Skip to main content
SpringerLink
Log in

N 6-Methyladenosine (m6A) Methylation in mRNA with A Dynamic and Reversible Epigenetic Modification

  • Review
  • Published:
Molecular Biotechnology Aims and scope Submit manuscript

Abstract

N 6-methyladenosine (m6A) is the most abundant and reversible internal modification ubiquitously occurring in eukaryotic mRNA, albeit the significant biological roles of m6A methylation have remained largely unclear. The well-known DNA and histone methylations play crucial roles in epigenetic modification of biologic processes in eukaryotes. Analogously, the dynamic and reversible m6A RNA modification, which is installed by methyltransferase (METTL3, METTL14, and WTAP), reversed by demethylases (FTO, ALKBH5) and mediated by m6A-binding proteins (YTHDF1–3, YTHDC1), may also have a profound impact on gene expression regulation. Recent discoveries of the distributions, functions, and mechanisms of m6A modification suggest that this methylation functionally modulates the eukaryotic transcriptome to influence mRNA transcription, splicing, nuclear export, localization, translation, and stability. This reversible mRNA methylation shed light on a new dimension of post-transcriptional regulation of gene expression at the RNA level. m6A methylation also plays significant and broad roles in various physiological processes, such as development, fertility, carcinogenesis, stemness, early mortality, meiosis and circadian cycle, and links to obesity, cancer, and other human diseases. This review mainly describes the current knowledge of m6A and perspectives on future investigations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Machnicka, M. A., Milanowska, K., Oglou, O. O., Purta, E., Kurkowska, M., Olchowik, A., et al. (2013). MODOMICS: A database of RNA modification pathways-2013 update. Nucleic Acids Research, 41, D262–D267.

    Article  CAS  Google Scholar 

  2. Ping, X. L., Sun, B. F., Wang, L., Xiao, W., Yang, X., Wang, W. J., et al. (2014). Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase. Cell Research, 24, 177–189.

    Article  CAS  Google Scholar 

  3. Suzuki, M. M., & Bird, A. (2008). DNA methylation landscapes: Provocative insights from epigenomics. Nature Reviews Genetics, 9, 465–476.

    Article  CAS  Google Scholar 

  4. Jones, P. A. (2012). Functions of DNA methylation: Islands, start sites, gene bodies and beyond. Nature Reviews Genetics, 13, 484–492.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  7. Reik, W., Dean, W., & Walter, J. (2001). Epigenetic reprogramming in mammalian development. Science, 293, 1089–1093.

    Article  CAS  Google Scholar 

  8. Desrosie, R., Frideric, K., & Rottman, F. (1974). Identification of methylated nucleosides in messenger-RNA from Novikoff hepatoma-cells. Proceedings of the National Academy of Sciences USA, 71, 3971–3975.

    Article  Google Scholar 

  9. Fu, Y., Dominissini, D., Rechavi, G., & He, C. (2014). Gene expression regulation mediated through reversible m(6)A RNA methylation. Nature Reviews Genetics, 15, 293–306.

    Article  CAS  Google Scholar 

  10. Yue, Y. N., Liu, J. Z., & He, C. (2015). RNA N-6-methyladenosine methylation in post-transcriptional gene expression regulation. Genes Development, 29, 1343–1355.

    Article  CAS  Google Scholar 

  11. Niu, Y., Zhao, X., Wu, Y. S., Li, M. M., Wang, X. J., & Yang, Y. G. (2013). N6-methyl-adenosine (m6A) in RNA: An old modification with a novel epigenetic function. Genomics, Proteomics & Bioinformatics, 11, 8–17.

    Article  CAS  Google Scholar 

  12. Keith, G. (1995). Mobilities of modified ribonucleotides on two-dimensional cellulose thin-layer chromatography. Biochimie, 77, 142–144.

    Article  CAS  Google Scholar 

  13. Jia, G. F., Fu, Y., Zhao, X., Dai, Q., Zheng, G. Q., Yang, Y., et al. (2011). N6-Methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nature Chemical Biology, 7, 885–887.

