m6A mRNA modifications are deposited in nascent pre-mRNA and are not required for splicing but do specify cytoplasmic turnover

Genes and Development

Volumn 31, Issue 10, 2017, Pages 990-1006

  Ke, Shengdong ^a   Pandya Jones, Amy ^b   Saito, Yuhki ^a   Fak, John J ^a   Vågbø, Cathrine Broberg ^c   Geula, Shay ^d   Hanna, Jacob H ^d   Black, Douglas L ^b   Darnell, James E ^a   Darnell, Robert B ^a  

^a ROCKEFELLER UNIVERSITY   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

^c NORWEGIAN UNIVERSITY OF SCIENCE AND TECHNOLOGY   (Norway)

^d WEIZMANN INSTITUTE OF SCIENCE   (Israel)

Author keywords

Cell fractionation; M6A CLIP; MRNA turnover; Pre mRNA

Indexed keywords

6 N METHYLADENOSINE; MESSENGER RNA; MESSENGER RNA PRECURSOR; CHROMATIN; METHYLTRANSFERASE; METTL3 PROTEIN, MOUSE; RNA PRECURSOR;

3' UNTRANSLATED REGION; ANIMAL CELL; ARTICLE; CELL COMPONENT; CHROMATIN; CYTOPLASM; DNA MODIFICATION; EXON; FEMALE; HELA CELL LINE; HUMAN; HUMAN CELL; INTRACELLULAR SPACE; INTRON; MOUSE; NONHUMAN; NUCLEOPLASM; NUCLEOSOME; PRIORITY JOURNAL; RNA METHYLATION; RNA SEQUENCE; RNA SPLICING; SEQUENCE ANALYSIS; STOP CODON; ANIMAL; EMBRYONIC STEM CELL; GENE INACTIVATION; GENETICS; METABOLISM; METHYLATION;

ANIMALS; CHROMATIN; CYTOPLASM; EMBRYONIC STEM CELLS; EXONS; GENE KNOCKOUT TECHNIQUES; HELA CELLS; HUMANS; INTRONS; METHYLATION; METHYLTRANSFERASES; MICE; RNA PRECURSORS; RNA SPLICING; RNA, MESSENGER;

EID: 85021235923     PISSN: 08909369     EISSN: 15495477     Source Type: Journal    
DOI: 10.1101/gad.301036.117     Document Type: Article

References (75)

