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Mapping and significance of the mRNA methylome

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Internal methylation of eukaryotic mRNAs in the form of N6‐methyladenosine (m6A) and 5‐methylcytidine (m5C) has long been known to exist, but progress in understanding its role was hampered by difficulties in identifying individual sites. This was recently overcome by high‐throughput sequencing‐based methods that mapped thousands of sites for both modifications throughout mammalian transcriptomes, with most sites found in mRNAs. The topology of m6A in mouse and human revealed both conserved and variable sites as well as plasticity in response to extracellular cues. Within mRNAs, m5C and m6A sites were relatively depleted in coding sequences and enriched in untranslated regions, suggesting functional interactions with post‐transcriptional gene control. Finer distribution analyses and preexisting literature point toward roles in the regulation of mRNA splicing, translation, or decay, through an interplay with RNA‐binding proteins and microRNAs. The methyltransferase (MTase) METTL3 ‘writes’ m6A marks on mRNA, whereas the demethylase FTO can ‘erase’ them. The RNA:m5C MTases NSUN2 and TRDMT1 have roles in tRNA methylation but they also act on mRNA. Proper functioning of these enzymes is important in development and there are clear links to human disease. For instance, a common variant of FTO is a risk allele for obesity carried by 1 billion people worldwide and mutations cause a lethal syndrome with growth retardation and brain deficits. NSUN2 is linked to cancer and stem cell biology and mutations cause intellectual disability. In this review, we summarize the advances, open questions, and intriguing possibilities in this emerging field that might be called RNA modomics or epitranscriptomics. WIREs RNA 2013, 4:437–461. doi: 10.1002/wrna.1166 This article is categorized under: RNA Processing > RNA Editing and Modification RNA in Disease and Development > RNA in Disease RNA in Disease and Development > RNA in Development

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Schematic representation of known eukaryotic mRNA modifications. The internal base modifications m6A and m5C are highlighted as red and green circles, respectively.
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Speculative models for roles of m6A and m5C in mRNA. Pictograms of several plausible molecular consequences of the presence of m5C or m6A (represented by blue circle) are shown along a stylized mRNA. These in turn could affect different aspects of mRNA utilization. Evidence consistent with some of the depicted scenarios has been published and others have been proposed. See main text for details and references.
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Biased distribution of m6A and m5C within mRNAs. (a) Metagene profiles of murine mRNAs displaying m6A distribution in areas near the mRNA 5′ end [transcription start site (TSS); left] and around the stop codon (right). Normalized high‐throughput sequencing (HTS) read coverage from anti‐m6A immunoprecipitation (blue) and input RNA libraries (red) is shown. (Reprinted with permission from Ref Copyright 2012 Nature Publishing Group). (b) Metagene profiles based on human bsRNA‐seq data showing relative enrichment of m5C in the mRNA 5′ and 3′ UTRs and relative depletion within the CDS. UTRs and CDS of each mRNA were divided into an equal number of intervals and the fraction of m5C candidate sites falling into each interval is plotted in blue. The fraction of all cytosines with ≥10 read coverage is plotted as background in red. (Reprinted with permission from Ref Copyright 2012 Oxford University Press)
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The m6A‐ and m5C‐modifying enzymes known to act on mRNA. (a) Schematic representations of the domain structures of the m6A MTase METTL3 and demethylase FTO and (b) the m5C MTases TRDMT1 and NSUN2. Roman numerals refer to secondary structure elements constituting the RFM MTase fold. Elements making up particular enzyme domains or specific amino acid residues are color‐coded as follows: green: AdoMet binding; red: catalytic domain; blue: RNA recognition; and purple: 2‐oxoglutarate (2‐OG) and iron (Fe) binding; see text for details and references. (c) Sequence logo representing the preferred sequence context for m6A in human mRNAs as determined by m6A‐seq mRNA. (Reprinted with permission from Ref Copyright 2012 Nature Publishing Group). (d) Elements recognized by NSUN2 or TRDMT1 in mRNA are not known. Shown are positions in the tRNA cloverleaf structure that are methylated by the two enzymes in animal tRNAs.
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Transcriptome‐wide approaches to map m6A and m5C in RNA. (a) MeRIP‐seq or m6A‐seq employs immunoprecipitation of fragmented RNA using an m6A antibody prior to high‐throughput sequencing (HTS). Peaks representing m6A sites are detected relative to RNA‐seq read coverage generated from input RNA. (b) The bsRNA‐seq uses bisulfite conversion chemistry and HTS to detect m5C sites. After mapping to the reference by allowing ambiguity of C or T positions with sufficiently high coverage and proportion of unconverted cytosines are candidate m5C sites. Bottom panels show examples of m6A sites detected in MAP3K1 mRNA (on left) and an m5C site found in CINP mRNA detected. Sites called as m6A or m5C are indicated above panels by red or green arrows, respectively. (Bottom right image reprinted with permission from Ref 44. Copyright 2012 Nature Publishing Group; bottom left image reprinted with permission from Ref 45. Copyright 2012 Oxford University Press.)
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RNA in Disease and Development > RNA in Disease
RNA Processing > RNA Editing and Modification
RNA in Disease and Development > RNA in Development

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