Skip to main content

Advertisement

SpringerLink
Log in

m6A RNA Methylation Controls Neural Development and Is Involved in Human Diseases

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

RNA modifications are involved in many aspects of biological functions. N6-methyladenosine (m6A) is one of the most important forms of RNA methylation and plays a vital role in regulating gene expression, protein translation, cell behaviors, and physiological conditions in many species, including humans. The dynamic and reversible modification of m6A is conducted by three elements: methyltransferases (“writers”), such as methyltransferase-like protein 3 (METTL3) and METTL14; m6A-binding proteins (“readers”), such as the YTH domain family proteins (YTHDFs) and YTH domain-containing protein 1 (YTHDC1); and demethylases (“erasers”), such as fat mass and obesity-associated protein (FTO) and AlkB homolog 5 (ALKBH5). In this review, we summarize the current knowledge on mapping mRNA positions of m6A modification and revealing molecular processes of m6A. We further highlight the biological significance of m6A modification in neural cells during development of the nervous system and its association with human diseases. m6A RNA methylation is becoming a new frontier in neuroscience and should help us better understand neural development and neurological diseases from a novel point of view.

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
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Maden BE, Corbett ME, Heeney PA, Pugh K, Ajuh PM (1995) Classical and novel approaches to the detection and localization of the numerous modified nucleotides in eukaryotic ribosomal RNA. Biochimie 77(1–2):22–29

    Article  CAS  PubMed  Google Scholar 

  2. Wang X, Lu Z, Gomez A, Hon GC, Yue Y, Han D, Fu Y, Parisien M et al (2014) N6-methyladenosine-dependent regulation of messenger RNA stability. Nature 505(7481):117–120. https://doi.org/10.1038/nature12730

    Article  CAS  PubMed  Google Scholar 

  3. Adams JM, Cory S (1975) Modified nucleosides and bizarre 5′-termini in mouse myeloma mRNA. Nature 255(5503):28–33

    Article  CAS  PubMed  Google Scholar 

  4. 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 the dipteran Drosophila melanogaster. J Mol Biol 120(4):487–515

    Article  CAS  PubMed  Google Scholar 

  5. Canaani D, Kahana C, Lavi S, Groner Y (1979) Identification and mapping of N6-methyladenosine containing sequences in simian virus 40 RNA. Nucleic Acids Res 6(8):2879–2899

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Chen-Kiang S, Nevins JR, Darnell JE Jr (1979) N-6-methyl-adenosine in adenovirus type 2 nuclear RNA is conserved in the formation of messenger RNA. J Mol Biol 135(3):733–752

    Article  CAS  PubMed  Google Scholar 

  7. Narayan P, Ayers DF, Rottman FM, Maroney PA, Nilsen TW (1987) Unequal distribution of N6-methyladenosine in influenza virus mRNAs. Mol Cell Biol 7(4):1572–1575

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Zhong S, Li H, Bodi Z, Button J, Vespa L, Herzog M, Fray RG (2008) MTA is an Arabidopsis messenger RNA adenosine methylase and interacts with a homolog of a sex-specific splicing factor. Plant Cell 20(5):1278–1288. https://doi.org/10.1105/tpc.108.058883

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Bodi Z, Button JD, Grierson D, Fray RG (2010) Yeast targets for mRNA methylation. Nucleic Acids Res 38(16):5327–5335. https://doi.org/10.1093/nar/gkq266

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Jia G, Fu Y, Zhao X, Dai Q, Zheng G, Yang Y, Yi C, Lindahl T et al (2011) N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat Chem Biol 7(12):885–887. https://doi.org/10.1038/nchembio.687

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Wang Y, Li Y, Toth JI, Petroski MD, Zhang Z, Zhao JC (2014) N6-methyladenosine modification destabilizes developmental regulators in embryonic stem cells. Nat Cell Biol 16(2):191–198. https://doi.org/10.1038/ncb2902

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Liu J, Yue Y, Han D, Wang X, Fu Y, Zhang L, Jia G, Yu M et al (2014) A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation. Nat Chem Biol 10(2):93–95. https://doi.org/10.1038/nchembio.1432

