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The dynamic epitranscriptome: N6-methyladenosine and gene expression control

Key Points

  • Two recent independent studies demonstrated that N6-methyladenosine (m6A) is a widespread base modification in the mammalian transcriptome, which exhibits a unique enrichment near the stop codon and in the untranslated regions (UTRs) of mRNAs.

  • Recent studies have identified methyltransferase-like 3 (METTL3), METTL14 and Wilms tumour 1-associated protein (WTAP) as components of an m6A methyltransferase complex. Further characterization of this complex will be needed to understand the dynamics and specificity of adenosine methylation in various classes of cellular RNA.

  • FTO (fat mass and obesity-associated protein) and ALKBH5 (α-ketoglutarate-dependent dioxygenase alkB homologue 5) are the two m6A demethylating enzymes identified to date. Based on studies of the mRNA targeting specificity and tissue-specific expression patterns of these enzymes, however, it is likely that additional m6A demethylases exist.

  • m6A probably functions by recruiting m6A binding proteins, which influence RNA processing and regulation. Although a small number of m6A-binding proteins have been identified, much work remains to understand the full repertoire of m6A-binding proteins and how they contribute to mRNA regulation.

  • Although m6A probably has many functions, studies so far suggest that it has a role in splicing regulation and mRNA stability.

Abstract

N6-methyladenosine (m6A) is a modified base that has long been known to be present in non-coding RNAs, ribosomal RNA, polyadenylated RNA and at least one mammalian mRNA. However, our understanding of the prevalence of this modification has been fundamentally redefined by transcriptome-wide m6A mapping studies, which have shown that m6A is present in a large subset of the transcriptome in specific regions of mRNA. This suggests that mRNA may undergo post-transcriptional methylation to regulate its fate and function, which is analogous to methyl modifications in DNA. Thus, the pattern of methylation constitutes an mRNA 'epitranscriptome'. The identification of adenosine methyltransferases ('writers'), m6A demethylating enzymes ('erasers') and m6A-binding proteins ('readers') is helping to define cellular pathways for the post-transcriptional regulation of mRNAs.

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Figure 1: Spatially distinct pools of N6-methyladenosine in mRNAs.
Figure 2: N6-methyladenosine methylation and demethylation pathways.
Figure 3: Mechanisms and functions of N6-methyladenosine.

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Acknowledgements

The authors thank O. Elemento and members of the Jaffrey laboratory for helpful comments and suggestions. This work was supported by US National Institutes of Health (NIH) grant R01 DA037150 (S.R.J.) and the Revson Senior Fellowship in Biomedical Sciences to K.D.M.

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Correspondence to Samie R. Jaffrey.

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Glossary

Non-coding RNAs

(ncRNAs). RNAs that are not translated into proteins. They include functional RNAs such as tRNAs, microRNAs and long ncRNAs.

Ribosomal RNA

(rRNA). A highly abundant species of cellular RNA that functions in complex with ribosomes to mediate mRNA translation.

Small nucleolar RNAs

(snoRNAs). This class of RNAs primarily functions to guide chemical modification of other RNAs, such as ribosomal RNAs, small nuclear RNAs and transfer RNAs.

Zero-mode waveguides

Nanostructures with highly confined optical observation volumes.

Nuclear speckles

Small, dynamic, subnuclear structures that are enriched in pre-mRNA splicing factors.

Small nuclear RNAs

(snRNAs). RNAs that associate with specific proteins and that are frequently involved in pre-mRNA processing events such as splicing.

Fe(II)- and 2-oxoglutarate dependent oxygenases

(Fe(II)/2-OG-dependent oxygenases). A family of proteins that catalyses cellular oxidative reactions, most notably hydroxylation. Several members of this family are involved in nucleic acid demethylation.

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Meyer, K., Jaffrey, S. The dynamic epitranscriptome: N6-methyladenosine and gene expression control. Nat Rev Mol Cell Biol 15, 313–326 (2014). https://doi.org/10.1038/nrm3785

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