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RNA modifications: what have we learned and where are we headed?

Nature Reviews Genetics volume 17, pages 365–372 (2016)Cite this article

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Abstract

Proper control of the transcriptome is key for diverse aspects of gene expression, cellular functions and development, and its disruption can result in disease. A rapidly accumulating wealth of studies are identifying and functionally characterizing diverse types of RNA base modifications in protein-coding and non-coding RNAs, which have energized the emerging field of 'epitranscriptomics'. In this Viewpoint article, five experts discuss our latest understanding of RNA modifications, including recommendations for best practices and visions for the future.

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References

  1. Machnicka, M. A. et al. MODOMICS: a database of RNA modification pathways — 2013 update. Nucleic Acids Res. 41, D262–D267 (2013).

    Article  CAS  Google Scholar 

  2. Dominissini, D. et al. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature 485, 201–206 (2012).

    Article  CAS  Google Scholar 

  3. Meyer, K. D. et al. Comprehensive analysis of mRNA methylation reveals enrichment in 3′ UTRs and near stop codons. Cell 149, 1635–1646 (2012).

    Article  CAS  Google Scholar 

  4. Squires, J. E. et al. Widespread occurrence of 5-methylcytosine in human coding and non-coding RNA. Nucleic Acids Res. 40, 5023–5033 (2012).

    Article  CAS  Google Scholar 

  5. Carlile, T. M. et al. Pseudouridine profiling reveals regulated mRNA pseudouridylation in yeast and human cells. Nature 515, 143–146 (2014).

    Article  CAS  Google Scholar 

  6. Schwartz, S. et al. Transcriptome-wide mapping reveals widespread dynamic-regulated pseudouridylation of ncRNA and mRNA. Cell 159, 148–162 (2014).

    Article  CAS  Google Scholar 

  7. Linder, B. et al. Single-nucleotide-resolution mapping of m6A and m6Am throughout the transcriptome. Nat. Methods 12, 767–772 (2015).

    Article  CAS  Google Scholar 

  8. Meyer, K. D. et al. 5′ UTR m6A promotes cap-independent translation. Cell 163, 999–1010 (2015).

    Article  CAS  Google Scholar 

  9. Grosjean, H. (ed) Fine-Tuning of RNA Functions by Modification and Editing (Springer-Verlag, 2005).

    Book  Google Scholar 

  10. Levanon, E. Y. et al. Systematic identification of abundant A-to-I editing sites in the human transcriptome. Nat. Biotechnol. 22, 1001–1005 (2004).

    Article  CAS  Google Scholar 

  11. Fu, Y., Dominissini, D., Rechavi, G. & He, C. Gene expression regulation mediated through reversible m6A RNA methylation. Nat. Rev. Genet. 15, 293–306 (2014).

    Article  CAS  Google Scholar 

  12. Meyer, K. D. & Jaffrey, S. R. The dynamic epitranscriptome: N6-methyladenosine and gene expression control. Nat. Rev. Mol. Cell Biol. 15, 313–326 (2014).

    Article  CAS  Google Scholar 

  13. Wang, X. et al. N6-methyladenosine-dependent regulation of messenger RNA stability. Nature 505, 117–120 (2014).

    Article  Google Scholar 

  14. Jia, G. et al. N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat. Chem. Biol. 7, 885–887 (2011).

    Article  CAS  Google Scholar 

  15. Dominissini, D. et al. The dynamic N1-methyladenosine methylome in eukaryotic messenger RNA Nature 530, 441–446 (2016).

    Article  CAS  Google Scholar 

  16. Alarcón, C. R. et al. HNRNPA2B1 is a mediator of m6A-dependent nuclear RNA processing events. Cell 162, 1299–1308 (2015).

    Article  Google Scholar 

  17. Liu, N. et al. N6-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions. Nature 518, 560–564 (2015).

    Article  CAS  Google Scholar 

  18. Rice, G. I. et al. Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature. Nat. Genet. 44, 1243–1248 (2012).

    Article  CAS  Google Scholar 

  19. Batista, P. J. et al. m6A RNA modification controls cell fate transition in mammalian embryonic stem cells. Cell Stem Cell 15, 707–719 (2014).