    Article  CAS  PubMed  Google Scholar 

  13. Ping XL, Sun BF, Wang L, Xiao W, Yang X, Wang WJ, Adhikari S, Shi Y et al (2014) Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase. Cell Res 24(2):177–189. https://doi.org/10.1038/cr.2014.3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Schwartz S, Mumbach MR, Jovanovic M, Wang T, Maciag K, Bushkin GG, Merkins P, Ter-Ovanesyan D et al (2014) Perturbation of m6A writers reveals two distinct classes of mRNA methylation at internal and 5′ sites. Cell Rep 8(1):284–296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Xu C, Wang X, Liu K, Roundtree IA, Tempel W, Li Y, Lu Z, He C et al (2014) Structural basis for selective binding of m6A RNA by the YTHDC1 YTH domain. Nat Chem Biol 10(11):927–929. https://doi.org/10.1038/nchembio.1654

    Article  CAS  PubMed  Google Scholar 

  16. Zhu T, Roundtree IA, Wang P, Wang X, Wang L, Sun C, Tian Y, Li J et al (2014) Crystal structure of the YTH domain of YTHDF2 reveals mechanism for recognition of N6-methyladenosine. Cell Res 24(12):1493–1496. https://doi.org/10.1038/cr.2014.152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Xiao W, Adhikari S, Dahal U, Chen YS, Hao YJ, Sun BF, Sun HY, Li A et al (2016) Nuclear m(6)A reader YTHDC1 regulates mRNA splicing. Mol Cell 61(4):507–519. https://doi.org/10.1016/j.molcel.2016.01.012

    Article  CAS  PubMed  Google Scholar 

  18. Alarcon CR, Goodarzi H, Lee H, Liu X, Tavazoie S, Tavazoie SF (2015) HNRNPA2B1 is a mediator of m(6)A-dependent nuclear RNA processing events. Cell 162(6):1299–1308. https://doi.org/10.1016/j.cell.2015.08.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Liu N, Dai Q, Zheng G, He C, Parisien M, Pan T (2015) N(6)-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions. Nature 518(7540):560–564. https://doi.org/10.1038/nature14234.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Zheng G, Dahl JA, Niu Y, Fedorcsak P, Huang CM, Li CJ, Vagbo CB, Shi Y et al (2013) ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol Cell 49(1):18–29. https://doi.org/10.1016/j.molcel.2012.10.015

    Article  CAS  PubMed  Google Scholar 

  21. Chandola U, Das R, Panda B (2015) Role of the N6-methyladenosine RNA mark in gene regulation and its implications on development and disease. Brief Funct Genomics 14(3):169–179. https://doi.org/10.1093/bfgp/elu039

  22. Widagdo J, Zhao Q-Y, Kempen MJ, Tan MC, Ratnu VS, Wei W, Leighton L, Spadaro PA et al (2016) Experience-dependent accumulation of N6-methyladenosine in the prefrontal cortex is associated with memory processes in mice. J Neurosci: Off J Soc Neurosci 36(25):6771–6777

    Article  CAS  Google Scholar 

  23. Levanon EY, Eisenberg E, Yelin R, Nemzer S, Hallegger M, Shemesh R, Fligelman ZY, Shoshan A et al (2004) Systematic identification of abundant A-to-I editing sites in the human transcriptome. Nat Biotechnol 22(8):1001–1005. https://doi.org/10.1038/nbt996

    Article  CAS  PubMed  Google Scholar 

  24. Dai Q, Fong R, Saikia M, Stephenson D, Yu YT, Pan T, Piccirilli JA (2007) Identification of recognition residues for ligation-based detection and quantitation of pseudouridine and N6-methyladenosine. Nucleic Acids Res 35(18):6322–6329. https://doi.org/10.1093/nar/gkm657

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Dominissini D, Moshitch-Moshkovitz S, Schwartz S, Salmon-Divon M, Ungar L, Osenberg S, Cesarkas K, Jacob-Hirsch J et al (2012) Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature 485(7397):201–206. https://doi.org/10.1038/nature11112

    Article  CAS  PubMed  Google Scholar 

  26. 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(7):1635–1646. https://doi.org/10.1016/j.cell.2012.05.003

  27. Cui Q, Shi H, Ye P, Li L, Qu Q, Sun G, Sun G, Lu Z et al (2017) m6A RNA methylation regulates the self-renewal and tumorigenesis of glioblastoma stem cells. Cell Rep 18(11):2622–2634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ke S, Alemu EA, Mertens C, Gantman EC, Fak JJ, Mele A, Haripal B, Zucker-Scharff I et al (2015) A majority of m6A residues are in the last exons, allowing the potential for 3′ UTR regulation. Genes Dev 29(19):2037–2053. https://doi.org/10.1101/gad.269415.115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Bokar JA, Shambaugh ME, Polayes D, Matera AG, Rottman FM (1997) Purification and cDNA cloning of the AdoMet-binding subunit of the human mRNA (N6-adenosine)-methyltransferase. RNA 3(11):1233–1247 http://www.ncbi.nlm.nih.gov/pubmed/9409616