    Article  CAS  Google Scholar 

  14. Zheng, G. Q., Dahl, J. A., Niu, Y. M., Fedorcsak, P., Huang, C. M., Li, C. J., et al. (2013). ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Molecular Cell, 49, 18–29.

    Article  CAS  Google Scholar 

  15. Dominissini, D., Moshitch-Moshkovitz, S., Schwartz, S., Salmon-Divon, M., Ungar, L., Osenberg, S., et al. (2012). Topology of the human and mouse m(6)A RNA methylomes revealed by m(6)A-seq. Nature, 485, 201-U284.

  16. Meyer, K. D., Saletore, Y., Zumbo, P., Elemento, O., Mason, C. E., & Jaffrey, S. R. (2012). Comprehensive analysis of mRNA methylation reveals enrichment in 3′UTRs and near Stop Codons. Cell, 149, 1635–1646.

    Article  CAS  Google Scholar 

  17. Chen, K., Lu, Z. K., Wang, X., Fu, Y., Luo, G. Z., Liu, N., et al. (2015). High-resolution N-6-methyladenosine (m(6)A) map using photo-crosslinking-assisted m(6)A sequencing. Angewandte Chemie International Edition, 54, 1587–1590.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  19. Perry, R. P., Kelley, D. E., Friderici, K., & Rottman, F. (1975). The methylated constituents of L cell messenger RNA: Evidence for an unusual cluster at the 5′ terminus. Cell, 4, 387–394.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  21. Ke, S., Alemu, E. A., Mertens, C., Gantman, E. C., Fak, J. J., Mele, A., et al. (2015). A majority of m6A residues are in the last exons, allowing the potential for 3′ UTR regulation. Genes & Development, 29, 2037–2053.

    Article  CAS  Google Scholar 

  22. Pan, T. (2013). N6-methyl-adenosine modification in messenger and long non-coding RNA. Trends in Biochemical Sciences, 38, 204–209.

    Article  CAS  Google Scholar 

  23. Schwartz, S., Mumbach, M. R., Jovanovic, M., Wang, T., Maciag, K., Bushkin, G. G., et al. (2014). Perturbation of m6A writers reveals two distinct classes of mRNA methylation at internal and 5’ sites. Cell Reports, 8, 284–296.

    Article  CAS  Google Scholar 

  24. Levis, R., & Penman, S. (1978). 5′-Terminal structures of Poly(a)+ cytoplasmic messenger-RNA and of Poly(a)+ and Poly(a)− heterogeneous nuclear-RNA of cells of dipteran Drosophila-melanogaster. Journal of Molecular Biology, 120, 487–515.

    Article  CAS  Google Scholar 

  25. Nichols, J. L. (1979). N6-methyladenosine in maize poly(A)-containing RNA. Plant Science Letters, 15, 357–367.

    Article  CAS  Google Scholar 

  26. Clancy, M. J., Shambaugh, M. E., Timpte, C. S., & Bokar, J. A. (2002). Induction of sporulation in Saccharomyces cerevisiae leads to the formation of N-6-methyladenosine in mRNA: A potential mechanism for the activity of the IME4 gene. Nucleic Acids Research, 30, 4509–4518.

    Article  CAS  Google Scholar 

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

    CAS  Google Scholar 

  28. Beemon, K., & Keith, J. (1977). Localization of N6-methyladenosine in Rous-Sarcoma virus genome. Journal of Molecular Biology, 113, 165–179.

    Article  CAS  Google Scholar 

  29. Csepany, T., Lin, A., Baldick, C. J, Jr, & Beemon, K. (1990). Sequence specificity of mRNA N6-adenosine methyltransferase. The Journal of Biological Chemistry, 265, 20117–20122.