1. Bachenheimer S, Darnell JE. 1975. Adenovirus-2 mRNA is transcribed as part of a high-molecular-weight precursor RNA. Proc Natl Acad Sci 72: 4445-4449.
2. Batista PJ, Molinie B, Wang J, Qu K, Zhang J, Li L, Bouley DM, Lujan E, Haddad B, Daneshvar K, et al. 2014. m6A RNA modification controls cell fate transition in mammalian embryonic stem cells. Cell Stem Cell 15: 707-719.
3. Bhatt DM, Pandya-Jones A, Tong AJ, Barozzi I, Lissner MM, Natoli G, Black DL, Smale ST. 2012. Transcript dynamics of proinflammatory genes revealed by sequence analysis of subcellular RNA fractions. Cell 150: 279-290.
4. 6-adenosine methyltransferase from HeLa cell nuclei. Internal mRNA methylation requires a multisubunit complex. J Biol Chem 269: 17697-17704.
5. 6-adenosine)-methyltransferase. RNA 3: 1233-1247.
6. 6-methyladenosine react with intact snRNPs U2 and U4/U6. FEBS Lett 213: 309-315.
7. Cao G, Li HB, Yin Z, Flavell RA. 2016. Recent advances in dynamic m6A RNA modification. Open Biol 6: 160003.
8. Chen-Kiang S, Nevins JR, Darnell JEJ. 1979. N-6-methyl-adenosine in adenovirus type 2 nuclear RNA is conserved in the formation of messenger RNA. J Mol Biol 135: 733-752.
9. Chu C, Zhang QC, da Rocha ST, Flynn RA, Bharadwaj M, Calabrese JM, Magnuson T, Heard E, Chang HY. 2015. Systematic discovery of Xist RNA binding proteins. Cell 161: 404-416.
10. Custódio N, Carmo-Fonseca M, Geraghty F, Pereira HS, Grosveld F, Antoniou M. 1999. Inefficient processing impairs release of RNA from the site of transcription. EMBO J 18: 2855-2866.
11. Damianov A, Ying Y, Lin CH, Lee JA, Tran D, Vashisht AA, Bahrami-Samani E, Xing Y, Martin KC, Wohlschlegel JA, et al. 2016. Rbfox proteins regulate splicing as part of a large multiprotein complex LASR. Cell 165: 606-619.
12. Darnell JE, Wall R, Tushinski RJ. 1971. An adenylic acid-rich sequence in messenger RNA of HeLa cells and its possible relationship to reiterated sites in DNA. Proc Natl Acad Sci 68: 1321-1325.
13. Desrosiers RC, Friderici KH, Rottman FM. 1975. Characterization of Novikoff hepatoma mRNA methylation and heterogeneity in the methylated 5′ terminus. Biochemistry 14: 4367-4374.
14. Dominissini D, Moshitch-Moshkovitz S, Schwartz S, Salmon-Divon M, Ungar L, Osenberg S, Cesarkas K, Jacob-Hirsch J, Amariglio N, Kupiec M, et al. 2012. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature 485: 201-206.
15. Edmonds M, Vaughan MHJ, Nakazato H. 1971. Polyadenylic acid sequences in the heterogeneous nuclear RNA and rapidly-labeled polyribosomal RNA of HeLa cells: possible evidence for a precursor relationship. Proc Natl Acad Sci 68: 1336-1340.
16. Evans RM, Fraser N, Ziff E, Weber J, Wilson M, Darnell JE. 1977. The initiation sites for RNA transcription in Ad2 DNA. Cell 12: 733-739.
17. Fraser NW, Nevins JR, Ziff E, Darnell JEJ. 1979. The major late adenovirus type-2 transcription unit: termination is downstream from the last poly(A) site. J Mol Biol 129: 643-656.
18. Fu Y, Dominissini D, Rechavi G, He C. 2014. Gene expression regulation mediated through reversible m6A RNA methylation. Nat Rev Genet 15: 293-306.
19. Furuichi Y, Morgan M, Muthukrishnan S, Shatkin AJ. 1975. Reovirus messenger RNA contains a methylated, blocked 5′-terminal structure: m-7G(5′)ppp(5′)G-MpCp-. Proc Natl Acad Sci 72: 362-366.
20. Geula S, Moshitch-Moshkovitz S, Dominissini D, Mansour AA, Kol N, Salmon-Divon M, Hershkovitz V, Peer E, Mor N, Manor YS, et al. 2015. Stem cells. m6A mRNA methylation facilitates resolution of naive pluripotency toward differentiation. Science 347: 1002-1006.
21. 6-adenosine methylase in vitro. Nucleic Acids Res 18: 5735-5741.
22. Harpold MM, Wilson MC, Darnell JEJ. 1981. Chinese hamster polyadenylated messenger ribonucleic acid: relationship to non-polyadenylated sequences and relative conservation during messenger ribonucleic acid processing. Mol Cell Biol 1: 188-198.
23. Ke S, Alemu EA, Mertens C, Gantman EC, Fak JJ, Mele A, Haripal B, Zucker-Scharff I, Moore MJ, Park CY, et al. 2015.Amajority of m6A residues are in the last exons, allowing the potential for 3′ UTR regulation. Genes Dev 29: 2037-2053.
24. 6position of the penultimate adenosine of capped mRNA on ribosome binding. J Biol Chem 253: 5039-5041.