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Su J, Li SJ, Chen ZH, Zeng CH, Zhou H, Li LS, Liu ZH (2010) Evaluation of podocyte lesion in patients with diabetic nephropathy: Wilms’ tumor-1 protein used as a podocyte marker. Diabetes Res Clin Pract 87(2):167–175. https://doi.org/10.1016/j.diabres.2009.10.022

    Article  CAS  PubMed  Google Scholar 

  31. Xi Z, Xue Y, Zheng J, Liu X, Ma J, Liu Y (2016) WTAP expression predicts poor prognosis in malignant glioma patients. J Mol Neurosci: MN 60(2):131–136. https://doi.org/10.1007/s12031-016-0788-6.

    Article  CAS  PubMed  Google Scholar 

  32. Haussmann IU, Bodi Z, Sanchez-Moran E, Mongan NP, Archer N, Fray RG, Soller M (2016) m6A potentiates Sxl alternative pre-mRNA splicing for robust Drosophila sex determination. Nature 540(7632):301–304. https://doi.org/10.1038/nature20577

    Article  CAS  PubMed  Google Scholar 

  33. Moindrot B, Cerase A, Coker H, Masui O, Grijzenhout A, Pintacuda G, Schermelleh L, Nesterova TB et al (2015) A pooled shRNA screen identifies Rbm15, Spen, and Wtap as factors required for Xist RNA-mediated silencing. Cell Rep 12(4):562–572. https://doi.org/10.1016/j.celrep.2015.06.053

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Patil DP, Chen CK, Pickering BF, Chow A, Jackson C, Guttman M, Jaffrey SR (2016) m(6)A RNA methylation promotes XIST-mediated transcriptional repression. Nature 537(7620):369–373. https://doi.org/10.1038/nature19342.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wang X, Feng J, Xue Y, Guan Z, Zhang D, Liu Z, Gong Z, Wang Q et al (2017) Corrigendum: Structural basis of N6-adenosine methylation by the METTL3-METTL14 complex. Nature 542(7640):260. https://doi.org/10.1038/nature21073

    Article  CAS  PubMed  Google Scholar 

  36. Wang P, Doxtader KA, Nam Y (2016) Structural basis for cooperative function of Mettl3 and Mettl14 methyltransferases. Mol Cell 63(2):306–317. https://doi.org/10.1016/j.molcel.2016.05.041

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Horiuchi K, Kawamura T, Iwanari H, Ohashi R, Naito M, Kodama T, Hamakubo T (2013) Identification of Wilms’ tumor 1-associating protein complex and its role in alternative splicing and the cell cycle. J Biol Chem 288(46):33292–33302. https://doi.org/10.1074/jbc.M113.500397.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Wen J, Lv R, Ma H, Shen H, He C, Wang J, Jiao F, Liu H et al (2018) Zc3h13 regulates nuclear RNA m(6)A methylation and mouse embryonic stem cell self-renewal. Mol Cell 69(6):1028–1038.e1026. https://doi.org/10.1016/j.molcel.2018.02.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Batista PJ (2017) The RNA modification N6-methyladenosine and its implications in human disease. Genomics Proteomics Bioinformatics. https://doi.org/10.1016/j.gpb.2017.03.002

  40. Finkel D, Groner Y (1983) Methylations of adenosine residues (m6A) in pre-mRNA are important for formation of late simian virus 40 mRNAs. Virology 131(2):409–425

    Article  CAS  PubMed  Google Scholar 

  41. Bodi Z, Zhong S, Mehra S, Song J, Graham N, Li H, May S, Fray RG (2012) Adenosine methylation in Arabidopsis mRNA is associated with the 3′ end and reduced levels cause developmental defects. Front Plant Sci 3:48. https://doi.org/10.3389/fpls.2012.00048

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Lichinchi G, Gao S, Saletore Y, Gonzalez GM (2016) Dynamics of the human and viral m(6)A RNA methylomes during HIV-1 infection of T cells. 1:16011. https://doi.org/10.1038/nmicrobiol.2016.11.

  43. 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(6076):1643–1646. https://doi.org/10.1126/science.1218469

    Article  CAS  PubMed  Google Scholar 

  44. Roundtree IA, Luo GZ, Zhang Z, Wang X, Zhou T, Cui Y, Sha J, Huang X et al (2017) YTHDC1 mediates nuclear export of N(6)-methyladenosine methylated mRNAs. Elife 6. https://doi.org/10.7554/eLife.31311

  45. Wang X, Zhao BS, Roundtree IA, Lu Z, Han D, Ma H, Weng X, Chen K et al. (2015) N(6)-methyladenosine modulates messenger RNA translation efficiency. Cell 161 (6):1388–1399. https://doi.org/10.1016/j.cell.2015.05.014.

