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      Reversible N6-methyladenosine of RNA: The regulatory mechanisms on gene expression and implications in physiology and pathology

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          Abstract

          N6-methyladenosine (m6A) is the most abundant inner RNA modification in eukaryotes. Due to the development of RNA sequencing technology, the distribution pattern of m6A in the transcriptome has been uncovered. Dynamically, the reversible N6-methylation is mediated by two types of proteins, which are classified as “writers” and “erasers”. Under the association of specific co-factors, writers show spatiotemporal N6-methyltransferase activity. Mechanically, m6A can be recognized by “reader” proteins or can directly modify RNA conformation, and it widely affects gene expression by mediating RNA stability, translation, splicing and export. m6A is involved in a series of physiology processes. Dysregulation of m6A is gradually defined as the pathogenesis of some diseases, e.g., cancer and cardiovascular disease. Therefore, a good understanding of m6A is essential for molecular biology and pathology research. In this article we systemically present an overview of the functions and mechanisms of identified m6A regulators. The discovered biological and pathological processes affected by m6A are also summarized. We hope that readers with related research interests benefit from our review.

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          Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq.

          An extensive repertoire of modifications is known to underlie the versatile coding, structural and catalytic functions of RNA, but it remains largely uncharted territory. Although biochemical studies indicate that N(6)-methyladenosine (m(6)A) is the most prevalent internal modification in messenger RNA, an in-depth study of its distribution and functions has been impeded by a lack of robust analytical methods. Here we present the human and mouse m(6)A modification landscape in a transcriptome-wide manner, using a novel approach, m(6)A-seq, based on antibody-mediated capture and massively parallel sequencing. We identify over 12,000 m(6)A sites characterized by a typical consensus in the transcripts of more than 7,000 human genes. Sites preferentially appear in two distinct landmarks--around stop codons and within long internal exons--and are highly conserved between human and mouse. Although most sites are well preserved across normal and cancerous tissues and in response to various stimuli, a subset of stimulus-dependent, dynamically modulated sites is identified. Silencing the m(6)A methyltransferase significantly affects gene expression and alternative splicing patterns, resulting in modulation of the p53 (also known as TP53) signalling pathway and apoptosis. Our findings therefore suggest that RNA decoration by m(6)A has a fundamental role in regulation of gene expression.
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            m6A-dependent regulation of messenger RNA stability

            N6 -methyladenosine (m6A) is the most prevalent internal (non-cap) modification present in the messenger RNA (mRNA) of all higher eukaryotes 1,2 . Although essential to cell viability and development 3–5 , the exact role of m6A modification remains to be determined. The recent discovery of two m6A demethylases in mammalian cells highlighted the importance of m6A in basic biological functions and disease 6–8 . Here we show that m6A is selectively recognized by the human YTH domain family 2 (YTHDF2) protein to regulate mRNA degradation. We identified over 3,000 cellular RNA targets of YTHDF2, most of which are mRNAs, but which also include non-coding RNAs, with a conserved core motif of G(m6A)C. We further establish the role of YTHDF2 in RNA metabolism, showing that binding of YTHDF2 results in the localization of bound mRNA from the translatable pool to mRNA decay sites, such as processing bodies 9 . The C-terminal domain of YTHDF2 selectively binds to m6A-containing mRNA whereas the N-terminal domain is responsible for the localization of the YTHDF2-mRNA complex to cellular RNA decay sites. Our results indicate that the dynamic m6A modification is recognized by selective-binding proteins to affect the translation status and lifetime of mRNA.
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              Comprehensive analysis of mRNA methylation reveals enrichment in 3' UTRs and near stop codons.

              Methylation of the N(6) position of adenosine (m(6)A) is a posttranscriptional modification of RNA with poorly understood prevalence and physiological relevance. The recent discovery that FTO, an obesity risk gene, encodes an m(6)A demethylase implicates m(6)A as an important regulator of physiological processes. Here, we present a method for transcriptome-wide m(6)A localization, which combines m(6)A-specific methylated RNA immunoprecipitation with next-generation sequencing (MeRIP-Seq). We use this method to identify mRNAs of 7,676 mammalian genes that contain m(6)A, indicating that m(6)A is a common base modification of mRNA. The m(6)A modification exhibits tissue-specific regulation and is markedly increased throughout brain development. We find that m(6)A sites are enriched near stop codons and in 3' UTRs, and we uncover an association between m(6)A residues and microRNA-binding sites within 3' UTRs. These findings provide a resource for identifying transcripts that are substrates for adenosine methylation and reveal insights into the epigenetic regulation of the mammalian transcriptome. Copyright © 2012 Elsevier Inc. All rights reserved.

                Author and article information

                Contributors
                Journal
                Genes Dis
                Genes Dis
                Genes & Diseases
                Chongqing Medical University
                2352-4820
                2352-3042
                06 July 2020
                December 2020
                06 July 2020
                : 7
                : 4
                : 585-597
                Affiliations
                [a ]School of Basic Medicine, Qingdao University, Qingdao 266071, China
                [b ]Institute for Translational Medicine, Qingdao University, Qingdao 266021, China
                [c ]Department of Cardiovascular Surgery, Affiliated Hospital, Qingdao University, Qingdao 266510, China
                Author notes
                []Corresponding author. wangjx@ 123456qdu.edu.cn
                [1]

                These authors contributed equally to this work.

                Article
                S2352-3042(20)30084-2
                10.1016/j.gendis.2020.06.011
                7729110
                33335958
                6d023b59-b0ef-4576-af93-c656edc2fc86
                © 2020 Chongqing Medical University. Production and hosting by Elsevier B.V.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 9 May 2020
                : 21 June 2020
                : 30 June 2020
                Categories
                Review Article

                diseases,epigenetics,gene expression,m6a,m6a regulator,rna
                diseases, epigenetics, gene expression, m6a, m6a regulator, rna

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