    CAS  Google Scholar 

  30. Batista, P. J., Molinie, B., Wang, J. K., Qu, K., Zhang, J. J., Li, L. J., et al. (2014). m(6)A RNA modification controls cell fate transition in mammalian embryonic stem cells. Cell Stem Cell, 15, 707–719.

    Article  CAS  Google Scholar 

  31. Schwartz, S., Agarwala, S. D., Mumbach, M. R., Jovanovic, M., Mertins, P., Shishkin, A., et al. (2013). High-resolution mapping reveals a conserved, widespread, dynamic mRNA methylation program in yeast meiosis. Cell, 155, 1409–1421.

    Article  CAS  Google Scholar 

  32. Geula, S., Moshitch-Moshkovitz, S., Dominissini, D., Mansour, A. A., Kol, N., Salmon-Divon, M., et al. (2015). m(6)A mRNA methylation facilitates resolution of naive pluripotency toward differentiation. Science, 347, 1002–1006.

    Article  CAS  Google Scholar 

  33. Deng, X., Chen, K., Luo, G. Z., Weng, X., Ji, Q., Zhou, T., et al. (2015). Widespread occurrence of N6-methyladenosine in bacterial mRNA. Nucleic Acids Research, 43, 6557–6567.

    Article  CAS  Google Scholar 

  34. Luo, G. Z., MacQueen, A., Zheng, G., Duan, H., Dore, L. C., Lu, Z., et al. (2014). Unique features of the m6A methylome in Arabidopsis thaliana. Nature Communications, 5, 5630.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  36. Bokar, J. A., Shambaugh, M. E., Polayes, D., Matera, A. G., & Rottman, F. M. (1997). Purification and cDNA cloning of the AdoMet-binding subunit of the human mRNA (N-6-adenosine)-methyltransferase. RNA, 3, 1233–1247.

    CAS  Google Scholar 

  37. Bokar, J. A. (2005). The biosynthesis and functional roles of methylated nucleosides in eukaryotic mRNA. In H. Grosjean (Ed.), Fine-tuning of RNA functions by modification and editing (pp. 141–177). Berlin: Springer.

    Chapter  Google Scholar 

  38. Zhong, S., Li, H., Bodi, Z., Button, J., Vespa, L., Herzog, M., et al. (2008). MTA is an Arabidopsis messenger RNA adenosine methylase and interacts with a homolog of a sex-specific splicing factor. The Plant Cell, 20, 1278–1288.

    Article  CAS  Google Scholar 

  39. Hongay, C. F., & Orr-Weaver, T. L. (2011). Drosophila inducer of MEiosis 4 (IME4) is required for Notch signaling during oogenesis. Proceedings of the National Academy of Sciences U S A, 108, 14855–14860.

    Article  CAS  Google Scholar 

  40. Bujnicki, J. M., Feder, M., Radlinska, M., & Blumenthal, R. M. (2002). Structure prediction and phylogenetic analysis of a functionally diverse family of proteins homologous to the MT-A70 subunit of the human mRNA:m(6)A methyltransferase. Journal of Molecular Evolution, 55, 431–444.

    Article  CAS  Google Scholar 

  41. Liu, J., Yue, Y., Han, D., Wang, X., Fu, Y., Zhang, L., et al. (2014). A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation. Nature Chemical Biology, 10, 93–95.

    Article  CAS  Google Scholar 

  42. Wang, Y., Li, Y., Toth, J. I., Petroski, M. D., Zhang, Z., & Zhao, J. C. (2014). N6-methyladenosine modification destabilizes developmental regulators in embryonic stem cells. Nature Cell Biology, 16, 191–198.

    Article  CAS  Google Scholar 

  43. Little, N. A., Hastie, N. D., & Davies, R. C. (2000). Identification of WTAP, a novel Wilms’ tumour 1-associating protein. Human Molecular Genetics, 9, 2231–2239.

    Article  CAS  Google Scholar 

  44. Horiuchi, K., Umetani, M., Minami, T., Okayama, H., Takada, S., Yamamoto, M., et al. (2006). Wilms’ tumor 1-associating protein regulates G(2)/M transition through stabilization of cyclin A2 mRNA. Proceedings of the National Academy of Sciences USA, 103, 17278–17283.

