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Post-transcriptional gene regulation by mRNA modifications

Nature Reviews Molecular Cell Biology volume 18, pages 31–42 (2017)Cite this article

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A Publisher Correction to this article was published on 19 October 2018

Key Points

  • N6-methyladenosine (m6A) is a prevalent post-transcriptional modification in mammalian mRNA. m6A is enriched in consensus sequences within long exons, near stop codons and at the 3′ untranslated regions (3′ UTRs).

  • m6A is the first confirmed reversible mRNA modification with dedicated methyltransferases, demethylases and binding (effector) proteins. To date, four components of the m6A methyltransferase complex, two m6A demethylases and several m6A-binding proteins have been identified in mammals.

  • m6A exerts its effects by directly recruiting effector proteins or by modulating RNA secondary structures, which modulate mRNA metabolism, including maturation, translation and decay. There is evidence to indicate that methylated transcripts can be sorted to synchronously fast track their metabolism.

  • m6A has regulatory roles in many cellular processes, including circadian rhythm maintenance, stem cell differentiation and stress responses. m6A may facilitate cell-state transitions by regulating the metabolism of transcripts of key transcription factors.

  • In addition to m6A, other modifications exist in mammalian mRNA, including N1-methyladenosine (m1A), 5-methylcytosine (m5C), pseudouridine and 2′-O-methylation (2′OMe). This collection of chemical modifications modulates nearly all aspects of RNA metabolism and related physiological processes, adding another layer to the already complex gene expression regulation pathways in eukaryotes, particularly in mammals.

Abstract

The recent discovery of reversible mRNA methylation has opened a new realm of post-transcriptional gene regulation in eukaryotes. The identification and functional characterization of proteins that specifically recognize RNA N6-methyladenosine (m6A) unveiled it as a modification that cells utilize to accelerate mRNA metabolism and translation. N6-adenosine methylation directs mRNAs to distinct fates by grouping them for differential processing, translation and decay in processes such as cell differentiation, embryonic development and stress responses. Other mRNA modifications, including N1-methyladenosine (m1A), 5-methylcytosine (m5C) and pseudouridine, together with m6A form the epitranscriptome and collectively code a new layer of information that controls protein synthesis.

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Figure 1: The writer, eraser and reader proteins of m6A.
Figure 2: m6A-dependent mRNA processing promotes translation and decay, and affects splicing.
Figure 3: m6A affects mouse embryonic stem cell differentiation.
Figure 4: m6A and other mRNA post-transcriptional modifications.
Figure 5: m6A synchronizes mRNA processing in response to various internal and external stimuli.

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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  PubMed  Google Scholar 

  2. Desrosiers, R., Friderici, K. & Rottman, F. Identification of methylated nucleosides in messenger RNA from Novikoff hepatoma cells. Proc. Natl Acad. Sci. USA 71, 3971–3975 (1974).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Perry, R. P. & Kelley, D. E. Existence of methylated messenger RNA in mouse L cells. Cell 1, 37–42 (1974). References 2 and 3 present the first reports of the existence of m6A in the internal region of mRNA.

    Article  CAS  Google Scholar 

  4. Lavi, S. & Shatkin, A. J. Methylated simian virus 40-specific RNA from nuclei and cytoplasm of infected BSC-1 cells. Proc. Natl Acad. Sci. USA 72, 2012–2016 (1975).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Wei, C. M. & Moss, B. Methylated nucleotides block 5′-terminus of vaccinia virus messenger-RNA. Proc. Natl Acad. Sci. USA 72, 318–322 (1975).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Furuichi, Y. et al. Methylated, blocked 5′ termini in HeLa cell mRNA. Proc. Natl Acad. Sci. USA 72, 1904–1908 (1975).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Adams, J. M. & Cory, S. Modified nucleosides and bizarre 5′-termini in mouse myeloma mRNA. Nature 255, 28–33 (1975).

    Article  CAS  PubMed  Google Scholar 

  8. Dubin, D. T. & Taylor, R. H. The methylation state of poly A-containing messenger RNA from cultured hamster cells. Nucleic Acids Res. 2, 1653–1668 (1975).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Nichols, J. L. N6-methyladenosine in maize poly(A)-containing RNA. Plant Sci. Lett. 15, 357–361 (1979).

    Article  CAS  Google Scholar 

  10. Kennedy, T. D. & Lane, B. G. Wheat embryo ribonucleates. XIII. Methyl-substituted nucleoside constituents and 5′-terminal dinucleotide sequences in bulk poly(AR)-rich RNA from imbibing wheat embryos. Can. J. Biochem. 57, 927–931 (1979).

    Article  CAS  PubMed  Google Scholar 

  11. Haugland, R. A. & Cline, M. G. Post-transcriptional modifications of oat coleoptile ribonucleic acids. 5′-Terminal capping and methylation of internal nucleosides in poly(A)-rich RNA. Eur. J. Biochem. 104, 271–277 (1980).