  46. Zhou J, Wan J, Gao X, Zhang X, Jaffrey SR, Qian SB (2015) Dynamic m(6)A mRNA methylation directs translational control of heat shock response. Nature 526(7574):591–594. https://doi.org/10.1038/nature15377

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Shi H, Wang X, Lu Z, Zhao BS, Ma H, Hsu PJ, Liu C, He C (2017) YTHDF3 facilitates translation and decay of N6-methyladenosine-modified RNA. Cell Res 27(3):315–328. https://doi.org/10.1038/cr.2017.15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Konig J, Zarnack K, Rot G, Curk T, Kayikci M, Zupan B, Turner DJ, Luscombe NM et al (2010) iCLIP reveals the function of hnRNP particles in splicing at individual nucleotide resolution. Nat Struct Mol Biol 17(7):909–915. https://doi.org/10.1038/nsmb.1838

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Zarnack K, Konig J, Tajnik M, Martincorena I, Eustermann S, Stevant I, Reyes A, Anders S et al (2013) Direct competition between hnRNP C and U2AF65 protects the transcriptome from the exonization of Alu elements. Cell 152(3):453–466. https://doi.org/10.1016/j.cell.2012.12.023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Rajagopalan LE, Westmark CJ, Jarzembowski JA, Malter JS (1998) hnRNP C increases amyloid precursor protein (APP) production by stabilizing APP mRNA. Nucleic Acids Res 26(14):3418–3423

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Cienikova Z, Damberger FF, Hall J, Allain FH, Maris C (2014) Structural and mechanistic insights into poly(uridine) tract recognition by the hnRNP C RNA recognition motif. J Am Chem Soc 136(41):14536–14544. https://doi.org/10.1021/ja507690d

    Article  CAS  PubMed  Google Scholar 

  52. Denli AM, Tops BB, Plasterk RH, Ketting RF, Hannon GJ (2004) Processing of primary microRNAs by the microprocessor complex. Nature 432(7014):231–235. https://doi.org/10.1038/nature03049

    Article  CAS  PubMed  Google Scholar 

  53. Gregory RI, Yan KP, Amuthan G, Chendrimada T, Doratotaj B, Cooch N, Shiekhattar R (2004) The microprocessor complex mediates the genesis of microRNAs. Nature 432(7014):235–240. https://doi.org/10.1038/nature03120

    Article  CAS  PubMed  Google Scholar 

  54. Han J, Lee Y, Yeom KH, Kim YK, Jin H, Kim VN (2004) The Drosha-DGCR8 complex in primary microRNA processing. Genes Dev 18(24):3016–3027. https://doi.org/10.1101/gad.1262504

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Han J, Lee Y, Yeom KH, Nam JW, Heo I, Rhee JK, Sohn SY, Cho Y et al (2006) Molecular basis for the recognition of primary microRNAs by the Drosha-DGCR8 complex. Cell 125(5):887–901. https://doi.org/10.1016/j.cell.2006.03.043

    Article  CAS  PubMed  Google Scholar 

  56. Landthaler M, Yalcin A, Tuschl T (2004) The human DiGeorge syndrome critical region gene 8 and its D. melanogaster homolog are required for miRNA biogenesis. Curr Biol 14(23):2162–2167. https://doi.org/10.1016/j.cub.2004.11.001

    Article  CAS  PubMed  Google Scholar 

  57. Jia G, Yang CG, Yang S, Jian X, Yi C, Zhou Z, He C (2008) Oxidative demethylation of 3-methylthymine and 3-methyluracil in single-stranded DNA and RNA by mouse and human FTO. FEBS Lett 582(23–24):3313–3319. https://doi.org/10.1016/j.febslet.2008.08.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Bartosovic M, Molares HC, Gregorova P, Hrossova D, Kudla G, Vanacova S (2017) N6-methyladenosine demethylase FTO targets pre-mRNAs and regulates alternative splicing and 3′-end processing. Nucleic Acids Res 45(19):11356–11370. https://doi.org/10.1093/nar/gkx778

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Hess ME, Hess S, Meyer KD, Verhagen LA, Koch L, Bronneke HS, Dietrich MO, Jordan SD et al (2013) The fat mass and obesity associated gene (Fto) regulates activity of the dopaminergic midbrain circuitry. Nat Neurosci 16(8):1042–1048. https://doi.org/10.1038/nn.3449