    Article  CAS  Google Scholar 

  45. Horiuchi, K., Kawamura, T., Iwanari, H., Ohashi, R., Naito, M., Kodama, T., et al. (2013). Identification of Wilms’ tumor 1-associating protein complex and its role in alternative splicing and the cell cycle. Journal of Biological Chemistry, 288, 33292–33302.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  48. Fischer, J., Koch, L., Emmerling, C., Vierkotten, J., Peters, T., Bruning, J. C., et al. (2009). Inactivation of the Fto gene protects from obesity. Nature, 458, 894-U810.

  49. Church, C., Moir, L., McMurray, F., Girard, C., Banks, G. T., Teboul, L., et al. (2010).Overexpression of Fto leads to increased food intake and results in obesity. Nature Genetics, 42, 1086-U1147.

  50. Frayling, T. M., Timpson, N. J., Weedon, M. N., Zeggini, E., Freathy, R. M., Lindgren, C. M., et al. (2007). A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science, 316, 889–894.

    Article  CAS  Google Scholar 

  51. Dina, C., Meyre, D., Gallina, S., Durand, E., Korner, A., Jacobson, P., et al. (2007). Variation in FTO contributes to childhood obesity and severe adult obesity. Nature Genetics, 39, 724–726.

    Article  CAS  Google Scholar 

  52. Scuteri, A., Sanna, S., Chen, W. M., Uda, M., Albai, G., Strait, J., et al. (2007). Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits. PLoS Genetics, 3, 1200–1210.

    Article  CAS  Google Scholar 

  53. Gerken, T., Girard, C. A., Tung, Y. C. L., Webby, C. J., Saudek, V., Hewitson, K. S., et al. (2007). The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Science, 318, 1469–1472.

    Article  CAS  Google Scholar 

  54. Boissel, S., Reish, O., Proulx, K., Kawagoe-Takaki, H., Sedgwick, B., Yeo, G. S. H., et al. (2009). Loss-of-function mutation in the dioxygenase-encoding FTO gene causes severe growth retardation and multiple malformations. American Journal of Human Genetics, 85, 106–111.

    Article  CAS  Google Scholar 

  55. Wang, X., Zhu, L., Chen, J., & Wang, Y. (2015). mRNA m(6)A methylation downregulates adipogenesis in porcine adipocytes. Biochemical and Biophysical Research Communications, 459, 201–207.

    Article  CAS  Google Scholar 

  56. Kurowski, M. A., Bhagwat, A. S., Papaj, G., & Bujnicki, J. M. (2003). Phylogenomic identification of five new human homologs of the DNA repair enzyme AlkB. BMC Genomics, 4, 48.

    Article  Google Scholar 

  57. Falnes, P. O., Johansen, R. F., & Seeberg, E. (2002). AlkB-mediated oxidative demethylation reverses DNA damage in Escherichia coli. Nature, 419, 178–182.

    Article  CAS  Google Scholar 

  58. Trewick, S. C., Henshaw, T. F., Hausinger, R. P., Lindahl, T., & Sedgwick, B. (2002). Oxidative demethylation by Escherichia coli AlkB directly reverts DNA base damage. Nature, 419, 174–178.

    Article  CAS  Google Scholar 

  59. Fu, Y., Jia, G., Pang, X., Wang, R. N., Wang, X., Li, C. J., et al. (2013). FTO-mediated formation of N6-hydroxymethyladenosine and N6-formyladenosine in mammalian RNA. Nature Communications, 4, 1798.

  60. Tahiliani, M., Koh, K. P., Shen, Y. H., Pastor, W. A., Bandukwala, H., Brudno, Y., et al. (2009). Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science, 324, 930–935.

