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The dynamic N1-methyladenosine methylome in eukaryotic messenger RNA

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Dominissini, Dan, Nachtergaele, Sigrid, Moshitch-Moshkovitz, Sharon, Peer, Eyal, Kol, Nitzan, Ben-Haim, Moshe Shay, Dai, Qing, Di Segni, Ayelet, Salmon-Divon, Mali, Clark, Wesley C., Zheng, Guanqun, Pan, Tao, Solomon, Oz, Eyal, Eran, Hershkovitz, Vera, Han, Dali, Doré, Louis C., Amariglio, Ninette, Rechavi, Gideon, He, Chuan·2016·Nature
DOI 10.1038/nature16998
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Abstract

Gene expression can be regulated post-transcriptionally through dynamic and reversible RNA modifications. A recent noteworthy example is N6-methyladenosine (m6A), which affects messenger RNA (mRNA) localization, stability, translation and splicing. Here we report on a new mRNA modification, N1-methyladenosine (m1A), that occurs on thousands of different gene transcripts in eukaryotic cells, from yeast to mammals, at an estimated average transcript stoichiometry of 20% in humans. Employing newly developed sequencing approaches, we show that m1A is enriched around the start codon upstream of the first splice site: it preferentially decorates more structured regions around canonical and alternative translation initiation sites, is dynamic in response to physiological conditions, and correlates positively with protein production. These unique features are highly conserved in mouse and human cells, strongly indicating a functional role for m1A in promoting translation of methylated mRNA.

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Research works printed but not linked: 60

