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The epitranscriptome beyond m6A

Abstract

Following its transcription, RNA can be modified by >170 chemically distinct types of modifications — the epitranscriptome. In recent years, there have been substantial efforts to uncover and characterize the modifications present on mRNA, motivated by the potential of such modifications to regulate mRNA fate and by discoveries and advances in our understanding of N 6-methyladenosine (m6A). Here, we review our knowledge regarding the detection, distribution, abundance, biogenesis, functions and possible mechanisms of action of six of these modifications — pseudouridine (Ψ), 5-methylcytidine (m5C), N 1-methyladenosine (m1A), N 4-acetylcytidine (ac4C), ribose methylations (Nm) and N 7-methylguanosine (m7G). We discuss the technical and analytical aspects that have led to inconsistent conclusions and controversies regarding the abundance and distribution of some of these modifications. We further highlight shared commonalities and important ways in which these modifications differ with respect to m6A, based on which we speculate on their origin and their ability to acquire functions over evolutionary timescales.

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Fig. 1: Sources of false-positive RNA modification detection.
Fig. 2: Statistical considerations for the accurate detection of RNA modifications.
Fig. 3: Schematic secondary structure of a tRNA.
Fig. 4: Mechanisms through which RNA modifications can act.

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Data availability

Data referenced in this study are available in NCBI Gene Expression Omnibus, with the accession codes GSE123365 (ref.59) and GSE112276 (ref.40).

Code availability

The authors declare that the R script supporting Fig. 2 of this study is available within the article’s Supplementary information files.

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Wiener, D., Schwartz, S. The epitranscriptome beyond m6A. Nat Rev Genet 22, 119–131 (2021). https://doi.org/10.1038/s41576-020-00295-8

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