Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Gene expression regulation mediated through reversible m6A RNA methylation

Key Points

  • RNA modifications may post-transcriptionally regulate RNA stability, localization, transport, splicing and translation.

  • METTL3 and METTL14 catalyse N6-methyladenosine (m6A) methylation of mRNA (and other types of nuclear RNA) both in vitro and in vivo. Wilms' tumour 1-associating protein (WTAP) is another crucial component of this methyltransferase complex.

  • α-ketoglutarate-dependent dioxygenases FTO and ALKBH5 are m6A demethylases of mRNA (and other types of nuclear RNA) that affect biological processes such as development, energy homeostasis and spermatogenesis.

  • Genome-wide mapping of m6A in mRNA reveals that m6A localizes around stop codons and at 3′ untranslated regions in mammals and yeast. The methylation is dynamic and seems to have regulatory roles.

  • The YTHDF domain family proteins preferentially bind to m6A in mRNA. The recognition of m6A in mRNA and other polyadenylated RNA by YTHDF2 reduces the half-lives of its substrate RNAs through processing-body-mediated degradation.

  • RNA methylation directly affects the cell circadian cycle, embryonic stem cell differentiation and yeast meiosis.

  • We propose that the reversible RNA methylation pathway has evolved to regulate processes that involve rapid expression changes of large groups of genes and proteins.

Abstract

Cellular RNAs carry diverse chemical modifications that used to be regarded as static and having minor roles in 'fine-tuning' structural and functional properties of RNAs. In this Review, we focus on reversible methylation through the most prevalent mammalian mRNA internal modification, N6-methyladenosine (m6A). Recent studies have discovered protein 'writers', 'erasers' and 'readers' of this RNA chemical mark, as well as its dynamic deposition on mRNA and other types of nuclear RNA. These findings strongly indicate dynamic regulatory roles that are analogous to the well-known reversible epigenetic modifications of DNA and histone proteins. This reversible RNA methylation adds a new dimension to the developing picture of post-transcriptional regulation of gene expression.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Reversible chemical modifications that regulate the flow of genetic information.
Figure 2: Profiling of m6A in RNA by m6A RNA immunoprecipitation.
Figure 3: Reversible m6A methylation of mRNA and other types of nuclear RNA.
Figure 4: Functions of the reader (that is, effector) proteins of m6A.
Figure 5: RNA methylation could affect various aspects of RNA metabolism and mRNA translation, and regulate protein expression post-transcrptionally.

References

  1. Suzuki, M. M. & Bird, A. DNA methylation landscapes: provocative insights from epigenomics. Nature Rev. Genet. 9, 465–476 (2008).

    Article  CAS  PubMed  Google Scholar 

  2. Kohli, R. M. & Zhang, Y. TET enzymes, TDG and the dynamics of DNA demethylation. Nature 502, 472–479 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Jones, P. A. Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nature Rev. Genet. 13, 484–492 (2012).

    Article  CAS  PubMed  Google Scholar 

  4. Branco, M. R., Ficz, G. & Reik, W. Uncovering the role of 5-hydroxymethylcytosine in the epigenome. Nature Rev. Genet. 13, 7–13 (2012).

    Article  CAS  Google Scholar 

  5. Bhutani, N., Burns, D. M. & Blau, H. M. DNA demethylation dynamics. Cell 146, 866–872 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Strahl, B. D. & Allis, C. D. The language of covalent histone modifications. Nature 403, 41–45 (2000).

    CAS  PubMed  Google Scholar 

  7. Shi, Y. Histone lysine demethylases: emerging roles in development, physiology and disease. Nature Rev. Genet. 8, 829–833 (2007).

    Article  CAS  PubMed  Google Scholar 

  8. Klose, R. J., Kallin, E. M. & Zhang, Y. JmjC-domain-containing proteins and histone demethylation. Nature Rev. Genet. 7, 715–727 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. Bird, A. Molecular biology. Methylation talk between histones and DNA. Science. 294, 2113–2115 (2001).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  11. Grosjean, H. & Benne, R. Modification and Editing of RNA (American Society for Microbiology Press, 1998).