    Article  CAS  PubMed  Google Scholar 

  60. Fischer J, Koch L, Emmerling C, Vierkotten J, Peters T, Bruning JC, Ruther U (2009) Inactivation of the Fto gene protects from obesity. Nature 458(7240):894–898. https://doi.org/10.1038/nature07848

    Article  CAS  PubMed  Google Scholar 

  61. Mauer J, Luo X, Blanjoie A, Jiao X, Grozhik AV, Patil DP, Linder B, Pickering BF et al (2017) Reversible methylation of m(6)Am in the 5′ cap controls mRNA stability. Nature 541(7637):371–375. https://doi.org/10.1038/nature21022

    Article  CAS  PubMed  Google Scholar 

  62. Wei CM, Gershowitz A, Moss B (1975) Methylated nucleotides block 5′ terminus of HeLa cell messenger RNA. Cell 4(4):379–386

    Article  CAS  PubMed  Google Scholar 

  63. Shah A, Rashid F, Awan HM, Hu S, Wang X, Chen L (2017) The DEAD-box RNA helicase DDX3 interacts with m(6)A RNA demethylase ALKBH5. 2017:8596135. https://doi.org/10.1155/2017/8596135.

  64. Cui Q, Shi H, Ye P, Li L, Qu Q, Sun G, Sun G, Lu Z et al (2017) m6A RNA methylation regulates the self-renewal and tumorigenesis of glioblastoma stem cells. Cell Rep 18(11):2622–2634. https://doi.org/10.1016/j.celrep.2017.02.059

  65. Batista PJ, Molinie B, Wang J, Qu K, Zhang J, Li L, Bouley DM, Lujan E et al (2014) m(6)A RNA modification controls cell fate transition in mammalian embryonic stem cells. Cell Stem Cell 15(6):707–719. https://doi.org/10.1016/j.stem.2014.09.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Geula S, Moshitch-Moshkovitz S, Dominissini D, Mansour AA, Kol N, Salmon-Divon M, Hershkovitz V, Peer E et al (2015) Stem cells. m6A mRNA methylation facilitates resolution of naive pluripotency toward differentiation. Science 347(6225):1002–1006. https://doi.org/10.1126/science.1261417.

    Article  CAS  PubMed  Google Scholar 

  67. Weng H, Huang H, Wu H, Qin X, Zhao BS, Dong L, Shi H, Skibbe J et al (2018) METTL14 inhibits hematopoietic stem/progenitor differentiation and promotes leukemogenesis via mRNA m(6)A modification. Cell Stem Cell 22(2):191–205.e199. https://doi.org/10.1016/j.stem.2017.11.016

    Article  CAS  PubMed  Google Scholar 

  68. Fustin JM, Doi M, Yamaguchi Y, Hida H, Nishimura S, Yoshida M, Isagawa T, Morioka MS et al (2013) RNA-methylation-dependent RNA processing controls the speed of the circadian clock. Cell 155(4):793–806. https://doi.org/10.1016/j.cell.2013.10.026

    Article  CAS  PubMed  Google Scholar 

  69. Roignant JY, Soller M (2017) m6A in mRNA: an ancient mechanism for fine-tuning gene expression. Trends Genet 33(6):380–390

    Article  CAS  PubMed  Google Scholar 

  70. Klungland A, Dahl JA (2016) Reversible RNA modifications in meiosis and pluripotency. Nat Methods 14(1):18–22. https://doi.org/10.1038/nmeth.4111

    Article  CAS  PubMed  Google Scholar 

  71. Schwartz S, Agarwala SD, Mumbach MR, Jovanovic M, Mertins P, Shishkin A, Tabach Y, Mikkelsen TS et al (2013) High-resolution mapping reveals a conserved, widespread, dynamic mRNA methylation program in yeast meiosis. Cell 155(6):1409–1421. https://doi.org/10.1016/j.cell.2013.10.047

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Xiang Y, Laurent B, Hsu CH, Nachtergaele S, Lu Z, Sheng W, Xu C, Chen H et al (2017) RNA m6A methylation regulates the ultraviolet-induced DNA damage response. Nature 543(7646):573–576. https://doi.org/10.1038/nature21671

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Roignant JY, Soller M (2017) m(6)A in mRNA: an ancient mechanism for fine-tuning gene expression. Trends Genet: TIG 33(6):380–390. https://doi.org/10.1016/j.tig.2017.04.003