  1. Dominissini, D. et al. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature 485, 201–206 (2012) · DOI · Paper page
  2. Carlile, T. M. et al. Pseudouridine profiling reveals regulated mRNA pseudouridylation in yeast and human cells. Nature 515, 143–146 (2014) · DOI · Paper page
  3. Schwartz, S. et al. Transcriptome-wide mapping reveals widespread dynamic-regulated pseudouridylation of ncRNA and mRNA. Cell 159, 148–162 (2014) · DOI
  4. Li, X. et al. Chemical pulldown reveals dynamic pseudouridylation of the mammalian transcriptome. Nature Chem. Biol. 11, 592–597 (2015) · DOI
  5. Squires, J. E. et al. Widespread occurrence of 5-methylcytosine in human coding and non-coding RNA. Nucleic Acids Res. 40, 5023–5033 (2012) · DOI
  6. Khoddami, V. & Cairns, B. R. Identification of direct targets and modified bases of RNA cytosine methyltransferases. Nature Biotechnol. 31, 458–464 (2013) · DOI
  7. Fu, Y., Dominissini, D., Rechavi, G. & He, C. Gene expression regulation mediated through reversible m6A RNA methylation. Nature Rev. Genet. 15, 293–306 (2014) · DOI
  8. Li, S. & Mason, C. E. The pivotal regulatory landscape of RNA modifications. Annu. Rev. Genomics Hum. Genet. 15, 127–150 (2014) · DOI
  9. Machnicka, M. A. et al. MODOMICS: a database of RNA modification pathways—2013 update. Nucleic Acids Res. 41, D262–D267 (2013) · DOI
  10. Dunn, D. B. The occurrence of 1-methyladenine in ribonucleic acid. Biochim. Biophys. Acta 46, 198–200 (1961) · DOI
  11. Hall, R. H. Method for isolation of 2′-O-methylribonucleotides and N1-methyladenosine from ribonucleic acid. Biochim. Biophys. Acta 68, 278–283 (1963) · DOI
  12. El Yacoubi, B., Bailly, M. & de Crécy-Lagard, V. Biosynthesis and function of posttranscriptional modifications of transfer RNAs. Annu. Rev. Genet. 46, 69–95 (2012) · DOI
  13. 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) · DOI
  14. Anderson, J. T. & Droogmans, L. in Fine-Tuning of RNA Functions by Modification and Editing Vol. 12 (ed. H. Grosjean ) 121–139 (2005) · DOI
  15. Macon, J. B. & Wolfenden, R. 1-Methyladenosine. Dimroth rearrangement and reversible reduction. Biochemistry 7, 3453–3458 (1968) · DOI
  16. 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) · DOI
  17. Zhang, Y. et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 9, R137 (2008) · DOI · Paper page
  18. Lee, S. et al. Global mapping of translation initiation sites in mammalian cells at single-nucleotide resolution. Proc. Natl Acad. Sci. USA 109, E2424–E2432 (2012)
  19. Gao, X. et al. Quantitative profiling of initiating ribosomes in vivo. Nature Methods 12, 147–153 (2015) · DOI
  20. Takuma, H. et al. Substrate tRNA recognition mechanism of eubacterial tRNA (m1A58) methyltransferase (TrmI). J. Biol. Chem. 290, 5912–5925 (2015) · DOI
  21. 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) · DOI
  22. Kozak, M. Regulation of translation via mRNA structure in prokaryotes and eukaryotes. Gene 361, 13–37 (2005) · DOI
  23. 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) · DOI
  24. Schwartz, S. et al. High-resolution mapping reveals a conserved, widespread, dynamic mRNA methylation program in yeast meiosis. Cell 155, 1409–1421 (2013) · DOI
  25. Peifer, C. et al. Yeast Rrp8p, a novel methyltransferase responsible for m1A 645 base modification of 25S rRNA. Nucleic Acids Res. 41, 1151–1163 (2013) · DOI
  26. Zur, H. & Tuller, T. New universal rules of eukaryotic translation initiation fidelity. PLOS Comput. Biol. 9, e1003136 (2013) · DOI
  27. Parsyan, A. et al. mRNA helicases: the tacticians of translational control. Nature Rev. Mol. Cell Biol. 12, 235–245 (2011) · DOI · Paper page
  28. 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) · DOI
  29. Lu, L., Yi, C., Jian, X., Zheng, G. & He, C. Structure determination of DNA methylation lesions N1-meA and N3-meC in duplex DNA using a cross-linked protein-DNA system. Nucleic Acids Res. 38, 4415–4425 (2010) · DOI
  30. He, C. et al. A methylation-dependent electrostatic switch controls DNA repair and transcriptional activation by E. coli Ada. Mol. Cell 20, 117–129 (2005) · DOI
  31. 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) · DOI
  32. Sonenberg, N. & Hinnebusch, A. G. Regulation of translation initiation in eukaryotes: mechanisms and biological targets. Cell 136, 731–745 (2009) · DOI · Paper page
  33. Wang, X. et al. N6-methyladenosine modulates messenger RNA translation efficiency. Cell 161, 1388–1399 (2015) · DOI · Paper page
  34. 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) · DOI
  35. 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) · DOI
  36. Li, X. et al. Transcriptome-wide mapping reveals reversible and dynamic N1-methyladenosine methylome. Nat. Chem. Biol. http://dx.doi.org/10.1038/nchembio.2040 (2016) · DOI