    Book  Google Scholar 

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

    Book  Google Scholar 

  13. 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 

  14. Motorin, Y. & Helm, M. RNA nucleotide methylation. Wiley Interdiscip. Rev. RNA 2, 611–631 (2011).

    Article  CAS  PubMed  Google Scholar 

  15. Jia, G. et al. N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nature Chem. Biol. 7, 885–887 (2011). This work describes a major breakthrough of discovering the first m6A RNA demethylase FTO, which highlights the possible biological function of m6A.

    Article  CAS  Google Scholar 

  16. Zheng, G. et al. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol. Cell 49, 18–29 (2013). This study discovered the second mammalian m6A demethylase ALKBH5 that affects mouse spermatogenesis.

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  18. Meyer, K. D. et al. Comprehensive analysis of mRNA methylation reveals enrichment in 3′ UTRs and near stop codons. Cell 149, 1635–1646 (2012). References 17 and 18 revealed, for the first time, the transcriptome-wide distributions of m6A in mammalian genomes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 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 

  20. 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 

  21. Rottman, F. M., Desrosiers, R. C. & Friderici, K. Nucleotide methylation patterns in eukaryotic mRNA. Prog. Nucleic Acid. Res. Mol. Biol. 19, 21–38 (1976).

    Article  CAS  PubMed  Google Scholar 

  22. 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 

  23. Schibler, U., Kelley, D. E. & Perry, R. P. Comparison of methylated sequences in messenger RNA and heterogeneous nuclear RNA from mouse L cells. J. Mol. Biol. 115, 695–714 (1977).

    Article  CAS  PubMed  Google Scholar 

  24. Wei, C. M. & Moss, B. Nucleotide sequences at the N6-methyladenosine sites of HeLa cell messenger ribonucleic acid. Biochemistry 16, 1672–1676 (1977).

    Article  CAS  PubMed  Google Scholar 

  25. 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 

  26. 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 

  27. 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 

  28. Rottman, F., Shatkin, A. J. & Perry, R. P. Sequences containing methylated nucleotides at 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. Keith, G. Mobilities of modified ribonucleotides on two-dimensional cellulose thin-layer chromatography. Biochimie 77, 142–144 (1995).

    Article  CAS  PubMed  Google Scholar 

  31. Clancy, M. J., Shambaugh, M. E., Timpte, C. S. & Bokar, J. A. Induction of sporulation in Saccharomyces cerevisiae leads to the formation of N6-methyladenosine in mRNA: a potential mechanism for the activity of the IME4 gene. Nucleic Acids Res. 30, 4509–4518 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 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 

  34. 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 

  35. 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 

  36. Harcourt, E. M., Ehrenschwender, T., Batista, P. J., Chang, H. Y. & Kool, E. T. Identification of a selective polymerase enables detection of N6-methyladenosine in RNA. J. Am. Chem. Soc. 135, 19079–19082 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Vilfan, I. D. et al. Analysis of RNA base modification and structural rearrangement by single-molecule real-time detection of reverse transcription. J. Nanobiotechnol. 11, 8 (2013).

    Article  CAS  Google Scholar 

  38. 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). This pivotal study identifies METTL3 as a key SAM-binding subunit of the RNA methyltransferase complex.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Bokar, J. A. in Fine-Tuning of RNA Functions by Modification and Editing 141–177 (Springer-Verlag, 2005).

    Book  Google Scholar 

  40. Liu, J. et al. A METTL3–METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation. Nature Chem. Biol. 10, 93–95 (2014). This paper uncovers the core components of the m6A RNA methyltransferase complex and reveals an overall negative correlation between the levels of m6A mRNA methylation and gene expression.

    Article  CAS  Google Scholar 

  41. Bujnicki, J. M., Feder, M., Radlinska, M. & Blumenthal, R. M. Structure prediction and phylogenetic analysis of a functionally diverse family of proteins homologous to the MT-A70 subunit of the human mRNA:m6A methyltransferase. J. Mol. Evol. 55, 431–444 (2002).

    Article  CAS  PubMed  Google Scholar 

  42. Wang, Y. et al. N6-methyladenosine modification destabilizes developmental regulators in embryonic stem cells. Nature Cell Biol. 16, 191–198 (2014). This study discovered that the m6A modification on mRNA affects embryonic cell differentiation.