    Article  CAS  PubMed  Google Scholar 

  12. Zhong, S. L. et al. MTA is an Arabidopsis messenger RNA adenosine methylase and interacts with a homolog of a sex-specific splicing factor. Plant Cell 20, 1278–1288 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Horowitz, S., Horowitz, A., Nilsen, T. W., Munns, T. W. & Rottman, F. M. Mapping of N6-methyladenosine residues in bovine prolactin mRNA. Proc. Natl Acad. Sci. USA 81, 5667–5671 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Bokar, J. A. in Fine-Tuning of RNA Functions by Modification and Editing (ed. Grosjean, H.) 141–177 (Springer Berlin Heidelberg, 2005).

    Book  Google Scholar 

  15. Desrosiers, R., Friderici, K. & Rottman, F. Characterization of Novikoff hepatoma messenger-RNA methylation. Fed. Proc. 34, 628 (1975).

    Google Scholar 

  16. Perry, R. P., Kelley, D. E., Friderici, K. & Rottman, F. Methylated constituents of L cell messenger-RNA — evidence for an unusual cluster at 5′ terminus. Cell 4, 387–394 (1975).

    Article  CAS  PubMed  Google Scholar 

  17. Perry, R. P., Kelley, D. E., Friderici, K. H. & Rottman, F. M. Methylated constituents of heterogeneous nuclear-RNA — presence in blocked 5′ terminal structures. Cell 6, 13–19 (1975).

    Article  CAS  PubMed  Google Scholar 

  18. Wei, C. M., Gershowitz, A. & Moss, B. Methylated nucleotides block 5′ terminus of HeLa cell messenger RNA. Cell 4, 379–386 (1975).

    Article  CAS  PubMed  Google Scholar 

  19. Dimock, K. & Stoltzfus, C. M. Sequence specificity of internal methylation in B77 avian sarcoma virus RNA subunits. Biochemistry 16, 471–478 (1977).

    Article  CAS  PubMed  Google Scholar 

  20. Beemon, K. & Keith, J. Localization of N6-methyladenosine in the Rous sarcoma virus genome. J. Mol. Biol. 113, 165–179 (1977).

    Article  CAS  PubMed  Google Scholar 

  21. Furuichi, Y., Shatkin, A. J., Stavnezer, E. & Bishop, J. M. Blocked, methylated 5′-terminal sequence in avian sarcoma virus RNA. Nature 257, 618–620 (1975).

    Article  CAS  PubMed  Google Scholar 

  22. Sommer, S. et al. The methylation of adenovirus-specific nuclear and cytoplasmic RNA. Nucleic Acids Res. 3, 749–765 (1976).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Canaani, D., Kahana, C., Lavi, S. & Groner, Y. Identification and mapping of N6-methyladenosine containing sequences in simian virus 40 RNA. Nucleic Acids Res. 6, 2879–2899 (1979).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kowalak, J. A., Dalluge, J. J., McCloskey, J. A. & Stetter, K. O. The role of posttranscriptional modification in stabilization of transfer RNA from hyperthermophiles. Biochemistry 33, 7869–7876 (1994).

    Article  CAS  PubMed  Google Scholar 

  25. Grosjean, H., Gupta, R. & Maxwell, E. S. in Archaea: New Models for Prokaryotic Biology (ed. Blum, P.) 171–196 (Norfolk Caister Academic Press, 2008).

    Google Scholar 

  26. Deng, X. et al. Widespread occurrence of N6-methyladenosine in bacterial mRNA. Nucleic Acids Res. 43, 6557–6567 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Krug, R. M., Morgan, M. A. & Shatkin, A. J. Influenza viral mRNA contains internal N6-methyladenosine and 5′-terminal 7-methylguanosine in cap structures. J. Virol. 20, 45–53 (1976).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Rottman, F., Shatkin, A. J. & Perry, R. P. Sequences containing methylated nucleotides at the 5′ termini of messenger RNAs: possible implications for processing. Cell 3, 197–199 (1974).

    Article  CAS  PubMed  Google Scholar 

  29. Bodi, Z., Button, J. D., Grierson, D. & Fray, R. G. Yeast targets for mRNA methylation. Nucleic Acids Res. 38, 5327–5335 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Narayan, P. & Rottman, F. M. in Advances in Enzymology and Related Areas of Molecular Biology Vol. 65 (ed. Nord, F.F.) 255–285 (John Wiley & Sons, 2006).

    Book  Google Scholar 

  31. Kane, S. E. & Beemon, K. Precise localization of m6A in Rous-sarcoma virus-RNA reveals clustering of methylation sites — implications for RNA processing. Mol. Cell. Biol. 5, 2298–2306 (1985). The first work reporting the consensus sequence of N6-adenosine methylation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Narayan, P. & Rottman, F. M. An in vitro system for accurate methylation of internal adenosine residues in messenger RNA. Science 242, 1159–1162 (1988).

    Article  CAS  PubMed  Google Scholar 

  33. Csepany, T., Lin, A., Baldick, C. J. Jr & Beemon, K. Sequence specificity of mRNA N6-adenosine methyltransferase. J. Biol. Chem. 265, 20117–20122 (1990).

    CAS  PubMed  Google Scholar 

  34. Narayan, P., Ludwiczak, R. L., Goodwin, E. C. & Rottman, F. M. Context effects on N6-adenosine methylation sites in prolactin mRNA. Nucleic Acids Res. 22, 419–426 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Bokar, J. A., Rath-Shambaugh, M. E., Ludwiczak, R., Narayan, P. & Rottman, F. Characterization and partial purification of mRNA N6-adenosine methyltransferase from HeLa cell nuclei. Internal mRNA methylation requires a multisubunit complex. J. Biol. Chem. 269, 17697–17704 (1994).