    Article  CAS  Google Scholar 

  61. Ito, S., D’Alessio, A. C., Taranova, O. V., Hong, K., Sowers, L. C. & Zhang, Y. (2010). Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature, 466, 1129-U1151.

  62. Ito, S., Shen, L., Dai, Q., Wu, S. C., Collins, L. B., Swenberg, J. A., et al. (2011). Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science, 333, 1300–1303.

    Article  CAS  Google Scholar 

  63. Zhao, X., Yang, Y., Sun, B. F., Shi, Y., Yang, X., Xiao, W., et al. (2014). FTO-dependent demethylation of N6-methyladenosine regulates mRNA splicing and is required for adipogenesis. Cell Research, 24, 1403–1419.

    Article  CAS  Google Scholar 

  64. Gulati, P., Cheung, M. K., Antrobus, R., Church, C. D., Harding, H. P., Tung, Y. C. L., et al. (2013). Role for the obesity-related FTO gene in the cellular sensing of amino acids. Proceedings of the National Academy of Sciences USA, 110, 2557–2562.

    Article  CAS  Google Scholar 

  65. Vujovic, P., Stamenkovic, S., Jasnic, N., Lakic, I., Djurasevic, S. F., Cvijic, G., et al. (2013). Fasting induced cytoplasmic Fto expression in some neurons of rat hypothalamus. PLoS One, 8, e63694.

    Article  CAS  Google Scholar 

  66. Zheng, G. Q., Dahl, J. A., Niu, Y. M., Fu, Y., Klungland, A., Yang, Y. G., et al. (2013). Sprouts of RNA epigenetics: The discovery of mammalian RNA demethylases. RNA Biology, 10, 915–918.

    Article  CAS  Google Scholar 

  67. Xu, C., Liu, K., Tempel, W., Demetriades, M., Aik, W., Schofield, C. J., et al. (2014). Structures of human ALKBH5 demethylase reveal a unique binding mode for specific single-stranded N-6-methyladenosine RNA demethylation. Journal of Biological Chemistry, 289, 17299–17311.

    Article  CAS  Google Scholar 

  68. Aik, W., Scotti, J. S., Choi, H., Gong, L. Z., Demetriades, M., Schofield, C. J., et al. (2014). Structure of human RNA N-6-methyladenine demethylase ALKBH5 provides insights into its mechanisms of nucleic acid recognition and demethylation. Nucleic Acids Research, 42, 4741–4754.

    Article  CAS  Google Scholar 

  69. Wang, X., Lu, Z. K., Gomez, A., Hon, G. C., Yue, Y. N., Han, D. L., et al. (2014). N-6-methyladenosine-dependent regulation of messenger RNA stability. Nature, 505, 117–120.

    Article  Google Scholar 

  70. Stoilov, P., Rafalska, I., & Stamm, S. (2002). YTH: A new domain in nuclear proteins. Trends in Biochemical Sciences, 27, 495–497.

    Article  CAS  Google Scholar 

  71. Zhang, Z. Y., Theler, D., Kaminska, K. H., Hiller, M., de la Grange, P., Pudimat, R., et al. (2010). The YTH domain is a novel RNA binding domain. Journal of Biological Chemistry, 285, 14701–14710.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  73. Cardelli, M., Marchegiani, F., Cavallone, L., Olivieri, F., Giovagnetti, S., Mugianesi, E., et al. (2006). A polymorphism of the YTHDF2 gene (1p35) located in an Alu-rich genomic domain is associated with human longevity. The Journal of Gerontology A, 61, 547–556.

    Google Scholar 

  74. Xu, C., Wang, X., Liu, K., Roundtree, I. A., Tempel, W., Li, Y. J., et al. (2014). Structural basis for selective binding of m(6)A RNA by the YTHDC1 YTH domain. Nature Chemical Biology, 10, 927–929.

    Article  CAS  Google Scholar 

  75. Wang, X., Zhao, B. S., Roundtree, I. A., Lu, Z. K., Han, D. L., Ma, H. H., et al. (2015). N-6-methyladenosine modulates messenger RNA translation efficiency. Cell, 161, 1388–1399.