    Article  CAS  PubMed  Google Scholar 

  43. Alexandrov, A., Martzen, M. R. & Phizicky, E. M. Two proteins that form a complex are required for 7-methylguanosine modification of yeast tRNA. RNA 8, 1253–1266 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Chujo, T. & Suzuki, T. Trmt61B is a methyltransferase responsible for 1-methyladenosine at position 58 of human mitochondrial tRNAs. RNA 18, 2269–2276 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Ozanick, S., Krecic, A., Andersland, J. & Anderson, J. T. The bipartite structure of the tRNA m1A58 methyltransferase from S. cerevisiae is conserved in humans. RNA 11, 1281–1290 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Leulliot, N. et al. Structure of the yeast tRNA m7G methylation complex. Structure 16, 52–61 (2008).

    Article  CAS  PubMed  Google Scholar 

  47. Zhong, S. 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 

  48. 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 

  49. Little, N. A., Hastie, N. D. & Davies, R. C. Identification of WTAP, a novel Wilms' tumour 1-associating protein. Hum. Mol. Genet. 9, 2231–2239 (2000).

    Article  CAS  PubMed  Google Scholar 

  50. 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 

  51. Horiuchi, K. et al. Identification of Wilms' Tumor 1-associating protein complex and its role in alternative splicing and the cell cycle. J. Biol. Chem. 288, 33292–33302 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. 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 

  53. 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  PubMed  PubMed Central  Google Scholar 

  54. Peters, T., Ausmeier, K. & Ruther, U. Cloning of Fatso (Fto), a novel gene deleted by the Fused toes (Ft) mouse mutation. Mamm. Genome 10, 983–986 (1999).

    Article  CAS  PubMed  Google Scholar 

  55. Dina, C. et al. Variation in FTO contributes to childhood obesity and severe adult obesity. Nature Genet. 39, 724–726 (2007).

    Article  CAS  PubMed  Google Scholar 

  56. 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 

  57. Scuteri, A. et al. Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits. PLoS Genet. 3, e115 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. 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 

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

    Article  CAS  PubMed  Google Scholar 

  60. Church, C. et al. Overexpression of Fto leads to increased food intake and results in obesity. Nature Genet. 42, 1086–1092 (2010).

    Article  CAS  PubMed  Google Scholar 

  61. Boissel, S. et al. Loss-of-function mutation in the dioxygenase-encoding FTO gene causes severe growth retardation and multiple malformations. Am. J. Hum. Genet. 85, 106–111 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. He, Y. F. et al. Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science 333, 1303–1307 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Ito, S. et al. Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science 333, 1300–1303 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Tahiliani, M. et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324, 930–935 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Jia, G. et al. Oxidative demethylation of 3-methylthymine and 3-methyluracil in single-stranded DNA and RNA by mouse and human FTO. FEBS Lett. 582, 3313–3319 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  67. Gulati, P. et al. Role for the obesity-related FTO gene in the cellular sensing of amino acids. Proc. Natl Acad. Sci. USA 110, 2557–2562 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  68. Han, Z. et al. Crystal structure of the FTO protein reveals basis for its substrate specificity. Nature 464, 1205–1209 (2010).

    Article  CAS  PubMed  Google Scholar 

  69. Zheng, G. et al. Sprouts of RNA epigenetics: the discovery of mammalian RNA demethylases. RNA Biol. 10, 915–918 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Baltz, A. G. et al. The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts. Mol. Cell 46, 674–690 (2012).

    Article  CAS  PubMed  Google Scholar 

  71. Fu, Y. et al. FTO-mediated formation of N6-hydroxymethyladenosine and N6-formyladenosine in mammalian RNA. Nature Commun. 4, 1798 (2013).

    Article  CAS  Google Scholar 

  72. Schwanhausser, B. et al. Global quantification of mammalian gene expression control. Nature 473, 337–342 (2011).

    Article  CAS  PubMed  Google Scholar 

  73. Rabani, M. et al. Metabolic labeling of RNA uncovers principles of RNA production and degradation dynamics in mammalian cells. Nature Biotech. 29, 436–442 (2011).

    Article  CAS  Google Scholar 

  74. Robbens, S. et al. The FTO gene, implicated in human obesity, is found only in vertebrates and marine algae. J. Mol. Evol. 66, 80–84 (2008).

