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      New Insights on the Role of N 6-Methyladenosine RNA Methylation in the Physiology and Pathology of the Nervous System

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          Abstract

          RNA modifications termed epitranscriptomics represent an additional layer of gene regulation similar to epigenetic mechanisms operating on DNA. The dynamic nature and the increasing number of RNA modifications offer new opportunities for a rapid fine-tuning of gene expression in response to specific environmental cues. In cooperation with a diverse and versatile set of effector proteins that “recognize” them, these RNA modifications have the ability to mediate and control diverse fundamental cellular functions, such as pre-mRNA splicing, nuclear export, stability, and translation. N 6-methyladenosine (m 6A) is the most abundant of these RNA modifications, particularly in the nervous system, where recent studies have highlighted it as an important post-transcriptional regulator of physiological functions from development to synaptic plasticity, learning and memory. Here we review recent findings surrounding the role of m 6A modification in regulating physiological responses of the mammalian nervous system and we discuss its emerging role in pathological conditions such as neuropsychiatric and neurodegenerative disorders.

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          Most cited references86

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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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            Rethinking m6A Readers, Writers, and Erasers.

            In recent years, m6A has emerged as an abundant and dynamically regulated modification throughout the transcriptome. Recent technological advances have enabled the transcriptome-wide identification of m6A residues, which in turn has provided important insights into the biology and regulation of this pervasive regulatory mark. Also central to our current understanding of m6A are the discovery and characterization of m6A readers, writers, and erasers. Over the last few years, studies into the function of these proteins have led to important discoveries about the regulation and function of m6A. However, during this time our understanding of these proteins has also evolved considerably, sometimes leading to the reversal of early concepts regarding the reading, writing and erasing of m6A. In this review, we summarize recent advances in m6A research, and we highlight how these new findings have reshaped our understanding of how m6A is regulated in the transcriptome.
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              m6A Modification in Coding and Non-coding RNAs: Roles and Therapeutic Implications in Cancer.

              N6-Methyladenosine (m6A) RNA modification has emerged in recent years as a new layer of regulatory mechanism controlling gene expression in eukaryotes. As a reversible epigenetic modification found not only in messenger RNAs but also in non-coding RNAs, m6A affects the fate of the modified RNA molecules and plays important roles in almost all vital bioprocesses, including cancer development. Here we review the up-to-date knowledge of the pathological roles and underlying molecular mechanism of m6A modifications (in both coding and non-coding RNAs) in cancer pathogenesis and drug response/resistance, and discuss the therapeutic potential of targeting m6A regulators for cancer therapy.
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                Author and article information

                Contributors
                Journal
                Front Mol Biosci
                Front Mol Biosci
                Front. Mol. Biosci.
                Frontiers in Molecular Biosciences
                Frontiers Media S.A.
                2296-889X
                02 September 2020
                2020
                : 7
                : 555372
                Affiliations
                [1] 1Center for Motor Neuron Biology and Disease, Department of Pathology and Cell Biology, Columbia University , New York City, NY, United States
                [2] 2Department of Neurology, Columbia University , New York City, NY, United States
                Author notes

                Edited by: Florence Rage, Délégation Languedoc Roussillon (CNRS), France

                Reviewed by: Sunny Sharma, Rutgers, The State University of New Jersey, United States; Florence Besse, INSERM U1091 Institut de Biologie de Valrose, France

                *Correspondence: Francesco Lotti, fl2219@ 123456columbia.edu

                This article was submitted to Protein and RNA Networks, a section of the journal Frontiers in Molecular Biosciences

                Article
                10.3389/fmolb.2020.555372
                7492240
                6e676f1d-8de9-4325-97a0-233db2ee77f6
                Copyright © 2020 Dermentzaki and Lotti.

                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
                : 24 April 2020
                : 12 August 2020
                Page count
                Figures: 1, Tables: 1, Equations: 0, References: 157, Pages: 13, Words: 0
                Funding
                Funded by: National Institutes of Health 10.13039/100000002
                Award ID: R21NS101575
                Categories
                Molecular Biosciences
                Review

                rna modifications,n6-methyladenosine,m6a,rna metabolism,neurodevelopment,mood disorders,neurodevelopmental disorders,neurodegenerative disorders

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