    Article  CAS  Google Scholar 

  20. Geula, S. et al. m6A mRNA methylation facilitates resolution of naive pluripotency toward differentiation. Science 347, 1002–1006 (2015).

    Article  CAS  Google Scholar 

  21. Dominissini, D., Moshitch-Moshkovitz, S., Amariglio, N. & Rechavi, G. Adenosine-to-inosine RNA editing meets cancer. Carcinogenesis. 32, 1569–1577 (2011).

    Article  CAS  Google Scholar 

  22. Roundtree, I. A. & He, C. RNA epigenetics-chemical messages for posttranscriptional gene regulation. Curr. Opin. Chem. Biol. 30, 46–51 (2016).

    Article  CAS  Google Scholar 

  23. Kietrys, A. M. & Kool, E. T. Epigenetics: a new methyl mark on messengers. Nature 530, 423–424 (2016).

    Article  Google Scholar 

  24. Karijolich, J., Yi, C. & Yu, Y. T. Transcriptome-wide dynamics of RNA pseudouridylation. Nat. Rev. Mol. Cell Biol. 16, 581–585 (2015).

    Article  CAS  Google Scholar 

  25. Shafik, A., Schumann, U., Evers, M., Sibbritt, T. & Preiss, T. The emerging epitranscriptomics of long noncoding RNAs. Biochim. Biophys. Acta 1859, 59–70 (2016).

    Article  CAS  Google Scholar 

  26. Torres, A. G., Batlle, E. & Ribas de Pouplana, L. Role of tRNA modifications in human diseases. Trends Mol. Med. 20, 306–314 (2014).

    Article  CAS  Google Scholar 

  27. Suzuki, T., Nagao, A. & Suzuki, T. Human mitochondrial tRNAs: biogenesis, function, structural aspects, and diseases. Annu. Rev. Genet. 45, 299–329 (2011).

    Article  CAS  Google Scholar 

  28. Kircher, M. & Kelso, J. High-throughput DNA sequencing — concepts and limitations. Bioessays 32, 524–536 (2010).

    Article  CAS  Google Scholar 

  29. Hussain, S., Aleksic, J., Blanco, S., Dietmann, S. & Frye, M. Characterizing 5-methylcytosine in the mammalian epitranscriptome. Genome Biol. 14, 215 (2013).

    Article  Google Scholar 

  30. Hauenschild, R. et al. The reverse transcription signature of N-1-methyladenosine in RNA-Seq is sequence dependent. Nucleic Acids Res. 43, 9950–9964 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Khoddami, V. & Cairns, B. R. Identification of direct targets and modified bases of RNA cytosine methyltransferases. Nat. Biotechnol. 31, 458–464 (2013).

    Article  CAS  Google Scholar 

  32. Yue, Y., Liu, J. & He, C. RNA N6-methyladenosine methylation in post-transcriptional gene expression regulation. Genes Dev. 29, 1343–1355 (2015).

    Article  CAS  Google Scholar 

  33. Sugimoto, Y. et al. Analysis of CLIP and iCLIP methods for nucleotide-resolution studies of protein-RNA interactions. Genome Biol. 13, R67 (2012).

    Article  Google Scholar 

  34. Hussain, S. et al. NSun2-mediated cytosine-5 methylation of vault noncoding RNA determines its processing into regulatory small RNAs. Cell Rep. 4, 255–261 (2013).

    Article  CAS  Google Scholar 

  35. Behm-Ansmant, I., Helm, M. & Motorin, Y. Use of specific chemical reagents for detection of modified nucleotides in RNA. J. Nucleic Acids 2011, 408053 (2011).

    Article  Google Scholar 

  36. Schwartz, S. et al. High-resolution mapping reveals a conserved, widespread, dynamic mRNA methylation program in yeast meiosis. Cell 155, 1409–1421 (2013).