    CAS  PubMed  Google Scholar 

  36. Bokar, J. A., Shambaugh, M. E., Polayes, D., Matera, A. G. & Rottman, F. M. Purification and cDNA cloning of the AdoMet-binding subunit of the human mRNA (N6-adenosine)-methyltransferase. RNA 3, 1233–1247 (1997). Pinpoints METTL3 as a key catalytic component of the m6A methyltransferase complex.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Liu, J. Z. et al. A METTL3–METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation. Nat. Chem. Biol. 10, 93–95 (2014). Characterizes the m6A methyltransferase complex comprising METTL3, METTL14 and WTAP as key components.

    Article  CAS  PubMed  Google Scholar 

  38. Wang, Y. et al. N6-methyladenosine modification destabilizes developmental regulators in embryonic stem cells. Nat. Cell Biol. 16, 191–198 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Ping, X.-L. et al. Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase. Cell Res. 24, 177–189 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Schwartz, S. et al. Perturbation of m6A writers reveals two distinct classes of mRNA methylation at internal and 5′ sites. Cell Rep. 8, 284–296 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Agarwala, S. D., Blitzblau, H. G., Hochwagen, A. & Fink, G. R. RNA methylation by the MIS complex regulates a cell fate decision in yeast. PLoS Genet. 8, e1002732 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. He, C. Grand challenge commentary: RNA epigenetics? Nat. Chem. Biol. 6, 863–865 (2010).

    Article  CAS  PubMed  Google Scholar 

  43. Jia, G. F. et al. N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat. Chem. Biol. 7, 885–887 (2011). Reports the discovery of the first m6A demethylase, FTO, thereby demonstrating m6A as the first reversible RNA modification and suggesting it has biological functions.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Zheng, G. Q. et al. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol. Cell 49, 18–29 (2013). Reports the second mammalian m6A demethylase ALKBH5 and its involvement in mouse spermatogenesis.

    Article  CAS  PubMed  Google Scholar 

  45. Gerken, T. et al. The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Science 318, 1469–1472 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Hess, M. E. et al. The fat mass and obesity associated gene (Fto) regulates activity of the dopaminergic midbrain circuitry. Nat. Neurosci. 16, 1042–1048 (2013).

    Article  CAS  PubMed  Google Scholar 

  47. Cheung, M. K., Gulati, P., O'Rahilly, S. & Yeo, G. S. H. FTO expression is regulated by availability of essential amino acids. Int. J. Obes. 37, 744–747 (2013).

    Article  CAS  Google Scholar 

  48. Vujovic, P. et al. Fasting induced cytoplasmic Fto expression in some neurons of rat hypothalamus. PLoS ONE 8, e63694 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Dominissini, D. et al. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature 485, 201–206 (2012). The first report of transcriptome-wide m6A distribution, identifying enrichment in long exons, near stop codons and at 3′ UTRs, and suggesting several RBPs as m6A readers.

    Article  CAS  PubMed  Google Scholar 

  50. Meyer, K. D. et al. Comprehensive analysis of mRNA methylation reveals enrichment in 3′ UTRs and near stop codons. Cell 149, 1635–1646 (2012). Together with reference 49, reports pervasive m6A sites in mammalian mRNA and non-coding RNA as a feature of the mammalian transcriptome with a unique distribution pattern within mRNAs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Luo, G. Z. et al. Unique features of the m6A methylome in Arabidopsis thaliana. Nat. Commun. 5, 5630 (2014).

    Article  CAS  PubMed  Google Scholar 

  52. Zhou, J. et al. Dynamic m6A mRNA methylation directs translational control of heat shock response. Nature 526, 591–594 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Liu, N. et al. Probing N6-methyladenosine RNA modification status at single nucleotide resolution in mRNA and long noncoding RNA. RNA 19, 1848–1856 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Chen, K. et al. High-resolution N6-methyladenosine (m6A) map using photo-crosslinking-assisted m6A sequencing. Angew. Chem. Int. Ed. Engl. 54, 1587–1590 (2015).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Ke, S. D. 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  PubMed  PubMed Central  Google Scholar 

  57. 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  PubMed  PubMed Central  Google Scholar 

  58. Sergiev, P. V. et al. N6-methylated adenosine in RNA: from bacteria to humans. J. Mol. Biol. 428, 2134–2145 (2016).

    Article  CAS  PubMed  Google Scholar 

  59. 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  PubMed  Google Scholar 

  60. Wang, X. et al. N6-methyladenosine-dependent regulation of messenger RNA stability. Nature 505, 117–120 (2014). Reports YTHDF2 as the first m6A reader and reveals that it promotes the degradation of target mRNAs.

    Article  PubMed  CAS  Google Scholar 

  61. Wang, X. et al. N6-methyladenosine modulates messenger RNA translation efficiency. Cell 161, 1388–1399 (2015). Characterizes the second m6A reader protein, YTHDF1 and reveals that it promotes translation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Xu, C. et al. Structural basis for selective binding of m6A RNA by the YTHDC1 YTH domain. Nat. Chem. Biol. 10, 927–929 (2014).

