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  • Perspective
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The importance of physiological and disease contexts in capturing mRNA modifications

Nature Structural & Molecular Biology volume 32, pages 780–789 (2025)Cite this article

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An Author Correction to this article was published on 11 July 2025

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Abstract

The variety of modifications decorating various RNA species has prompted researchers to study messenger RNA (mRNA) modifications that are likely to have, like N6-methyladenosine (m6A), important biological functions. Yet tackling these modifications has proved more complicated than anticipated. In this Perspective, we discuss two major obstacles to progress in epitranscriptomic research: the low abundance of most mRNA modification and the nonspecificity of many mRNA modifiers. We then shift our focus to the removal of mRNA modifications and their upstream regulation, emphasizing the context-dependent nature of epitranscriptomic regulation. We illustrate how specific modifications, such as N1-methyladenosine (m1A) and pseudouridine, are enriched in distinct environments, most notably within mitochondria and in certain physiopathological conditions. By focusing on biological settings in which non-m6A modifications are more abundant, we could deepen our understanding of their precise roles in gene regulation.

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Fig. 1: Major challenges in characterizing mRNA modifications.
Fig. 2: The roles of context in regulating modification machineries.
Fig. 3: The interplay between m6A and chromatin.

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Acknowledgements

We apologize to colleagues whose work could not be cited owing to space constraints. A.P. is supported by the FNRS, the ULB Foundation and the Association Jules Bordet. J.J. is a Chercheur Qualifiée supported by the FNRS. F.F. is a ULB professor, and his work is funded by grants from the FNRS and Télévie, the “Action de Recherche Concertée” (ARC) (AUWB-2018-2023 ULB-No 7), a Walloon Region grant (Win2Wal), FNRS Welbio grants (FNRS-WELBIO-CR-2017A-04 and FNRS-WELBIO-CR-2019A-04R), the FWO and FNRS under the Excellence of Science (EOS O.0020.22/RG3483) programme, the ULB Foundation, the Belgian Foundation against Cancer (FCC 2016-086 FAF-F/2016/872), and H2020-MSCA-ITN ROPES. Supplementary Fig. 1 was created in BioRender. Primac, I. (2025) https://biorender.com/n99g078.

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  1. Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB-Cancer Research Centre, Université libre de Bruxelles (ULB), Institut Jules Bordet, Brussels, Belgium

    Audrey Penning, Jana Jeschke & François Fuks

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  1. Audrey Penning
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A.P. researched data for the Perspective and prepared the figures. A.P., J.J. and F.F. wrote the manuscript.

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Correspondence to François Fuks.

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Penning, A., Jeschke, J. & Fuks, F. The importance of physiological and disease contexts in capturing mRNA modifications. Nat Struct Mol Biol 32, 780–789 (2025). https://doi.org/10.1038/s41594-025-01548-y

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