25. Khodor YL, Rodriguez J, Abruzzi KC, Tang CH, Marr MT, Rosbash M. 2011. Nascent-seq indicates widespread cotranscriptional pre-mRNA splicing in Drosophila. Genes Dev 25: 2502-2512.
26. Khodor YL, Menet JS, Tolan M, Rosbash M. 2012. Cotranscriptional splicing efficiency differs dramatically between Drosophila and mouse. RNA 18: 2174-2186.
27. Konig J, Zarnack K, Rot G, Curk T, Kayikci M, Zupan B, Turner DJ, Luscombe NM, Ule J. 2010. iCLIP reveals the function of hnRNP particles in splicing at individual nucleotide resolution. Nat Struct Mol Biol 17: 909-915.
28. Le Hir H, Izaurralde E, Maquat LE, Moore MJ. 2000. The spliceosome deposits multiple proteins 20-24 nucleotides upstream of mRNA exon-exon junctions. EMBO J 19: 6860-6869.
29. Le Hir H, Gatfield D, Izaurralde E, Moore MJ. 2001. The exon-exon junction complex provides a binding platform for factors involved in mRNA export and nonsense-mediated mRNA decay. EMBO J 20: 4987-4997.
30. Licatalosi DD, Mele A, Fak JJ, Ule J, Kayikci M, Chi SW, Clark TA, Schweitzer AC, Blume JE, Wang X, et al. 2008. HITSCLIP yields genome-wide insights into brain alternative RNA processing. Nature 456: 464-469.
31. 6-adenosine methylation. Nat Chem Biol 10: 93-95.
32. 6-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions. Nature 518: 560-564.
33. Maquat LE, Carmichael GG. 2001. Quality control of mRNA function. Cell 104: 173-176.
34. Mauer J, Luo X, Blanjoie A, Jiao X, Grozhik AV, Patil DP, Linder B, Pickering BF, Vasseur JJ, Chen Q, et al. 2017. Reversible methylation of m6Am in the 5′ cap controls mRNA stability. Nature 541: 371-375.
35. Meyer KD, Saletore Y, Zumbo P, Elemento O, Mason CE, Jaffrey SR. 2012. Comprehensive analysis of mRNA methylation reveals enrichment in 3′ UTRs and near stop codons. Cell 149: 1635-1646.
36. Meyer KD, Patil DP, Zhou J, Zinoviev A, Skabkin MA, Elemento O, Pestova TV, Qian SB, Jaffrey SR. 2015. 5′ UTR m(6)A promotes cap-independent translation. Cell 163: 999-1010.
37. Mitchell SF, Parker R. 2015. Modifications on Translation Initiation. Cell 163: 796-798.
38. Murphy W, Attardi G. 1973. Stability of cytoplasmic messenger RNA in HeLa cells. Proc Natl Acad Sci 70: 115-119.
39. Neff AT, Lee JY, Wilusz J, Tian B, Wilusz CJ. 2012. Global analysis reveals multiple pathways for unique regulation of mRNA decay in induced pluripotent stem cells. Genome Res 22: 1457-1467.
40. Nevins JR, Chen-Kiang S. 1981. Processing of adenovirus nuclear RNA to mRNA. Adv Virus Res 26: 1-35.
41. Nevins JR, Darnell JE Jr. 1978. Steps in the processing of Ad2 mRNA: poly(A)+ nuclear sequences are conserved and poly (A) addition precedes splicing. Cell 15: 1477-1493.
42. Pandya-Jones A, Black DL. 2009. Co-transcriptional splicing of constitutive and alternative exons. RNA 15: 1896-1908.
43. Pandya-Jones A, Bhatt DM, Lin CH, Tong AJ, Smale ST, Black DL. 2013. Splicing kinetics and transcript release from the chromatin compartment limit the rate of Lipid A-induced gene expression. RNA 19: 811-827.
44. Perry RP, Kelley DE. 1974. Existence of methylated messenger RNA in mouse L cells. Cell 1: 37-42.
45. Perry RP, Kelley DE, LaTorre J. 1974. Synthesis and turnover of nuclear and cytoplasmic polyadenylic acid in mouse L cells. J Mol Biol 82: 315-331.
46. Ping XL, Sun BF, Wang L, Xiao W, Yang X, Wang WJ, Adhikari S, Shi Y, Lv Y, Chen YS, et al. 2014. Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase. Cell Res 24: 177-189.
47. Puckett L, Darnell JE. 1977. Essential factors in the kinetic analysis of RNA synthesis in HeLa cells. J Cell Physiol 90: 521-534.
48. Puckett L, Chambers S, Darnell JE. 1975. Short-lived messenger RNA in HeLa cells and its impact on the kinetics of accumulation of cytoplasmic polyadenylate. Proc Natl Acad Sci 72: 389-393.
49. Rottman FM, Bokar JA, Narayan P, Shambaugh ME, Ludwiczak R. 1994. N6-adenosine methylation in mRNA: substrate specificity and enzyme complexity. Biochimie 76: 1109-1114.
50. Salditt-Georgieff M, Jelinek W, Darnell JE, Furuichi Y, Morgan M, Shatkin A. 1976. Methyl labeling of HeLa cell hnRNA: a comparison with mRNA. Cell 7: 227-237.
51. Schwartz S, Mumbach MR, Jovanovic M, Wang T, Maciag K, Bushkin GG, Mertins P, Ter-Ovanesyan D, Habib N, Cacchiarelli D, et al. 2014. Perturbation of m6A writers reveals two distinct classes of mRNA methylation at internal and 5′ sites. Cell Rep 8: 284-296.
