genetics
                Frontiers Media S.A.
                1664-8021
                12 November 2019
                2019
                : 10
                : 987
                Affiliations
                [1]Department of Biology, Clarkson University , Potsdam, NY, United States
                Author notes

                Edited by: Hehuang Xie, Virginia Tech, United States

                Reviewed by: Chengqi Yi, Peking University, China; Chao Xu, University of Toronto, Canada

                *Correspondence: Cintia F. Hongay, Chongay@ 123456clarkson.edu

                This article was submitted to Epigenomics and Epigenetics, a section of the journal Frontiers in Genetics

                Article
                10.3389/fgene.2019.00987
                6862867
                e631cb29-820e-413e-8184-6f80c295c79f
                Copyright © 2019 Rockwell and Hongay

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 14 June 2019
                : 17 September 2019
                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 54, Pages: 7, Words: 3247
                Funding
                Funded by: National Institute of General Medical Sciences 10.13039/100000057
                Categories
                Genetics
                Review

                Genetics
                m6a effector,profiling,ime4,alternative splicing,rna processing alterations
                Genetics
                m6a effector, profiling, ime4, alternative splicing, rna processing alterations

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