    Article  CAS  PubMed  Google Scholar 

  63. Xiao, W. et al. Nuclear m6A reader YTHDC1 regulates mRNA splicing. Mol. Cell 61, 507–519 (2016).

    Article  CAS  PubMed  Google Scholar 

  64. Luo, S. & Tong, L. Molecular basis for the recognition of methylated adenines in RNA by the eukaryotic YTH domain. Proc. Natl Acad. Sci. USA 111, 13834–13839 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Zhu, T. et al. Crystal structure of the YTH domain of YTHDF2 reveals mechanism for recognition of N6-methyladenosine. Cell Res. 24, 1493–1496 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Liu, N. et al. N6-methyladenosine-dependent RNA structural switches regulate RNA–protein interactions. Nature 518, 560–564 (2015). Reports m6A-dependent modulation of RNA secondary structures (m6A switch) and an indirect m6A reader, HNRNPC.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Kierzek, E. & Kierzek, R. The thermodynamic stability of RNA duplexes and hairpins containing N6-alkyladenosines and 2-methylthio-N6-alkyladenosines. Nucleic Acids Res. 31, 4472–4480 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. 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  PubMed  PubMed Central  Google Scholar 

  70. Roost, C. et al. Structure and thermodynamics of N6-methyladenosine in RNA: a spring-loaded base modification. J. Am. Chem. Soc. 137, 2107–2115 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. El Yacoubi, B., Bailly, M. & de Crecy-Lagard, V. Biosynthesis and function of posttranscriptional modifications of transfer RNAs. Annu. Rev. Genet. 46, 69–95 (2012).

    Article  CAS  PubMed  Google Scholar 

  72. Spitale, R. C. et al. Structural imprints in vivo decode RNA regulatory mechanisms. Nature 519, 486–490 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Wan, Y. et al. Landscape and variation of RNA secondary structure across the human transcriptome. Nature 505, 706–709 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Schwartz, S. et al. High-resolution mapping reveals a conserved, widespread, dynamic mRNA methylation program in yeast meiosis. Cell 155, 1409–1421 (2013). Reveals transcriptome-wide m6A dynamics during meiosis in yeast.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Choi, J. et al. N6-methyladenosine in mRNA disrupts tRNA selection and translation-elongation dynamics. Nat. Struct. Mol. Biol. 23, 110–115 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Zhou, K. I. et al. N6-methyladenosine modification in a long noncoding RNA hairpin predisposes its conformation to protein binding. J. Mol. Biol. 428, 822–833 (2016).

    Article  CAS  PubMed  Google Scholar 

  77. Salditt-Georgieff, M. et al. Methyl labeling of HeLa cell hnRNA: a comparison with mRNA. Cell 7, 227–237 (1976).

    Article  CAS  PubMed  Google Scholar 

  78. Carroll, S. M., Narayan, P. & Rottman, F. M. N6-methyladenosine residues in an intron-specific region of prolactin pre-mRNA. Mol. Cell. Biol. 10, 4456–4465 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Stoltzfus, C. M. & Dane, R. W. Accumulation of spliced avian retrovirus mRNA is inhibited in S-adenosylmethionine-depleted chicken embryo fibroblasts. J. Virol. 42, 918–931 (1982).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Geula, S. et al. m6A mRNA methylation facilitates resolution of naïve pluripotency toward differentiation. Science 347, 1002–1006 (2015). Reference 38, 69 and 80 report the effects of m6A in embryonic cell differentiation, with reference 80 providing a thorough demonstration of m6A functions under different stages of differentiation.

    Article  CAS  PubMed  Google Scholar 

  81. Zhao, X. et al. FTO-dependent demethylation of N6-methyladenosine regulates mRNA splicing and is required for adipogenesis. Cell Res. 24, 1403–1419 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Konig, J. et al. iCLIP reveals the function of hnRNP particles in splicing at individual nucleotide resolution. Nat. Struct. Mol. Biol. 17, 909–915 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. David, C. J., Chen, M., Assanah, M., Canoll, P. & Manley, J. L. HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer. Nature 463, 364–368 (2010).

    Article  CAS  PubMed  Google Scholar 

  84. Alarcon, C. R., Lee, H., Goodarzi, H., Halberg, N. & Tavazoie, S. F. N6-methyladenosine marks primary microRNAs for processing. Nature 519, 482–485 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Movassat, M., Crabb, T., Busch, A., Shi, Y. & Hertel, K. Coupling between alternative polyadenylation and alternative splicing is limited to terminal introns. RNA Biol. 13, 646–655 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  86. Molinie, B. et al. m6A-LAIC-seq reveals the census and complexity of the m6A epitranscriptome. Nat. Methods 13, 692–698 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Wickramasinghe, V. O. & Laskey, R. A. Control of mammalian gene expression by selective mRNA export. Nat. Rev. Mol. Cell Biol. 16, 431–442 (2015).

    Article  CAS  PubMed  Google Scholar 

  88. Fustin, J.-M. et al. RNA-methylation-dependent RNA processing controls the speed of the circadian clock. Cell 155, 793–806 (2013). Reports that m6A affects mRNA nuclear processing and regulates the circadian clock.