    Article  CAS  Google Scholar 

  76. Abdelmohsen, K., & Gorospe, M. (2010). Posttranscriptional regulation of cancer traits by HuR. Wires RNA, 1, 214–229.

    Article  CAS  Google Scholar 

  77. Filippova, N., Yang, X. H., King, P., & Nabors, L. B. Z. (2012). Phosphoregulation of the RNA-binding protein Hu antigen R (HuR) by Cdk5 Affects centrosome function. Journal of Biological Chemistry, 287, 32277–32287.

    Article  CAS  Google Scholar 

  78. Wan, Y., Kertesz, M., Spitale, R. C., Segal, E., & Chang, H. Y. (2011). Understanding the transcriptome through RNA structure. Nature Reviews Genetics, 12, 641–655.

    Article  CAS  Google Scholar 

  79. Dreyfuss, G., Kim, V. N., & Kataoka, N. (2002). Messenger-RNA-binding proteins and the messages they carry. Nature Reviews Molecular Cell Biology, 3, 195–205.

    Article  CAS  Google Scholar 

  80. Ray, D., Kazan, H., Cook, K. B., Weirauch, M. T., Najafabadi, H. S., Li, X., et al. (2013). A compendium of RNA-binding motifs for decoding gene regulation. Nature, 499, 172–177.

    Article  CAS  Google Scholar 

  81. Liu, N., Dai, Q., Zheng, G. Q., He, C., Parisien, M., & Pan, T. (2015). N-6-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions. Nature, 518, 560–564.

    Article  CAS  Google Scholar 

  82. Konig, J., Zarnack, K., Rot, G., Curk, T., Kayikci, M., Zupan, B., et al. (2010). iCLIP reveals the function of hnRNP particles in splicing at individual nucleotide resolution. Nature Structural & Molecular Biology, 17, 909-U166.

  83. McCloskey, A., Taniguchi, I., Shinmyozu, K., & Ohno, M. (2012). hnRNP C tetramer measures RNA length to classify RNA polymerase II transcripts for export. Science, 335, 1643–1646.

    Article  CAS  Google Scholar 

  84. Liu, N., Parisien, M., Dai, Q., Zheng, G. Q., He, C., & Pan, T. (2013). Probing N-6-methyladenosine RNA modification status at single nucleotide resolution in mRNA and long noncoding RNA. RNA, 19, 1848–1856.

    Article  CAS  Google Scholar 

  85. Theler, D., & Allain, F. H. T. (2015). Molecular biology RNA modification does a regulatory two-step. Nature, 518, 492–493.

    Article  CAS  Google Scholar 

  86. Thomson, J. A., Itskovitz-Eldor, J., Shapiro, S. S., Waknitz, M. A., Swiergiel, J. J., Marshall, V. S., et al. (1998). Embryonic stem cell lines derived from human blastocysts. Science, 282, 1145–1147.

    Article  CAS  Google Scholar 

  87. Dunn, S. J., Martello, G., Yordanov, B., Emmott, S., & Smith, A. G. (2014). Defining an essential transcription factor program for naive pluripotency. Science, 344, 1156–1160.

    Article  CAS  Google Scholar 

  88. Young, R. A. (2011). Control of the embryonic stem cell state. Cell, 144, 940–954.

    Article  CAS  Google Scholar 

  89. Chen, T., Hao, Y. J., Zhang, Y., Li, M. M., Wang, M., Han, W., et al. (2015). m(6)A RNA methylation is regulated by microRNAs and promotes reprogramming to pluripotency. Cell Stem Cell, 16, 289–301.

    Article  CAS  Google Scholar 

  90. Fustin, J. M., Doi, M., Yamaguchi, Y., Hida, H., Nishimura, S., Yoshida, M., et al. (2013). RNA-methylation-dependent RNA processing controls the speed of the circadian clock. Cell, 155, 793–806.