    Article  CAS  PubMed  Google Scholar 

  74. Lence T, Akhtar J, Bayer M, Schmid K, Spindler L, Ho CH, Kreim N, Andrade-Navarro MA et al (2016) m6A modulates neuronal functions and sex determination in Drosophila. Nature 540(7632):242–247. https://doi.org/10.1038/nature20568

    Article  CAS  PubMed  Google Scholar 

  75. Slobodin B, Han R, Calderone V, Vrielink J, Loayza-Puch F, Elkon R, Agami R (2017) Transcription impacts the efficiency of mRNA translation via co-transcriptional N6-adenosine methylation. Cell 169(2):326–337.e312. https://doi.org/10.1016/j.cell.2017.03.031

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Li HB, Tong J, Zhu S, Batista PJ, Duffy EE, Zhao J, Bailis W, Cao G et al (2017) m(6)A mRNA methylation controls T cell homeostasis by targeting the IL-7/STAT5/SOCS pathways. Nature 548(7667):338–342. https://doi.org/10.1038/nature23450

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Zhang C, Chen Y, Sun B, Wang L, Yang Y, Ma D, Lv J, Heng J et al (2017) m6A modulates haematopoietic stem and progenitor cell specification. Nature 549(7671):273–276. https://doi.org/10.1038/nature23883

    Article  CAS  PubMed  Google Scholar 

  78. Agarwala SD, Blitzblau HG, Hochwagen A, Fink GR (2012) RNA methylation by the MIS complex regulates a cell fate decision in yeast. PLoS Genet 8(6):e1002732. https://doi.org/10.1371/journal.pgen.1002732

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Hongay CF, Grisafi PL, Galitski T, Fink GR (2006) Antisense transcription controls cell fate in Saccharomyces cerevisiae. Cell 127(4):735–745. https://doi.org/10.1016/j.cell.2006.09.038

    Article  CAS  PubMed  Google Scholar 

  80. Luo GZ, MacQueen A, Zheng G, Duan H, Dore LC, Lu Z, Liu J, Chen K et al (2014) Unique features of the m6A methylome in Arabidopsis thaliana. Nat Commun 5:5630. https://doi.org/10.1038/ncomms6630

    Article  CAS  PubMed  Google Scholar 

  81. Vu LP, Pickering BF, Cheng Y, Zaccara S, Nguyen D, Minuesa G, Chou T, Chow A et al. (2017) The N6-methyladenosine (m6A)-forming enzyme METTL3 controls myeloid differentiation of normal hematopoietic and leukemia cells. https://doi.org/10.1038/nm.4416.

  82. Haussmann IU, Bodi Z, Sanchez-Moran E, Mongan NP, Archer N, Fray RG, Soller M (2016) m(6)A potentiates Sxl alternative pre-mRNA splicing for robust Drosophila sex determination. Nature 540(7632):301–304. https://doi.org/10.1038/nature20577.

    Article  CAS  PubMed  Google Scholar 

  83. Knuckles P, Lence T, Haussmann IU, Jacob D, Kreim N, Carl SH, Masiello I, Hares T et al (2018) Zc3h13/Flacc is required for adenosine methylation by bridging the mRNA-binding factor Rbm15/Spenito to the m(6)A machinery component Wtap/Fl(2)d. Genes Dev 32(5–6):415–429. https://doi.org/10.1101/gad.309146.117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. DeBoer EM, Kraushar ML, Hart RP, Rasin MR (2013) Post-transcriptional regulatory elements and spatiotemporal specification of neocortical stem cells and projection neurons. Neuroscience 248:499–528. https://doi.org/10.1016/j.neuroscience.2013.05.042

    Article  CAS  PubMed  Google Scholar 

  85. Yoon KJ, Ringeling FR, Vissers C, Jacob F, Pokrass M, Jimenez-Cyrus D, Su Y, Kim NS et al (2017) Temporal control of mammalian cortical neurogenesis by m(6)A methylation. Cell 171(4):877–889.e817. https://doi.org/10.1016/j.cell.2017.09.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Gerken T, Girard CA, Tung YC, Webby CJ, Saudek V, Hewitson KS, Yeo GS, McDonough MA et al (2007) The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Science 318(5855):1469–1472. https://doi.org/10.1126/science.1151710

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. McTaggart JS, Lee S, Iberl M, Church C, Cox RD, Ashcroft FM (2011) FTO is expressed in neurones throughout the brain and its expression is unaltered by fasting. PLoS One 6(11):e27968. https://doi.org/10.1371/journal.pone.0027968

