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Reading, writing and erasing mRNA methylation

Nature Reviews Molecular Cell Biology volume 20, pages 608–624 (2019)Cite this article

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A Publisher Correction to this article was published on 21 August 2023

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Abstract

RNA methylation to form N 6-methyladenosine (m6A) in mRNA accounts for the most abundant mRNA internal modification and has emerged as a widespread regulatory mechanism that controls gene expression in diverse physiological processes. Transcriptome-wide m6A mapping has revealed the distribution and pattern of m6A in cellular RNAs, referred to as the epitranscriptome. These maps have revealed the specific mRNAs that are regulated by m6A, providing mechanistic links connecting m6A to cellular differentiation, cancer progression and other processes. The effects of m6A on mRNA are mediated by an expanding list of m6A readers and m6A writer-complex components, as well as potential erasers that currently have unclear relevance to m6A prevalence in the transcriptome. Here we review new and emerging methods to characterize and quantify the epitranscriptome, and we discuss new concepts — in some cases, controversies — regarding our understanding of the mechanisms and functions of m6A readers, writers and erasers.

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Fig. 1: The m6A mRNA life cycle.
Fig. 2: m6A recruits YTHDF proteins, leading to their phase separation.
Fig. 3: Mechanisms for transcript and site specificity in m6A writing.

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Acknowledgements

The authors thank the members of the Jaffrey laboratory for comments and suggestions.

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Authors and Affiliations

  1. Department of Pharmacology, Weill Medical College, Cornell University, New York, NY, USA

    Sara Zaccara, Ryan J. Ries & Samie R. Jaffrey

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  1. Sara Zaccara
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Contributions

S.Z., R.J.R. and S.R.J. researched data for the review; R.J.R. and S.R.J. made substantial contributions to the discussion of the m6A writer complex; S.Z. and S.R.J. made substantial contributions to the rest of the review; S.Z., R.J.R. and S.R.J. wrote, reviewed and edited the manuscript before submission.

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Correspondence to Samie R. Jaffrey.

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S.R.J. is scientific founder and adviser to Gotham Therapeutics, in which he also owns equity.

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Glossary

Transcriptome turnover

Term used to indicate the rate at which mRNAs are produced and degraded in order to control the final mRNA quantity and quality in a cell.

mRNA looping

A mechanism of interaction between the 3′ UTR of an mRNA and the 5′ UTR of the same mRNA to favour ribosome reloading and a high translation rate.

Liquid–liquid phase separation

(LLPS). Condensation into a dense phase of RNA and proteins that often resembles a liquid droplet and is strictly related to microenvironment conditions, such as pH, temperature and salt concentration.

Low-complexity domain

Regions of a protein in which specific amino acids are over-represented compared with their amino acid proportions found in the proteome.

Stress granules

Membraneless cytoplasmic liquid–liquid phase compartments where RNA and RNA-bound proteins are found under conditions of cellular stress.

P-bodies

Membraneless liquid–liquid phase compartments where RNA and RNA-bound proteins are assembled in order to store and/or degrade the RNA.

RNA granules

RNA- and protein-containing liquid–liquid phase compartments assembled in order to transport RNA to dendrites in neurons.

Allosteric adaptor

A protein that indirectly influences the effects of a second protein on the bound target. In this case, the second protein may directly influence the function of the target.

Exon skipping

A specific mechanism of mRNA splicing used to ‘skip over’ an exon normally included in the processed mRNA. Thus, in this case, the final processed mRNA will not include this exon.

Nuclear speckles

Membraneless compartments enriched in pre-mRNA splicing factors, located in the interchromatin regions of the nucleoplasm and implicated in different aspects of RNA metabolism.

UV crosslinking immunoprecipitation

(CLIP). An antibody-based method used to identify the RNA sites directly bound by RNA-binding proteins.

Ribosome profiling

A method used to determine the ribosome footprints on mRNAs and thus to identify the translating mRNAs.

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Zaccara, S., Ries, R.J. & Jaffrey, S.R. Reading, writing and erasing mRNA methylation. Nat Rev Mol Cell Biol 20, 608–624 (2019). https://doi.org/10.1038/s41580-019-0168-5

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