    Article  CAS  PubMed  Google Scholar 

  89. Lin, S., Choe, J., Du, P., Triboulet, R. & Gregory, R. I. The m6A methyltransferase METTL3 promotes translation in human cancer cells. Mol. Cell 62, 335–345 (2016). Provides molecular evidence of direct regulatory roles of m6A in cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Du, H. et al. YTHDF2 destabilizes m6A-containing RNA through direct recruitment of the CCR4–NOT deadenylase complex. Nat. Commun. 7, 12626 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Brennan, C. M. & Steitz, J. A. HuR and mRNA stability. Cell. Mol. Life Sci. 58, 266–277 (2001).

    Article  CAS  PubMed  Google Scholar 

  93. Grimson, A. et al. MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Mol. Cell 27, 91–105 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Kariko, K., Buckstein, M., Ni, H. & Weissman, D. Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA. Immunity 23, 165–175 (2005).

    Article  CAS  PubMed  Google Scholar 

  95. Koike, N. et al. Transcriptional architecture and chromatin landscape of the core circadian clock in mammals. Science 338, 349–354 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Feillet, C., van der Horst, G. T. J., Levi, F., Rand, D. A. & Delaunay, F. Coupling between the circadian clock and cell cycle oscillators: implication for healthy cells and malignant growth. Front. Neurol. 6, 96 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Aguilo, F. et al. Coordination of m6A mRNA methylation and gene transcription by ZFP217 regulates pluripotency and reprogramming. Cell Stem Cell 17, 689–704 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Merkestein, M. et al. FTO influences adipogenesis by regulating mitotic clonal expansion. Nat. Commun. 6, 6792 (2015).

    Article  CAS  PubMed  Google Scholar 

  99. Zhang, C. et al. Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m6A-demethylation of NANOG mRNA. Proc. Natl Acad. Sci. USA 113, E2047–E2056 (2016). Demonstrates that the m6A demethylase ALKBH5 can be tuned by an intrinsic signalling pathway and provides molecular evidence of direct regulatory roles of m6A in cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006).

    Article  CAS  PubMed  Google Scholar 

  101. Agris, P. F. The importance of being modified: an unrealized code to RNA structure and function. RNA 21, 552–554 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Phizicky, E. M. & Hopper, A. K. tRNA processing, modification, and subcellular dynamics: past, present, and future. RNA 21, 483–485 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Gu, C., Begley, T. J. & Dedon, P. C. tRNA modifications regulate translation during cellular stress. FEBS Lett. 588, 4287–4296 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Wei, F. Y. et al. Cdk5rap1-mediated 2-methylthio modification of mitochondrial tRNAs governs protein translation and contributes to myopathy in mice and humans. Cell Metab. 21, 428–442 (2015).

    Article  CAS  PubMed  Google Scholar 

  105. Dunn, D. B. The occurence of 1-methyladenine in ribonucleic acid. Biochim. Biophys. Acta 46, 198–200 (1961).

    Article  CAS  PubMed  Google Scholar 

  106. Helm, M., Giegé, R. & Florentz, C. A. Watson–Crick base-pair-disrupting methyl group (m1A9) is sufficient for cloverleaf folding of human mitochondrial tRNALys. Biochemistry 38, 13338–13346 (1999).

    Article  CAS  PubMed  Google Scholar 

  107. Sharma, S., Watzinger, P., Kötter, P. & Entian, K.-D. Identification of a novel methyltransferase, Bmt2, responsible for the N-1-methyl-adenosine base modification of 25S rRNA in Saccharomyces cerevisiae. Nucleic Acids Res. 41, 5428–5443 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Li, X. et al. Transcriptome-wide mapping reveals reversible and dynamic N1-methyladenosine methylome. Nat. Chem. Biol. 12, 311–316 (2016). References 108 and 109 describe high-throughput methods to map the transcriptome-wide distribution of m1A.

    Article  CAS  PubMed  Google Scholar 

  110. Zhou, H. et al. m1A and m1G disrupt A-RNA structure through the intrinsic instability of Hoogsteen base pairs. Nat. Struct. Mol. Biol. 23, 803–810 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Schaefer, M., Pollex, T., Hanna, K. & Lyko, F. RNA cytosine methylation analysis by bisulfite sequencing. Nucleic Acids Res. 37, e12 (2009).

    Article  PubMed  CAS  Google Scholar 

  113. Schaefer, M., Hagemann, S., Hanna, K. & Lyko, F. Azacytidine inhibits RNA methylation at DNMT2 target sites in human cancer cell lines. Cancer Res. 69, 8127–8132 (2009).

    Article  CAS  PubMed  Google Scholar 

  114. 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  PubMed  PubMed Central  Google Scholar 

  115. Motorin, Y. & Grosjean, H. Multisite-specific tRNA:m5C-methyltransferase (Trm4) in yeast Saccharomyces cerevisiae: identification of the gene and substrate specificity of the enzyme. RNA 5, 1105–1118 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Goll, M. G. et al. Methylation of tRNAAsp by the DNA methyltransferase homolog Dnmt2. Science 311, 395–398 (2006).