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Gulati P, Cheung MK, Antrobus R, Church CD, Harding HP, Tung YC, Rimmington D, Ma M et al (2013) Role for the obesity-related FTO gene in the cellular sensing of amino acids. Proc Natl Acad Sci U S A 110(7):2557–2562. https://doi.org/10.1073/pnas.1222796110

    Article  PubMed  PubMed Central  Google Scholar 

  89. Garcia-Tornadu I, Risso G, Perez-Millan MI, Noain D, Diaz-Torga G, Low MJ, Rubinstein M, Becu-Villalobos D (2010) Neurotransmitter modulation of the GHRH-GH axis. Front Horm Res 38:59–69. https://doi.org/10.1159/000318495

    Article  CAS  PubMed  Google Scholar 

  90. Namima M, Sugihara K, Watanabe Y, Sasa H, Umekage T, Okamoto K (1999) Quantitative analysis of the effects of lithium on the reverse tolerance and the c-Fos expression induced by methamphetamine in mice. Brain Res Brain Res Protocols 4(1):11–18

    Article  CAS  Google Scholar 

  91. Di Chiara G, Bassareo V (2007) Reward system and addiction: what dopamine does and doesn’t do. Curr Opin Pharmacol 7(1):69–76. https://doi.org/10.1016/j.coph.2006.11.003

    Article  CAS  PubMed  Google Scholar 

  92. Anderson AM, Weasner BP, Weasner BM, Kumar JP (2014) The Drosophila Wilms tumor 1-associating protein (WTAP) homolog is required for eye development. Dev Biol 390(2):170–180. https://doi.org/10.1016/j.ydbio.2014.03.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Boissel S, Reish O, Proulx K, Kawagoe-Takaki H, Sedgwick B, Yeo GS, Meyre D, Golzio C et al (2009) Loss-of-function mutation in the dioxygenase-encoding FTO gene causes severe growth retardation and multiple malformations. Am J Hum Genet 85(1):106–111. https://doi.org/10.1016/j.ajhg.2009.06.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Choudhry Z, Sengupta SM, Grizenko N, Thakur GA, Fortier ME, Schmitz N, Joober R (2013) Association between obesity-related gene FTO and ADHD. Obesity (Silver Spring, Md) 21(12):E738–E744. https://doi.org/10.1002/oby.20444.

    Article  CAS  Google Scholar 

  95. Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM, Perry JR, Elliott KS 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(5826):889–894. https://doi.org/10.1126/science.1141634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Ho AJ, Stein JL, Hua X, Lee S, Hibar DP, Leow AD, Dinov ID, Toga AW et al (2010) A commonly carried allele of the obesity-related FTO gene is associated with reduced brain volume in the healthy elderly. Proc Natl Acad Sci U S A 107(18):8404–8409. https://doi.org/10.1073/pnas.0910878107

    Article  PubMed  PubMed Central  Google Scholar 

  97. Smemo S, Tena JJ, Kim KH, Gamazon ER, Sakabe NJ, Gomez-Marin C, Aneas I, Credidio FL et al (2014) Obesity-associated variants within FTO form long-range functional connections with IRX3. Nature 507(7492):371–375. https://doi.org/10.1038/nature13138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Sobczyk-Kopciol A, Broda G, Wojnar M, Kurjata P, Jakubczyk A, Klimkiewicz A, Ploski R (2011) Inverse association of the obesity predisposing FTO rs9939609 genotype with alcohol consumption and risk for alcohol dependence. Addiction 106(4):739–748. https://doi.org/10.1111/j.1360-0443.2010.03248.x.

    Article  PubMed  Google Scholar 

  99. Bertero A, Brown S, Madrigal P, Osnato A, Ortmann D, Yiangou L, Kadiwala J, Hubner NC et al (2018) The SMAD2/3 interactome reveals that TGFbeta controls m(6)A mRNA methylation in pluripotency. Nature 555(7695):256–259. https://doi.org/10.1038/nature25784

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Linnebacher M, Wienck A, Boeck I, Klar E (2010) Identification of an MSI-H tumor-specific cytotoxic T cell epitope generated by the (−1) frame of U79260(FTO). J Biomed Biotechnol 2010:841451. https://doi.org/10.1155/2010/841451

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Pierce BL, Austin MA, Ahsan H (2011) Association study of type 2 diabetes genetic susceptibility variants and risk of pancreatic cancer: an analysis of PanScan-I data. Cancer Causes Control 22(6):877–883. https://doi.org/10.1007/s10552-011-9760-5