    Article  CAS  Google Scholar 

  91. Akhtar, R. A., Reddy, A. B., Maywood, E. S., Clayton, J. D., King, V. M., Smith, A. G., et al. (2002). Circadian cycling of the mouse liver transcriptome, as revealed by cDNA microarray, is driven by the suprachiasmatic nucleus. Current Biology, 12, 540–550.

    Article  CAS  Google Scholar 

  92. Koike, N., Yoo, S. H., Huang, H. C., Kumar, V., Lee, C., Kim, T. K., et al. (2012). Transcriptional architecture and chromatin landscape of the core circadian clock in mammals. Science, 338, 349–354.

    Article  CAS  Google Scholar 

  93. Jackson, R. J., Hellen, C. U. T., & Pestova, T. V. (2010). The mechanism of eukaryotic translation initiation and principles of its regulation. Nature Reviews Molecular Cell Biology, 11, 113–127.

    Article  CAS  Google Scholar 

  94. Hinnebusch, A. G. (2014). The scanning mechanism of eukaryotic translation initiation. Annual Review of Biochemistry, 83, 779–812.

    Article  CAS  Google Scholar 

  95. Zhou, J., Wan, J., Gao, X. W., Zhang, X. Q., Jaffrey, S. R. and Qian, S. B. (2015). Dynamic m(6)A mRNA methylation directs translational control of heat shock response. Nature, 526, 591-U332.

  96. Meyer, K. D., Patil, D. P., Zhou, J., Zinoviev, A., Skabkin, M. A., Elemento, O., et al. (2015). 5’ UTR m(6)A promotes cap-independent translation. Cell, 163, 999–1010.

    Article  CAS  Google Scholar 

  97. Sibbritt, T., Patel, H. R., & Preiss, T. (2013). Mapping and significance of the mRNA methylome. Wires RNA, 4, 397–422.

    Article  CAS  Google Scholar 

  98. Loos, R. J. F., & Bouchard, C. (2008). FTO: The first gene contributing to common forms of human obesity. Obesity Reviews, 9, 246–250.

    Article  CAS  Google Scholar 

  99. Loos, R. J. F., & Yeo, G. S. H. (2014). The bigger picture of FTO-the first GWAS-identified obesity gene. Nature Reviews Endocrinology, 10, 51–61.

    Article  CAS  Google Scholar 

  100. Alarcon, C. R., Lee, H., Goodarzi, H., Halberg, N., & Tavazoie, S. F. (2015). N-6-methyladenosine marks primary microRNAs for processing. Nature, 519, 482–485.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Natural Science Foundation of China (Grant No. 31372320) and the Special Fund for Cultivation and Breeding of New Transgenic Organism (No. 2014ZX0800949B).

Author information

Authors and Affiliations

  1. College of Animal Sciences, Zhejiang University, No. 866 Yuhangtang Road, Hangzhou, 310058, Zhejiang, China

    Ruifan Wu, Denghu Jiang, Yizhen Wang & Xinxia Wang

  2. Key Laboratory of Animal Nutrition & Feed Sciences, Ministry of Agriculture, No. 866 Yuhangtang Road, Hangzhou, 310058, Zhejiang, China

    Ruifan Wu, Denghu Jiang, Yizhen Wang & Xinxia Wang

  3. Zhejiang Provincial Laboratory of Feed and Animal Nutrition, No. 866 Yuhangtang Road, Hangzhou, 310058, Zhejiang, China

    Ruifan Wu, Denghu Jiang, Yizhen Wang & Xinxia Wang

Authors
  1. Ruifan Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Denghu Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yizhen Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xinxia Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xinxia Wang.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wu, R., Jiang, D., Wang, Y. et al. N 6-Methyladenosine (m6A) Methylation in mRNA with A Dynamic and Reversible Epigenetic Modification. Mol Biotechnol 58, 450–459 (2016). https://doi.org/10.1007/s12033-016-9947-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12033-016-9947-9

Keywords

Search

Navigation