    Article  CAS  PubMed  Google Scholar 

  117. Rai, K. et al. Dnmt2 functions in the cytoplasm to promote liver, brain, and retina development in zebrafish. Genes Dev. 21, 261–266 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Jurkowski, T. P. et al. Human DNMT2 methylates tRNAAsp molecules using a DNA methyltransferase-like catalytic mechanism. RNA 14, 1663–1670 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Brzezicha, B. et al. Identification of human tRNA:m5C methyltransferase catalysing intron-dependent m5C formation in the first position of the anticodon of the pre-tRNALeu(CAA) . Nucleic Acids Res. 34, 6034–6043 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. 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  PubMed  PubMed Central  Google Scholar 

  123. Delatte, B. et al. RNA biochemistry. Transcriptome-wide distribution and function of RNA hydroxymethylcytosine. Science 351, 282–285 (2016).

    Article  CAS  PubMed  Google Scholar 

  124. Fu, L. et al. Tet-mediated formation of 5-hydroxymethylcytosine in RNA. J. Am. Chem. Soc. 136, 11582–11585 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Zhang, H. Y., Xiong, J., Qi, B. L., Feng, Y. Q. & Yuan, B. F. The existence of 5-hydroxymethylcytosine and 5-formylcytosine in both DNA and RNA in mammals. Chem. Commun. (Camb.) 52, 737–740 (2016).

    Article  CAS  Google Scholar 

  126. Huber, S. M. et al. Formation and abundance of 5-hydroxymethylcytosine in RNA. Chembiochem 16, 752–755 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Lane, B. G. in Modification and Editing of RNA (eds Grosjean, H. & Benne, R.) 1–20 (American Society of Microbiology, 1998).

    Book  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Li, X. Y. et al. Chemical pulldown reveals dynamic pseudouridylation of the mammalian transcriptome. Nat. Chem. Biol. 11, 592–597 (2015). References 128–130 describe high-throughput methods to map the transcriptome-wide distribution of pseudouridylation, with references 127 and 128 reporting single-base resolution and reference 129 high sensitivity.

    Article  CAS  PubMed  Google Scholar 

  131. Fernandez, I. S. et al. Unusual base pairing during the decoding of a stop codon by the ribosome. Nature 500, 107–110 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Karijolich, J. & Yu, Y. T. Converting nonsense codons into sense codons by targeted pseudouridylation. Nature 474, 395–398 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Smith, J. D. & Dunn, D. B. An additional sugar component of ribonucleic acids. Biochim. Biophys. Acta 31, 573–575 (1959).

    Article  CAS  PubMed  Google Scholar 

  134. Hall, R. H. Method for isolation of 2′-O-methylribonucleosides and N1-methyladenosine from ribonucleic acid. Biochim. Biophys. Acta 68, 278–283 (1963).

    Article  CAS  Google Scholar 

  135. Cantara, W. A. et al. The RNA modification database, RNAMDB: 2011 update. Nucleic Acids Res. 39, D195–D201 (2011).

    Article  CAS  PubMed  Google Scholar 

  136. Beal, P. A., Maydanovych, O. & Pokharel, S. The chemistry and biology of RNA editing by adenosine deaminases. Nucleic Acids Symp. Ser. (Oxf.) 51, 83–84 (2007).

    Article  CAS  Google Scholar 

  137. Bachellerie, J.-P., Cavaillé, J. & Hüttenhofer, A. The expanding snoRNA world. Biochimie 84, 775–790 (2002).

    Article  CAS  PubMed  Google Scholar 

  138. Cavaillé, J. et al. Identification of brain-specific and imprinted small nucleolar RNA genes exhibiting an unusual genomic organization. Proc. Natl Acad. Sci. USA 97, 14311–14316 (2000).

    Article  PubMed  PubMed Central  Google Scholar 

  139. Kellner, S., Burhenne, J. & Helm, M. Detection of RNA modifications. RNA Biol. 7, 237–247 (2010).

    Article  CAS  PubMed  Google Scholar 

  140. Dong, Z. W. et al. RTL-P: a sensitive approach for detecting sites of 2′-O-methylation in RNA molecules. Nucleic Acids Res. 40, e157 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Aschenbrenner, J. & Marx, A. Direct and site-specific quantification of RNA 2′-O-methylation by PCR with an engineered DNA polymerase. Nucleic Acids Res. 44, 3495–3502 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Birkedal, U. et al. Profiling of ribose methylations in RNA by high-throughput sequencing. Angew. Chem. Int. Ed. Engl. 54, 451–455 (2015).

    CAS  PubMed  Google Scholar 

  143. Chen, T. et al. m6A RNA methylation is regulated by microRNAs and promotes reprogramming to pluripotency. Cell Stem Cell 16, 289–301 (2015).

    Article  CAS  PubMed  Google Scholar 

  144. Bodi, Z. et al. Adenosine methylation in Arabidopsis mRNA is associated with the 3′ end and reduced levels cause developmental defects. Front. Plant Sci. 3, 48 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Wan, Y. et al. Transcriptome-wide high-throughput deep m6A-seq reveals unique differential m6A methylation patterns between three organs in Arabidopsis thaliana. Genome Biol. 16, 272 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  146. Levis, R. & Penman, S. 5′-terminal structures of poly(A)+ cytoplasmic messenger RNA and of poly(A)+ and poly(A)- heterogeneous nuclear RNA of cells of the dipteran Drosophila melanogaster. J. Mol. Biol. 120, 487–515 (1978).