    Article  PubMed  PubMed Central  Google Scholar 

  102. Jin DI, Lee SW, Han ME, Kim HJ, Seo SA, Hur GY, Jung S, Kim BS et al (2012) Expression and roles of Wilms’ tumor 1-associating protein in glioblastoma. Cancer Sci 103(12):2102–2109. https://doi.org/10.1111/cas.12022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Reddy SM, Sadim M, Li J, Yi N, Agarwal S, Mantzoros CS, Kaklamani VG (2013) Clinical and genetic predictors of weight gain in patients diagnosed with breast cancer. Br J Cancer 109(4):872–881. https://doi.org/10.1038/bjc.2013.441

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Long J, Zhang B, Signorello LB, Cai Q, Deming-Halverson S, Shrubsole MJ, Sanderson M, Dennis J et al (2013) Evaluating genome-wide association study-identified breast cancer risk variants in African-American women. PLoS One 8(4):e58350. https://doi.org/10.1371/journal.pone.0058350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Lin S, Choe J, Du P, Triboulet R, Gregory RI (2016) The m(6)A methyltransferase METTL3 promotes translation in human cancer cells. Mol Cell 62(3):335–345. https://doi.org/10.1016/j.molcel.2016.03.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Zhang C, Samanta D, Lu H, Bullen JW, Zhang H, Chen I, He X, Semenza GL (2016) Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m(6)A-demethylation of NANOG mRNA. Proc Natl Acad Sci U S A 113(14):E2047–E2056. https://doi.org/10.1073/pnas.1602883113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Kwok CT, Marshall AD, Rasko JE, Wong JJ (2017) Genetic alterations of m(6)A regulators predict poorer survival in acute myeloid leukemia. J Hematol Oncol 10(1):39. https://doi.org/10.1186/s13045-017-0410-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Nishizawa Y, Konno M, Asai A, Koseki J, Kawamoto K, Miyoshi N, Takahashi H, Nishida N et al (2018) Oncogene c-Myc promotes epitranscriptome m(6)A reader YTHDF1 expression in colorectal cancer. Oncotarget 9(7):7476–7486. https://doi.org/10.18632/oncotarget.23554

    Article  PubMed  Google Scholar 

  109. Zhang S, Zhao BS, Zhou A, Lin K, Zheng S, Lu Z, Chen Y, Sulman EP et al (2017) m(6)A demethylase ALKBH5 maintains tumorigenicity of glioblastoma stem-like cells by sustaining FOXM1 expression and cell proliferation program. Cancer Cell 31(4):591–606.e596. https://doi.org/10.1016/j.ccell.2017.02.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Du T, Rao S, Wu L, Ye N, Liu Z, Hu H, Xiu J, Shen Y et al (2015) An association study of the m6A genes with major depressive disorder in Chinese Han population. J Affect Disord 183:279–286. https://doi.org/10.1016/j.jad.2015.05.025

  111. Hibar DP, Adams HH, Jahanshad N, Chauhan G, Stein JL, Hofer E, Renteria ME, Bis JC et al (2017) Novel genetic loci associated with hippocampal volume. Nat Commun 8:13624. https://doi.org/10.1038/ncomms13624

  112. Li H, Ren Y, Mao K, Hua F, Yang Y, Wei N, Yue C, Li D et al (2018) FTO is involved in Alzheimer’s disease by targeting TSC1-mTOR-Tau signaling. Biochem Biophys Res Commun 498(1):234–239. https://doi.org/10.1016/j.bbrc.2018.02.201

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the members of the Sun Laboratory for their valuable discussions and advice.

Funding

This work was supported by the Subsidized Project for Postgraduates’ Innovative Fund in Scientific Research of Huaqiao University (K.D.), an R01-MH083680 grant from the NIH/NIMH (T.S.), and the National Natural Science Foundation of China (81471152, 31771141, and 81701132).

Author information

Authors and Affiliations

  1. Center for Precision Medicine, School of Medicine and School of Biomedical Sciences, Huaqiao University, Xiamen, 361021, Fujian, China

    Kunzhao Du, Longbin Zhang & Tao Sun

  2. Department of Cell and Developmental Biology, Cornell University Weill Medical College, 1300 York Avenue, Box 60, New York, NY, 10065, USA

    Trevor Lee & Tao Sun

Authors
  1. Kunzhao Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Longbin Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Trevor Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tao Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tao Sun.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Du, K., Zhang, L., Lee, T. et al. m6A RNA Methylation Controls Neural Development and Is Involved in Human Diseases. Mol Neurobiol 56, 1596–1606 (2019). https://doi.org/10.1007/s12035-018-1138-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-018-1138-1

Keywords

Search

Navigation