52. Sharova LV, Sharov AA, Nedorezov T, Piao Y, Shaik N, Ko MS. 2009. Database for mRNA half-life of 19,977 genes obtained byDNAmicroarray analysis of pluripotent and differentiating mouse embryonic stem cells. DNA Res 16: 45-58.
53. Singer RH, Penman S. 1973. MessengerRNAin HeLa cells: kinetics of formation and decay. J Mol Biol 78: 321-334.
54. Sommer S, Lavi U, Darnell JEJ. 1978. The absolute frequency of labeled N-6-methyladenosine in HeLa cell messenger RNA decreases with label time. J Mol Biol 124: 487-499.
55. Tani H, Mizutani R, Salam KA, Tano K, Ijiri K, Wakamatsu A, Isogai T, Suzuki Y, Akimitsu N. 2012. Genome-wide determination of RNA stability reveals hundreds of short-lived noncoding transcripts in mammals. Genome Res 22: 947-956.
56. Ule J, Jensen KB, Ruggiu M, Mele A, Ule A, Darnell RB. 2003. CLIP identifies Nova-regulated RNA networks in the brain. Science 302: 1212-1215.
57. Venkatesan S, Moss B. 1982. EukaryoticmRNAcapping enzyme-guanylate covalent intermediate. Proc Natl Acad Sci 79: 340-344.
58. Wang X, He C. 2014. Reading RNA methylation codes through methyl-specific binding proteins. RNA Biol 11: 669-672.
59. Wang Y, Liu CL, Storey JD, Tibshirani RJ, Herschlag D, Brown PO. 2002. Precision and functional specificity in mRNA decay. Proc Natl Acad Sci 99: 5860-5865.
60. Wang X, Lu Z, Gomez A, Hon GC, Yue Y, Han D, Fu Y, Parisien M, Dai Q, Jia G, et al. 2014a. N6-methyladenosine-dependent regulation of messenger RNA stability. Nature 505: 117-120.
61. Wang Y, Li Y, Toth JI, Petroski MD, Zhang Z, Zhao JC. 2014b.N6-methyladenosine modification destabilizes developmental regulators in embryonic stem cells. Nat Cell Biol 16: 191-198.
62. Wang X, Zhao BS, Roundtree IA, Lu Z, Han D, Ma H, Weng X, Chen K, Shi H, He C. 2015. N6-methyladenosine modulates messenger RNA translation efficiency. Cell 161: 1388-1399.
63. Wang P, Doxtader KA, Nam Y. 2016a. Structural basis for cooperative function of Mettl3 and Mettl14 methyltransferases. Mol Cell 63: 306-317.
64. Wang X, Feng J, Xue Y, Guan Z, Zhang D, Liu Z, Gong Z, Wang Q, Huang J, Tang C, et al. 2016b. Structural basis ofN6-adenosine methylation by the METTL3-METTL14 complex. Nature 534: 575-578.
65. Weber J, Jelinek W, Darnell JEJ. 1977. The definition of a large viral transcription unit late in Ad2 infection of HeLa cells: mapping of nascentRNAmolecules labeled in isolated nuclei. Cell 10: 611-616.
66. Wei CM, Gershowitz A, Moss B. 1975. Methylated nucleotides block 5′ terminus of HeLa cell messenger RNA. Cell 4: 379-386.
67. Wuarin J, Schibler U. 1994. Physical isolation of nascent RNA chains transcribed by RNApolymerase II: evidence for cotranscriptional splicing. Mol Cell Biol 14: 7219-7225.
68. Xiao W, Adhikari S, Dahal U, Chen YS, Hao YJ, Sun BF, Sun HY, Li A, Ping XL, Lai WY, et al. 2016. Nuclear m(6)A reader YTHDC1 regulates mRNA splicing. Mol Cell 61: 507-519.
69. Yang E, van Nimwegen E, Zavolan M, Rajewsky N, Schroeder M, Magnasco M, Darnell JEJ. 2003. Decay rates of human mRNAs: correlation with functional characteristics and sequence attributes. Genome Res 13: 1863-1872.
70. Young RA. 2011. Control of the embryonic stem cell state. Cell 144: 940-954.
71. Zhang C, Darnell RB. 2011. Mapping in vivo protein-RNA interactions at single-nucleotide resolution from HITS-CLIP data. Nat Biotechnol 29: 607-614.
72. Zhang Z, Theler D, Kaminska KH, Hiller M, de la Grange P, Pudimat R, Rafalska I, Heinrich B, Bujnicki JM, Allain FH, et al. 2010. The YTH domain is a novel RNA binding domain. J Biol Chem 285: 14701-14710.
73. Zhao X, Yang Y, Sun BF, Shi Y, Yang X, Xiao W, Hao YJ, Ping XL, Chen YS, Wang WJ, et al. 2014. FTO-dependent demethylation of N6-methyladenosine regulates mRNA splicing and is required for adipogenesis. Cell Res 24: 1403-1419.
74. Zheng G, Dahl JA, Niu Y, Fedorcsak P, Huang C-M, Li CJ, Vågbø CB, Shi Y, Wang W-L, Song S-H. 2013. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol Cell 49: 18-29.
75. Zhou J, Wan J, Gao X, Zhang X, Jaffrey SR, Qian SB. 2015. Dynamic m6A mRNA methylation directs translational control of heat shock response. Nature 526: 591-594.