    Article  CAS  PubMed  Google Scholar 

  75. Iyer, L. M., Tahiliani, M., Rao, A. & Aravind, L. Prediction of novel families of enzymes involved in oxidative and other complex modifications of bases in nucleic acids. Cell Cycle 8, 1698–1710 (2009).

    Article  CAS  PubMed  Google Scholar 

  76. Wang, X. et al. N6-methyladenosine-dependent regulation of messenger RNA stability. Nature 505, 117–120 (2014). This work presents the first m6A reader protein to be characterized, YTHDF2, and a main function of m6A: YTHDF2 mediates the m6A-dependent RNA decay by targeting RNA substrates to P-bodies.

    Article  CAS  PubMed  Google Scholar 

  77. Schoenberg, D. R. & Maquat, L. E. Regulation of cytoplasmic mRNA decay. Nature Rev. Genet. 13, 246–259 (2012).

    Article  CAS  PubMed  Google Scholar 

  78. Isken, O. & Maquat, L. E. The multiple lives of NMD factors: balancing roles in gene and genome regulation. Nature Rev. Genet. 9, 699–712 (2008).

    Article  CAS  PubMed  Google Scholar 

  79. Sheth, U. & Parker, R. Decapping and decay of messenger RNA occur in cytoplasmic processing bodies. Science 300, 805–808 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Han, D. et al. IRE1α kinase activation modes control alternate endoribonuclease outputs to determine divergent cell fates. Cell 138, 562–575 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Marzluff, W. F., Wagner, E. J. & Duronio, R. J. Metabolism and regulation of canonical histone mRNAs: life without a poly(A) tail. Nature Rev. Genet. 9, 843–854 (2008).

    Article  CAS  PubMed  Google Scholar 

  82. Dasgupta, T. & Ladd, A. N. The importance of CELF control: molecular and biological roles of the CUG-BP, Elav-like family of RNA-binding proteins. Wiley Interdiscip. Rev. RNA 3, 104–121 (2012).

    Article  CAS  PubMed  Google Scholar 

  83. Yang, F. & Schoenberg, D. R. Endonuclease-mediated mRNA decay involves the selective targeting of PMR1 to polyribosome-bound substrate mRNA. Mol. Cell 14, 435–445 (2004).

    Article  CAS  PubMed  Google Scholar 

  84. Ghosh, S. & Jacobson, A. RNA decay modulates gene expression and controls its fidelity. Wiley Interdiscip. Rev. RNA 1, 351–361 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. He, L. & Hannon, G. J. MicroRNAs: small RNAs with a big role in gene regulation. Nature Rev. Genet. 5, 522–531 (2004).

    Article  CAS  PubMed  Google Scholar 

  86. Ameres, S. L. & Zamore, P. D. Diversifying microRNA sequence and function. Nature Rev. Mol. Cell Biol. 14, 475–488 (2013).

    Article  CAS  Google Scholar 

  87. Harigaya, Y. et al. Selective elimination of messenger RNA prevents an incidence of untimely meiosis. Nature 442, 45–50 (2006).

    Article  CAS  PubMed  Google Scholar 

  88. 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 

  89. Kawai, T. & Akira, S. Toll-like receptor and RIG-I-like receptor signaling. Ann. NY Acad. Sci. 1143, 1–20 (2008).

    Article  CAS  PubMed  Google Scholar 

  90. Newby, M. I. & Greenbaum, N. L. Sculpting of the spliceosomal branch site recognition motif by a conserved pseudouridine. Nature Struct. Biol. 9, 958–965 (2002).

    Article  CAS  PubMed  Google Scholar 

  91. Lebedeva, S. et al. Transcriptome-wide analysis of regulatory interactions of the RNA-binding protein HuR. Mol. Cell 43, 340–352 (2011).

    Article  CAS  PubMed  Google Scholar 

  92. Mukherjee, N. et al. Integrative regulatory mapping indicates that the RNA-binding protein HuR couples pre-mRNA processing and mRNA stability. Mol. Cell 43, 327–339 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Srikantan, S. & Gorospe, M. UneCLIPsing HuR nuclear function. Mol. Cell 43, 319–321 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Dormoy-Raclet, V. et al. HuR and miR-1192 regulate myogenesis by modulating the translation of HMGB1 mRNA. Nature Commun. 4, 2388 (2013).