    Article  CAS  Google Scholar 

  37. Ke, S. et al. A majority of m6A residues are in the last exons, allowing the potential for 3′ UTR regulation. Genes Dev. 29, 2037–2053 (2015).

    Article  CAS  Google Scholar 

  38. Pickrell, J. K., Gilad, Y. & Pritchard, J. K. Comment on “Widespread RNA & DNA sequence differences in the human transcriptome”. Science 335, 1302 (2012).

    Article  CAS  Google Scholar 

  39. Sakurai, M., Yano, T., Kawabata, H., Ueda, H. & Suzuki, T. Inosine cyanoethylation identifies A-to-I RNA editing sites in the human transcriptome. Nat. Chem. Biol. 6, 733–740 (2010).

    Article  CAS  Google Scholar 

  40. Tuorto, F. et al. RNA cytosine methylation by Dnmt2 and NSun2 promotes tRNA stability and protein synthesis. Nat. Struct. Mol. Biol. 19, 900–905 (2012).

    Article  CAS  Google Scholar 

  41. Blanco, S. et al. Aberrant methylation of tRNAs links cellular stress to neuro-developmental disorders. EMBO J. 33, 2020–2039 (2014).

    Article  CAS  Google Scholar 

  42. Schaefer, M. et al. RNA methylation by Dnmt2 protects transfer RNAs against stress-induced cleavage. Genes Dev. 24, 1590–1595 (2010).

    Article  CAS  Google Scholar 

  43. Wei, C., Gershowitz, A. & Moss, B. N6, O2′-dimethyladenosine a novel methylated ribonucleoside next to the 5′ terminal of animal cell and virus mRNAs. Nature 257, 251–253 (1975).

    Article  CAS  Google Scholar 

  44. O'Connell, M. R. et al. Programmable RNA recognition and cleavage by CRISPR/Cas9. Nature 516, 263–266 (2014).

    Article  CAS  Google Scholar 

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Acknowledgements

S.R.J. is supported by US National Institutes of Health (NIH) grants R01DA037755 and R01CA186702. T.P. is supported by NIH grant R01GM113194. G.R. acknowledges D.Dominissini, S. Moshitch-Moshkovitz and N. Amariglio for helpful discussions and comments. G.R is supported by the Kahn Family Foundation, the Flight Attendant Medical Research Institute (FAMRI), Israel Science Foundation (ISF grant no. 1667/12), Israeli Centers of Excellence (I-CORE) Program (ISF grants no. 41/11 and no. 1796/12), the Sagol Neuroscience Network and the Teva National Network of Excellence in Neuroscience. T.S. is supported by Grants-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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Authors and Affiliations

  1. Wellcome Trust – Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Tennis Court Road, CB2 1QR, Cambridge, UK

    Michaela Frye

  2. Department of Pharmacology, Weill Cornell Medical College, Cornell University, New York City, 10065, New York, USA

    Samie R. Jaffrey

  3. Department of Biochemistry and Molecular Biology, The University of Chicago, 929 East 57th Street, Chicago, 60637, Illinois, USA

    Tao Pan

  4. Cancer Research Center, Chaim Sheba Medical Center, Tel Hashomer 52621, Israel,

    Gideon Rechavi

  5. and the Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.,

    Gideon Rechavi

  6. Department of Chemistry and Biotechnology, Graduate School of Engineering, University of Tokyo, 113–8656, Tokyo, Japan

    Tsutomu Suzuki

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  1. Michaela Frye
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  4. Gideon Rechavi
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  5. Tsutomu Suzuki
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Corresponding authors

Correspondence to Michaela Frye, Samie R. Jaffrey, Tao Pan, Gideon Rechavi or Tsutomu Suzuki.

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Frye, M., Jaffrey, S., Pan, T. et al. RNA modifications: what have we learned and where are we headed?. Nat Rev Genet 17, 365–372 (2016). https://doi.org/10.1038/nrg.2016.47

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