    Article  CAS  PubMed  Google Scholar 

  147. Hongay, C. F. & Orr-Weaver, T. L. Drosophila Inducer of MEiosis 4 (IME4) is required for Notch signaling during oogenesis. Proc. Natl Acad. Sci. USA 108, 14855–14860 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Granadino, B., Campuzano, S. & Sanchez, L. The Drosophila melanogaster fl(2)d gene is needed for the female-specific splicing of Sex-lethal RNA. EMBO J. 9, 2597–2602 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Granadino, B., Penalva, L. O. & Sanchez, L. The gene fl(2)d is needed for the sex-specific splicing of transformer pre-mRNA but not for double-sex pre-mRNA in Drosophila melanogaster. Mol. Gen. Genet. 253, 26–31 (1996).

    Article  CAS  PubMed  Google Scholar 

  150. Walser, C. B. & Lipshitz, H. D. Transcript clearance during the maternal-to-zygotic transition. Curr. Opin. Genet. Dev. 21, 431–443 (2011).

    Article  CAS  PubMed  Google Scholar 

  151. Fischer, J. et al. Inactivation of the Fto gene protects from obesity. Nature 458, 894–898 (2009).

    Article  CAS  PubMed  Google Scholar 

  152. Akilzhanova, A. et al. Genetic profile and determinants of homocysteine levels in Kazakhstan patients with breast cancer. Anticancer Res. 33, 4049–4059 (2013).

    CAS  PubMed  Google Scholar 

  153. Reddy, S. M. et al. Clinical and genetic predictors of weight gain in patients diagnosed with breast cancer. Br. J. Cancer 109, 872–881 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Heiliger, K.-J. et al. Novel candidate genes of thyroid tumourigenesis identified in Trk-T1 transgenic mice. Endocr. Relat. Cancer 19, 409–421 (2012).

    Article  CAS  PubMed  Google Scholar 

  155. Ortega, A. et al. Biochemical function of female-lethal (2)D/Wilms' tumor suppressor-1-associated proteins in alternative pre-mRNA splicing. J. Biol. Chem. 278, 3040–3047 (2003).

    Article  CAS  PubMed  Google Scholar 

  156. Jin, D.-I. et al. Expression and roles of Wilms' tumor 1-associating protein in glioblastoma. Cancer Sci. 103, 2102–2109 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Lin, Y. et al. Association between variations in the fat mass and obesity-associated gene and pancreatic cancer risk: a case–control study in Japan. BMC Cancer 13, 337 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Casalegno-Garduño, R., Schmitt, A., Wang, X., Xu, X. & Schmitt, M. Wilms' tumor 1 as a novel target for immunotherapy of leukemia. Transplant. Proc. 42, 3309–3311 (2010).

    Article  PubMed  CAS  Google Scholar 

  159. Linnebacher, M., Wienck, A., Boeck, I. & Klar, E. Identification of an MSI-H tumor-specific cytotoxic T cell epitope generated by the (–1) frame of U79260(FTO). J. Biomed. Biotechnol. 2010, 841451 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  160. Machiela, M. J. et al. Association of type 2 diabetes susceptibility variants with advanced prostate cancer risk in the Breast and Prostate Cancer Cohort Consortium. Am. J. Epidemiol. 176, 1121–1129 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  161. Long, J. et al. Evaluating genome-wide association study-identified breast cancer risk variants in African-American women. PLoS ONE 8, e58350 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Kaklamani, V. et al. The role of the fat mass and obesity associated gene (FTO) in breast cancer risk. BMC Med. Genet. 12, 52 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Pierce, B. L., Austin, M. A. & Ahsan, H. Association study of type 2 diabetes genetic susceptibility variants and risk of pancreatic cancer: an analysis of PanScan-I data. Cancer Causes Control 22, 877–883 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  164. Zhang, M. et al. The demethylase activity of FTO (fat mass and obesity associated protein) is required for preadipocyte differentiation. PLoS ONE 10, e0133788 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  165. Loos, R. J. & Yeo, G. S. The bigger picture of FTO: the first GWAS-identified obesity gene. Nat. Rev. Endocrinol. 10, 51–61 (2014).

    Article  CAS  PubMed  Google Scholar 

  166. Frayling, T. M. et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316, 889–894 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Wang, L. et al. Variant rs1421085 in the FTO gene contribute childhood obesity in Chinese children aged 3–6 years. Obes. Res. Clin. Pract. 7, e14–e22 (2013).

    Article  PubMed  Google Scholar 

  168. Kalnina, I. et al. Polymorphisms in FTO and near TMEM18 associate with type 2 diabetes and predispose to younger age at diagnosis of diabetes. Gene 527, 462–468 (2013).

    Article  CAS  PubMed  Google Scholar 

  169. Karra, E. et al. A link between FTO, ghrelin, and impaired brain food-cue responsivity. J. Clin. Invest. 123, 3539–3551 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Smemo, S. et al. Obesity-associated variants within FTO form long-range functional connections with IRX3. Nature 507, 371–375 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Kim, H. J. et al. Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature 495, 467–473 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Du, T. et al. An association study of the m6A genes with major depressive disorder in Chinese Han population. J. Affect. Disord. 183, 279–286 (2015).