    Article  Google Scholar 

  95. Barnhart, M. D., Moon, S. L., Emch, A. W., Wilusz, C. J. & Wilusz, J. Changes in cellular mRNA stability, splicing, and polyadenylation through HuR protein sequestration by a cytoplasmic RNA virus. Cell Rep. 5, 909–917 (2013).

    Article  CAS  PubMed  Google Scholar 

  96. Abdelmohsen, K. & Gorospe, M. Posttranscriptional regulation of cancer traits by HuR. Wiley Interdiscip. Rev. RNA 1, 214–229 (2010).

    Article  CAS  PubMed  Google Scholar 

  97. Ambros, V. The functions of animal microRNAs. Nature 431, 350–355 (2004).

    Article  CAS  PubMed  Google Scholar 

  98. Chen, K. & Rajewsky, N. The evolution of gene regulation by transcription factors and microRNAs. Nature Rev. Genet. 8, 93–103 (2007).

    Article  CAS  PubMed  Google Scholar 

  99. Filipowicz, W., Bhattacharyya, S. N. & Sonenberg, N. Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nature Rev. Genet. 9, 102–114 (2008).

    Article  CAS  PubMed  Google Scholar 

  100. Parker, R. & Sheth, U. P bodies and the control of mRNA translation and degradation. Mol. Cell 25, 635–646 (2007).

    Article  CAS  PubMed  Google Scholar 

  101. Keene, J. D. RNA regulons: coordination of post-transcriptional events. Nature Rev. Genet. 8, 533–543 (2007).

    Article  CAS  PubMed  Google Scholar 

  102. Gallego, M. & Virshup, D. M. Post-translational modifications regulate the ticking of the circadian clock. Nature Rev. Mol. Cell Biol. 8, 139–148 (2007).

    Article  CAS  Google Scholar 

  103. Eulalio, A., Behm-Ansmant, I. & Izaurralde, E. P bodies: at the crossroads of post-transcriptional pathways. Nature Rev. Mol. Cell Biol. 8, 9–22 (2007).

    Article  CAS  Google Scholar 

  104. Fustin, J. M. et al. RNA-methylation-dependent RNA processing controls the speed of the circadian clock. Cell 155, 793–806 (2013). This study shows that the m6A modification affects the export of several mRNAs that are related to the circadian cycle.

    Article  CAS  PubMed  Google Scholar 

  105. Khan, Z. et al. Primate transcript and protein expression levels evolve under compensatory selection pressures. Science 342, 1100–1104 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Wu, L. et al. Variation and genetic control of protein abundance in humans. Nature 499, 79–82 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Saletore, Y. et al. The birth of the epitranscriptome: deciphering the function of RNA modifications. Genome Biol. 13, 175 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. 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 

  109. 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 

  110. Ge, J. & Yu, Y. T. RNA pseudouridylation: new insights into an old modification. Trends Biochem. Sci. 38, 210–218 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Edelheit, S., Schwartz, S., Mumbach, M. R., Wurtzel, O. & Sorek, R. Transcriptome-wide mapping of 5-methylcytidine RNA modifications in bacteria, archaea, and yeast reveals m5C within archaeal mRNAs. PLoS Genet. 9, e1003602 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. 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 

  113. 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 

  114. Bykhovskaya, Y., Casas, K., Mengesha, E., Inbal, A. & Fischel-Ghodsian, N. Missense mutation in pseudouridine synthase 1 (PUS1) causes mitochondrial myopathy and sideroblastic anemia (MLASA). Am. J. Hum. Genet. 74, 1303–1308 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Patton, J. R., Bykhovskaya, Y., Mengesha, E., Bertolotto, C. & Fischel-Ghodsian, N. Mitochondrial myopathy and sideroblastic anemia (MLASA): missense mutation in the pseudouridine synthase 1 (PUS1) gene is associated with the loss of tRNA pseudouridylation. J. Biol. Chem. 280, 19823–19828 (2005).

    Article  CAS  PubMed  Google Scholar 

  116. Sahoo, T. et al. Prader–Willi phenotype caused by paternal deficiency for the HBII-85 C/D box small nucleolar RNA cluster. Nature Genet. 40, 719–721 (2008).