  37. Geula, S. et al. m6A mRNA methylation facilitates resolution of naïve pluripotency toward differentiation. Science 347, 1002–1006 (2015) · DOI · Paper page
  38. Hienzsch, A., Deiml, C., Reiter, V. & Carell, T. Total synthesis of the hypermodified RNA bases wybutosine and hydroxywybutosine and their quantification together with other modified RNA bases in plant materials. Chemistry 19, 4244–4248 (2013) · DOI
  39. Pearson, D. et al. LC-MS based quantification of 2′-ribosylated nucleosides Ar(p) and Gr(p) in tRNA. Chem. Commun. (Camb.) 47, 5196–5198 (2011) · DOI
  40. Hauenschild, R. et al. The reverse transcription signature of N-1-methyladenosine in RNA-Seq is sequence dependent. Nucleic Acids Res. 43, 9950–9964 (2015)
  41. Jones, J. W. & Robins, R. K. Purine Nucleosides. III. Methylation studies of certain naturally occurring purine nucleosides. J. Am. Chem. Soc. 85, 193–201 (1963) · DOI
  42. Dai, Q. et al. Identification of recognition residues for ligation-based detection and quantitation of pseudouridine and N6-methyladenosine. Nucleic Acids Res. 35, 6322–6329 (2007) · DOI
  43. Hobartner, C. et al. The synthesis of 2′-O-[(triisopropylsilyl)oxy] methyl (TOM) phosphoramidites of methylated ribonucleosides (m1G, m2G, m22 G, m1I, m3U, m4C, m6A, m26 A) for use in automated RNA solid-phase synthesis. Monatsh. Chem. 134, 851–873 (2003) · DOI
  44. Dominissini, D., Moshitch-Moshkovitz, S., Salmon-Divon, M., Amariglio, N. & Rechavi, G. Transcriptome-wide mapping of N6-methyladenosine by m6A-seq based on immunocapturing and massively parallel sequencing. Nature Protocols 8, 176–189 (2013) · DOI
  45. Langmead, B. & Salzberg, S. L. Fast gapped-read alignment with Bowtie 2. Nature Methods 9, 357–359 (2012) · DOI · Paper page
  46. Robinson, M. D., McCarthy, D. J. & Smyth, G. K. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26, 139–140 (2010) · DOI · Paper page
  47. Salmon-Divon, M., Dvinge, H., Tammoja, K. & Bertone, P. PeakAnalyzer: genome-wide annotation of chromatin binding and modification loci. BMC Bioinformatics 11, 415 (2010) · DOI
  48. Lorenz, R. et al. ViennaRNA Package 2.0. Algorithms Mol. Biol. 6, 26 (2011) · DOI · Paper page
  49. Trotta, E. On the normalization of the minimum free energy of RNAs by sequence length. PLoS One 9, e113380 (2014) · DOI
  50. Wan, Y., Qu, K., Ouyang, Z. & Chang, H. Y. Genome-wide mapping of RNA structure using nuclease digestion and high-throughput sequencing. Nature Protocols 8, 849–869 (2013) · DOI
  51. Kertesz, M. et al. Genome-wide measurement of RNA secondary structure in yeast. Nature 467, 103–107 (2010) · DOI
  52. Heinz, S. et al. Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol. Cell 38, 576–589 (2010) · DOI · Paper page
  53. Bailey, T. L. & Elkan, C. Fitting a mixture model by expectation maximization to discover motifs in biopolymers. Proc. Int. Conf. Intell. Syst. Mol. Biol. 2, 28–36 (1994)
  54. Crooks, G. E., Hon, G., Chandonia, J. M. & Brenner, S. E. WebLogo: a sequence logo generator. Genome Res. 14, 1188–1190 (2004) · DOI
  55. Hinrichs, A. S. et al. The UCSC Genome Browser Database: update 2006. Nucleic Acids Res. 34, D590–D598 (2006) · DOI · Paper page
  56. Graumann, J. et al. Stable isotope labeling by amino acids in cell culture (SILAC) and proteome quantitation of mouse embryonic stem cells to a depth of 5,111 proteins. Mol. Cell. Proteomics 7, 672–683 (2008) · DOI · Paper page
  57. Noderer, W. L. et al. Quantitative analysis of mammalian translation initiation sites by FACS-seq. Mol. Syst. Biol. 10, 748 (2014) · DOI · Paper page
  58. Huppert, J. L., Bugaut, A., Kumari, S. & Balasubramanian, S. G-quadruplexes: the beginning and end of UTRs. Nucleic Acids Res. 36, 6260–6268 (2008) · DOI
  59. Beaudoin, J. D. & Perreault, J. P. 5′-UTR G-quadruplex structures acting as translational repressors. Nucleic Acids Res. 38, 7022–7036 (2010) · DOI · Paper page
  60. Lewis, B. P., Burge, C. B. & Bartel, D. P. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120, 15–20 (2005) · DOI · Paper page

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Metadata

Authors
Dominissini, D., Nachtergaele, S., Moshitch-Moshkovitz, S., Peer, E., Kol, N., Ben-Haim, M. S., Dai, Q., Di Segni, A., Salmon-Divon, M., Clark, W. C., Zheng, G., Pan, T., Solomon, O., Eyal, E., Hershkovitz, V., Han, D., Doré, L. C., Amariglio, N., Rechavi, G., & He, C.
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2016-02-10
Volume
530
Issue
7591
Pages
441-446
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/nature16998
OpenAlex
W2271995006
Cited by
1,021
References
17
FWCI
51.46
Type
journal article
Language
en
Open access
green
Licence

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