    Article  CAS  PubMed  Google Scholar 

  173. Milaneschi, Y. et al. The effect of FTO rs9939609 on major depression differs across MDD subtypes. Mol. Psychiatry 19, 960–962 (2014).

    Article  CAS  PubMed  Google Scholar 

  174. Rivera, M. et al. Depressive disorder moderates the effect of the FTO gene on body mass index. Mol. Psychiatry 17, 604–611 (2012).

    Article  CAS  PubMed  Google Scholar 

  175. Samaan, Z. et al. The protective effect of the obesity-associated rs9939609 A variant in fat mass- and obesity-associated gene on depression. Mol. Psychiatry 18, 1281–1286 (2013).

    Article  CAS  PubMed  Google Scholar 

  176. Choudhry, Z. et al. Association between obesity-related gene FTO and ADHD. Obesity (Silver Spring) 21, E738–E744 (2013).

    Article  CAS  Google Scholar 

  177. Sobczyk-Kopciol, A. et al. Inverse association of the obesity predisposing FTO rs9939609 genotype with alcohol consumption and risk for alcohol dependence. Addiction 106, 739–748 (2011).

    Article  PubMed  Google Scholar 

  178. Rowles, J., Wong, M., Powers, R. & Olsen, M. FTO, RNA epigenetics and epilepsy. Epigenetics 7, 1094–1097 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Lichinchi, G. et al. Dynamics of the human and viral m6A RNA methylomes during HIV-1 infection of T cells. Nat. Microbiol. 1, 16011 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Kennedy, Edward, M. et al. Posttranscriptional m6A editing of HIV-1 mRNAs enhances viral gene expression. Cell Host Microbe 19, 675–685 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Song do, K., Lee, H., Oh, J. Y., Hong, Y. S. & Sung, Y. A. FTO gene variants are associated with PCOS susceptibility and hyperandrogenemia in young Korean women. Diabetes Metab. J. 38, 302–310 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  182. Utsch, B. et al. Exclusion of WTAP and HOXA13 as candidate genes for isolated hypospadias. Scand. J. Urol. Nephrol. 37, 498–501 (2003).

    Article  CAS  PubMed  Google Scholar 

  183. Tirumuru, N. et al. N6-methyladenosine of HIV-1 RNA regulates viral infection and HIV-1 Gag protein expression. eLife 5, e15528 (2016). References 180, 181 and 183 report the high-resolution maps of m6A in the HIV genome and the effects of m6A during HIV infection.

    Article  PubMed  PubMed Central  Google Scholar 

  184. Patil, D. P. et al. m6A RNA methylation promotes XIST-mediated transcriptional repression. Nature 537, 369–373 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors apologize to colleagues whose work was not cited owing to space limitations. This research was supported by grants from the US National Institutes of Health (HG008688 and GM071440 to C.H.). C.H. is an investigator of the Howard Hughes Medical Institute (HHMI). B.S.Z. is an HHMI International Student Research Fellow. I.A.R. is supported by a National Research Service Award F30GM117646 from the National Institute of General Medical Sciences of the National Institutes of Health. The Mass Spectrometry Facility of the University of Chicago is funded by the National Science Foundation (CHE-1048528).

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  1. Department of Chemistry, Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, Howard Hughes Medical Institute, The University of Chicago, 929 East 57th Street, Chicago, 60637, Illinois, USA

    Boxuan Simen Zhao, Ian A. Roundtree & Chuan He

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Supplementary information

Supplementary information S1 (box)

N6-methyladenosine in simpler life forms (PDF 151 kb)

Supplementary information S2 (box)

Roles of m6A in RNA species other than mRNAs (PDF 142 kb)

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Glossary

S-Adenosyl methionine

A biochemical cofactor and methyl donor for mRNA N6-methyladenosine methylation and other methyl group transfer processes.

Epitranscriptome

The biochemical features of the transcriptome that are not genetically encoded in the ribonucleotide sequence.

m6A switch

mRNA sequence that adopts a secondary structure in dependence on N6-adenosine methylation.

Alternative polyadenylation

(APA). The alternative use of different polyadenylation sites at 3′ ends of transcripts.

CCR4–NOT complex

The complex multi-subunit carbon catabolite repression 4 (CCR4)–negative on TATA-less (NOT) is one of the major deadenylases in eukaryotic cells.

Clock output genes

A set of genes that are regulated transcriptionally by clock genes; usually they control metabolic processes.

Embryonic priming

The molecular transition of mouse embryonic stem cells from a naive cell state to a more differentiated or primed cell state, resembling transitions that occur during embryonic development in vivo.

Dimroth rearrangement

A rearrangement of 1,2,3-triazoles in which the endocyclic and exocyclic nitrogen atoms change place (here, allowing conversion of N6-methyladenosine to N1-methyladenosine in basic conditions).

Bisulfite treatment

Treatment of nucleic acid with bisulfite to convert cytosine to uracil, leaving 5-methylcytosine unchanged and distinguishable by reverse transcription or PCR.

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Zhao, B., Roundtree, I. & He, C. Post-transcriptional gene regulation by mRNA modifications. Nat Rev Mol Cell Biol 18, 31–42 (2017). https://doi.org/10.1038/nrm.2016.132

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