    Article  CAS  PubMed  Google Scholar 

  117. Sedgwick, B. Repairing DNA-methylation damage. Nature Rev. Mol. Cell Biol. 5, 148–157 (2004).

    Article  CAS  Google Scholar 

  118. Mishina, Y., Duguid, E. M. & He, C. Direct reversal of DNA alkylation damage. Chem. Rev. 106, 215–232 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Fu, Y. et al. The AlkB domain of mammalian ABH8 catalyzes hydroxylation of 5-methoxycarbonylmethyluridine at the wobble position of tRNA. Angew. Chem. Int. Ed Engl. 49, 8885–8888 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. van den Born, E. et al. ALKBH8-mediated formation of a novel diastereomeric pair of wobble nucleosides in mammalian tRNA. Nature Commun. 2, 172 (2011).

    Article  CAS  Google Scholar 

  121. Aik, W. et al. Structure of human RNA N6-methyladenine demethylase ALKBH5 provides insights into its mechanisms of nucleic acid recognition and demethylation. Nucleic Acids Res. http://dx.doi.org/10.1093/nar/gku085 (2014).

  122. Chen, W. et al. Crystal structure of the RNA demethylase ALKBH5 from zebrafish. FEBS Lett. 588, 892–898 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors apologize to colleagues whose work was not cited owing to space limitation. They thank T. Pan, X. Wang, Y. Yue and J. Liu for discussion. C.H. is supported by the US National Institutes of Health grants GM071440 and the EUREKA grant GM088599. This work was also supported partly by grants from the Israel Science Foundation, the Flight Attendant Medical Research Institute (FAMRI) and the Israeli Centers of Research Excellence. S.F. Reichard contributed to editing of this manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Chuan He.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

PowerPoint slides

Glossary

Epigenetic modifications

Reversible chemical modifications on DNA and histones that regulate gene expression independently of the genome sequences and that are heritable through cell division.

'Writers', 'erasers' and 'readers'

Enzymes or proteins that add, remove or preferentially bind to the chemical modifications at designated DNA or RNA nucleotides and amino acid residues of histones.

Methyltransferase

An enzyme that transfers a methyl group to its substrate. Most methyltransferases use S-adenosyl-l-methionine (SAM) as the methyl donor.

Two-dimensional thin layer chromatography

A technique to separate and identify nucleosides on cellulose plates according to their differential migration patterns in two different solvents. The nucleoside is typically radiolabelled for detection.

High-performance liquid chromatography coupled with triple-quadrupole tandem mass spectrometry

(HPLC–QqQ-MS/MS). A liquid chromatography method coupled with triple-quadrupole tandem mass spectrometry, which can quantitatively and simultaneously monitor multiple molecular species according to their fragmentation patterns.

m6A RNA immunoprecipitation

An immunoprecipitation method to selectively enrich for N6-methyladenosine (m6A)-containing RNA using an m6A-targeted antibody.

Nuclear speckles

Nuclear domains located in the interchromatin regions of the nucleoplasm and enriched with pre-mRNA processing factors.

Photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation

(PAR–CLIP). A biochemical method that takes advantage of incorporated photoreactive ribonucleoside analogues to identify the binding sites of RNA-binding proteins in cells.

Yeast two-hybrid screens

A method in which one protein is fused to the GAL4 activation domain and the other to the GAL4 DNA-binding domain, and both fusion proteins are introduced into yeast. Expression of a GAL4-regulated reporter gene indicates that the two proteins physically interact.

Demethylase

An enzyme that removes a methyl group from its substrate.

Oxidative demethylation

A chemical reaction in which the C–H bond of a methyl group attached to a nitrogen or an oxygen atom is oxidized to –OH by demethylases, and the intermediate decomposes to release the methyl group as formaldehyde.

Ribosome profiling

Qualitative and quantitative sequencing of the RNA attached to ribosomes as a signature of genes that are expressed.

Processing bodies

(P-bodies). Distinct foci in the cytoplasm that are enriched with RNA degradation factors.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Fu, Y., Dominissini, D., Rechavi, G. et al. Gene expression regulation mediated through reversible m6A RNA methylation. Nat Rev Genet 15, 293–306 (2014). https://doi.org/10.1038/nrg3724

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrg3724

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing