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Epitranscriptomic regulation of transcriptome plasticity in development and diseases of the brain

  • Park, Chan-Woo (Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST)) ;
  • Lee, Sung-Min (Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST)) ;
  • Yoon, Ki-Jun (Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST))
  • Received : 2020.09.02
  • Published : 2020.11.30

Abstract

Proper development of the nervous system is critical for its function, and deficits in neural development have been implicated in many brain disorders. A precise and predictable developmental schedule requires highly coordinated gene expression programs that orchestrate the dynamics of the developing brain. Especially, recent discoveries have been showing that various mRNA chemical modifications can affect RNA metabolism including decay, transport, splicing, and translation in cell type- and tissue-specific manner, leading to the emergence of the field of epitranscriptomics. Moreover, accumulating evidences showed that certain types of RNA modifications are predominantly found in the developing brain and their dysregulation disrupts not only the developmental processes, but also neuronal activities, suggesting that epitranscriptomic mechanisms play critical post-transcriptional regulatory roles in development of the brain and etiology of brain disorders. Here, we review recent advances in our understanding of molecular regulation on transcriptome plasticity by RNA modifications in neurodevelopment and how alterations in these RNA regulatory programs lead to human brain disorders.

Keywords

References

  1. Telley L, Govindan S, Prados J et al (2016) Sequential transcriptional waves direct the differentiation of newborn neurons in the mouse neocortex. Science 351, 1443-1446 https://doi.org/10.1126/science.aad8361
  2. Yoon KJ, Vissers C, Ming GL and Song H (2018) Epigenetics and epitranscriptomics in temporal patterning of cortical neural progenitor competence. J Cell Biol 217, 1901-1914 https://doi.org/10.1083/jcb.201802117
  3. Livneh I, Moshitch-Moshkovitz S, Amariglio N, Rechavi G and Dominissini D (2020) The m6A epitranscriptome: transcriptome plasticity in brain development and function. Nat Rev Neurosci 21, 36-51 https://doi.org/10.1038/s41583-019-0244-z
  4. Zhao BS, Roundtree IA and He C (2017) Post-transcriptional gene regulation by mRNA modifications. Nat Rev Mol Cell Biol 18, 31-42 https://doi.org/10.1038/nrm.2016.132
  5. Meyer KD and Jaffrey SR (2017) Rethinking m(6)A readers, writers, and erasers. Annu Rev Cell Dev Biol 33, 319-342 https://doi.org/10.1146/annurev-cellbio-100616-060758
  6. Hussain S (2017) Shaping and reshaping transcriptome plasticity during evolution. Trends Biochem Sci 42, 682-684 https://doi.org/10.1016/j.tibs.2017.06.009
  7. Meyer KD, Saletore Y, Zumbo P, Elemento O, Mason CE and Jaffrey SR (2012) Comprehensive analysis of mRNA methylation reveals enrichment in 3' UTRs and near stop codons. Cell 149, 1635-1646 https://doi.org/10.1016/j.cell.2012.05.003
  8. Liu J, Li K, Cai J et al (2020) Landscape and regulation of m(6)A and m(6)Am Methylome across human and mouse tissues. Mol Cell 77, 426-440 e426 https://doi.org/10.1016/j.molcel.2019.09.032
  9. Liu J, An Z, Luo J, Li J, Li F and Zhang Z (2020) Episo: quantitative estimation of RNA 5-methylcytosine at isoform level by high-throughput sequencing of RNA treated with bisulfite. Bioinformatics 36, 2033-2039 https://doi.org/10.1093/bioinformatics/btz900
  10. Li X, Zhu P, Ma S et al (2015) Chemical pulldown reveals dynamic pseudouridylation of the mammalian transcriptome. Nat Chem Biol 11, 592-597 https://doi.org/10.1038/nchembio.1836
  11. Dominissini D, Moshitch-Moshkovitz S, Schwartz S et al (2012) Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature 485, 201-206 https://doi.org/10.1038/nature11112
  12. Meyer KD, Patil DP, Zhou J et al (2015) 5' UTR m(6)A Promotes Cap-Independent Translation. Cell 163, 999-1010 https://doi.org/10.1016/j.cell.2015.10.012
  13. Liu J, Yue Y, Han D et al (2014) A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation. Nat Chem Biol 10, 93-95 https://doi.org/10.1038/nchembio.1432
  14. Jia G, Fu Y, Zhao X et al (2011) N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat Chem Biol 7, 885-887 https://doi.org/10.1038/nchembio.687
  15. Zheng G, Dahl JA, Niu Y et al (2013) ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol Cell 49, 18-29 https://doi.org/10.1016/j.molcel.2012.10.015
  16. Wei J, Liu F, Lu Z et al (2018) Differential m(6)A, m(6)Am, and m(1)A demethylation mediated by FTO in the cell nucleus and cytoplasm. Mol Cell 71, 973-985 e975 https://doi.org/10.1016/j.molcel.2018.08.011
  17. Mauer J and Jaffrey SR (2018) FTO, m(6) Am , and the hypothesis of reversible epitranscriptomic mRNA modifications. FEBS Lett 592, 2012-2022 https://doi.org/10.1002/1873-3468.13092
  18. Wang X, Zhao BS, Roundtree IA et al (2015) N(6)-methyladenosine modulates messenger RNA translation efficiency. Cell 161, 1388-1399 https://doi.org/10.1016/j.cell.2015.05.014
  19. Du H, Zhao Y, He J et al (2016) YTHDF2 destabilizes m(6)A-containing RNA through direct recruitment of the CCR4-NOT deadenylase complex. Nat Commun 7, 12626 https://doi.org/10.1038/ncomms12626
  20. Park OH, Ha H, Lee Y et al (2019) Endoribonucleolytic cleavage of m(6)A-containing RNAs by RNase P/MRP complex. Mol Cell 74, 494-507 e498 https://doi.org/10.1016/j.molcel.2019.02.034
  21. Shi H, Wang X, Lu Z et al (2017) YTHDF3 facilitates translation and decay of N(6)-methyladenosine-modified RNA. Cell Res 27, 315-328 https://doi.org/10.1038/cr.2017.15
  22. Zaccara S and Jaffrey SR (2020) A unified model for the function of YTHDF proteins in regulating m(6)A-modified mRNA. Cell 181, 1582-1595 e1518 https://doi.org/10.1016/j.cell.2020.05.012
  23. Lasman L, Krupalnik V, Viukov S et al (2020) Contextdependent functional compensation between Ythdf m6A reader proteins. Genes Dev 34, 19-20
  24. Xiao W, Adhikari S, Dahal U et al (2016) Nuclear m(6)A reader YTHDC1 regulates mRNA splicing. Mol Cell 61, 507-519 https://doi.org/10.1016/j.molcel.2016.01.012
  25. Roundtree IA, Luo GZ, Zhang Z et al (2017) YTHDC1 mediates nuclear export of N(6)-methyladenosine methylated mRNAs. Elife 6, e31311 https://doi.org/10.7554/elife.31311
  26. Patil DP, Chen CK, Pickering BF et al (2016) m(6)A RNA methylation promotes XIST-mediated transcriptional repression. Nature 537, 369-373 https://doi.org/10.1038/nature19342
  27. Mao Y, Dong L, Liu XM et al (2019) m(6)A in mRNA coding regions promotes translation via the RNA helicase-containing YTHDC2. Nat Commun 10, 5332 https://doi.org/10.1038/s41467-019-13317-9
  28. Alarcon CR, Lee H, Goodarzi H, Halberg N and Tavazoie SF (2015) N6-methyladenosine marks primary microRNAs for processing. Nature 519, 482-485 https://doi.org/10.1038/nature14281
  29. Huang H, Weng H, Sun W et al (2018) Recognition of RNA N(6)-methyladenosine by IGF2BP proteins enhances mRNA stability and translation. Nat Cell Biol 20, 285-295 https://doi.org/10.1038/s41556-018-0045-z
  30. Wu R, Li A, Sun B et al (2019) A novel m(6)A reader Prrc2a controls oligodendroglial specification and myelination. Cell Res 29, 23-41 https://doi.org/10.1038/s41422-018-0113-8
  31. Dimitrova DG, Teysset L and Carre C (2019) RNA 2'-O-methylation (Nm) modification in human diseases. Genes (Basel) 10, 117 https://doi.org/10.3390/genes10020117
  32. Byszewska M, Smietanski M, Purta E and Bujnicki JM (2014) RNA methyltransferases involved in 5' cap biosynthesis. RNA Biol 11, 1597-1607 https://doi.org/10.1080/15476286.2015.1004955
  33. Dai Q, Moshitch-Moshkovitz S, Han D et al (2017) Nm-seq maps 2'-O-methylation sites in human mRNA with base precision. Nat Methods 14, 695-698 https://doi.org/10.1038/nmeth.4294
  34. Guy MP and Phizicky EM (2015) Conservation of an intricate circuit for crucial modifications of the tRNAPhe anticodon loop in eukaryotes. RNA 21, 61-74 https://doi.org/10.1261/rna.047639.114
  35. Leschziner GD, Coffey AJ, Andrew T et al (2011) Q8IYL2 is a candidate gene for the familial epilepsy syndrome of Partial Epilepsy with Pericentral Spikes (PEPS). Epilepsy Res 96, 109-115 https://doi.org/10.1016/j.eplepsyres.2011.05.010
  36. Reichow SL, Hamma T, Ferre-D'Amare AR and Varani G (2007) The structure and function of small nucleolar ribonucleoproteins. Nucleic Acids Res 35, 1452-1464 https://doi.org/10.1093/nar/gkl1172
  37. Belanger F, Stepinski J, Darzynkiewicz E and Pelletier J (2010) Characterization of hMTr1, a human Cap1 2'-O-ribose methyltransferase. J Biol Chem 285, 33037-33044 https://doi.org/10.1074/jbc.M110.155283
  38. Khoddami V and Cairns BR (2013) Identification of direct targets and modified bases of RNA cytosine methyltransferases. Nat Biotechnol 31, 458-464 https://doi.org/10.1038/nbt.2566
  39. Yang X, Yang Y, Sun BF et al (2017) 5-methylcytosine promotes mRNA export - NSUN2 as the methyltransferase and ALYREF as an m(5)C reader. Cell Res 27, 606-625 https://doi.org/10.1038/cr.2017.55
  40. Xing J, Yi J, Cai X et al (2015) NSun2 promotes cell growth via elevating cyclin-dependent kinase 1 translation. Mol Cell Biol 35, 4043-4052 https://doi.org/10.1128/MCB.00742-15
  41. Motorin Y, Lyko F and Helm M (2010) 5-methylcytosine in RNA: detection, enzymatic formation and biological functions. Nucleic Acids Res 38, 1415-1430 https://doi.org/10.1093/nar/gkp1117
  42. Basanta-Sanchez M, Wang R, Liu Z et al (2017) TET1-mediated oxidation of 5-formylcytosine (5fC) to 5-carboxycytosine (5caC) in RNA. Chembiochem 18, 72-76 https://doi.org/10.1002/cbic.201600328
  43. Jobert L, Skjeldam HK, Dalhus B et al (2013) The human base excision repair enzyme SMUG1 directly interacts with DKC1 and contributes to RNA quality control. Mol Cell 49, 339-345 https://doi.org/10.1016/j.molcel.2012.11.010
  44. Schwartz S, Bernstein DA, Mumbach MR et al (2014) Transcriptome-wide mapping reveals widespread dynamicregulated pseudouridylation of ncRNA and mRNA. Cell 159, 148-162 https://doi.org/10.1016/j.cell.2014.08.028
  45. Carlile TM, Rojas-Duran MF, Zinshteyn B, Shin H, Bartoli KM and Gilbert WV (2014) Pseudouridine profiling reveals regulated mRNA pseudouridylation in yeast and human cells. Nature 515, 143-146 https://doi.org/10.1038/nature13802
  46. Duan J, Li L, Lu J, Wang W and Ye K (2009) Structural mechanism of substrate RNA recruitment in H/ACA RNA-guided pseudouridine synthase. Mol Cell 34, 427-439 https://doi.org/10.1016/j.molcel.2009.05.005
  47. Carlile TM, Martinez NM, Schaening C et al (2019) mRNA structure determines modification by pseudouridine synthase 1. Nat Chem Biol 15, 966-974 https://doi.org/10.1038/s41589-019-0353-z
  48. Yoon KJ, Ringeling FR, Vissers C et al (2017) Temporal control of mammalian cortical neurogenesis by m(6)A methylation. Cell 171, 877-889 e817 https://doi.org/10.1016/j.cell.2017.09.003
  49. Wang Y, Li Y, Yue M et al (2018) N(6)-methyladenosine RNA modification regulates embryonic neural stem cell self-renewal through histone modifications. Nat Neurosci 21, 195-206 https://doi.org/10.1038/s41593-017-0057-1
  50. Li Y, Xia L, Tan K et al (2020) N(6)-Methyladenosine co-transcriptionally directs the demethylation of histone H3K9me2. Nat Genet 52, 870-877 https://doi.org/10.1038/s41588-020-0677-3
  51. Yao B, Christian KM, He C, Jin P, Ming GL and Song H (2016) Epigenetic mechanisms in neurogenesis. Nat Rev Neurosci 17, 537-549 https://doi.org/10.1038/nrn.2016.70
  52. Li M, Zhao X, Wang W et al (2018) Ythdf2-mediated m(6)A mRNA clearance modulates neural development in mice. Genome Biol 19, 69 https://doi.org/10.1186/s13059-018-1436-y
  53. Guy MP, Shaw M, Weiner CL et al (2015) Defects in tRNA anticodon loop 2'-O-methylation are implicated in nonsyndromic X-linked intellectual disability due to mutations in FTSJ1. Hum Mutat 36, 1176-1187 https://doi.org/10.1002/humu.22897
  54. Higa-Nakamine S, Suzuki T, Uechi T et al (2012) Loss of ribosomal RNA modification causes developmental defects in zebrafish. Nucleic Acids Res 40, 391-398 https://doi.org/10.1093/nar/gkr700
  55. Bouffard S, Dambroise E, Brombin A et al (2018) Fibrillarin is essential for S-phase progression and neuronal differentiation in zebrafish dorsal midbrain and retina. Dev Biol 437, 1-16 https://doi.org/10.1016/j.ydbio.2018.02.006
  56. Cavaille J, Buiting K, Kiefmann M et al (2000) Identification of brain-specific and imprinted small nucleolar RNA genes exhibiting an unusual genomic organization. Proc Natl Acad Sci U S A 97, 14311-14316 https://doi.org/10.1073/pnas.250426397
  57. Peters J (2008) Prader-Willi and snoRNAs. Nat Genet 40, 688-689 https://doi.org/10.1038/ng0608-688
  58. Rai K, Chidester S, Zavala CV et al (2007) Dnmt2 functions in the cytoplasm to promote liver, brain, and retina development in zebrafish. Genes Dev 21, 261-266 https://doi.org/10.1101/gad.1472907
  59. Goll MG, Kirpekar F, Maggert KA et al (2006) Methylation of tRNAAsp by the DNA methyltransferase homolog Dnmt2. Science 311, 395-398 https://doi.org/10.1126/science.1120976
  60. Blanco S, Dietmann S, Flores JV et al (2014) Aberrant methylation of tRNAs links cellular stress to neuro-developmental disorders. EMBO J 33, 2020-2039 https://doi.org/10.15252/embj.201489282
  61. Flores JV, Cordero-Espinoza L, Oeztuerk-Winder F et al (2017) Cytosine-5 RNA methylation regulates neural stem cell differentiation and motility. Stem Cell Reports 8, 112-124 https://doi.org/10.1016/j.stemcr.2016.11.014
  62. Tuorto F, Liebers R, Musch T et al (2012) RNA cytosine methylation by Dnmt2 and NSun2 promotes tRNA stability and protein synthesis. Nat Struct Mol Biol 19, 900-905 https://doi.org/10.1038/nsmb.2357
  63. Angelova MT, Dimitrova DG, Dinges N et al (2018) The emerging field of epitranscriptomics in neurodevelopmental and neuronal disorders. Front Bioeng Biotechnol 6, 46 https://doi.org/10.3389/fbioe.2018.00046
  64. Shaheen R, Han L, Faqeih E et al (2016) A homozygous truncating mutation in PUS3 expands the role of tRNA modification in normal cognition. Hum Genet 135, 707-713 https://doi.org/10.1007/s00439-016-1665-7
  65. Heiss NS, Bachner D, Salowsky R, Kolb A, Kioschis P and Poustka A (2000) Gene structure and expression of the mouse dyskeratosis congenita gene, dkc1. Genomics 67, 153-163 https://doi.org/10.1006/geno.2000.6227
  66. Xu H, Dzhashiashvili Y, Shah A et al (2020) m(6)A mRNA methylation is essential for oligodendrocyte maturation and CNS myelination. Neuron 105, 293-309 e295 https://doi.org/10.1016/j.neuron.2019.12.013
  67. Chizhikov V and Millen KJ (2003) Development and malformations of the cerebellum in mice. Mol Genet Metab 80, 54-65 https://doi.org/10.1016/j.ymgme.2003.08.019
  68. Wang CX, Cui GS, Liu X et al (2018) METTL3-mediated m6A modification is required for cerebellar development. PLoS Biol 16, e2004880 https://doi.org/10.1371/journal.pbio.2004880
  69. Ma C, Chang M, Lv H et al (2018) RNA m(6)A methylation participates in regulation of postnatal development of the mouse cerebellum. Genome Biol 19, 68 https://doi.org/10.1186/s13059-018-1435-z
  70. Ma DK, Bonaguidi MA, Ming GL and Song H (2009) Adult neural stem cells in the mammalian central nervous system. Cell Res 19, 672-682 https://doi.org/10.1038/cr.2009.56
  71. Chen J, Zhang YC, Huang C et al (2019) m(6)A regulates neurogenesis and neuronal development by modulating histone methyltransferase Ezh2. Genomics Proteomics Bioinformatics 17, 154-168 https://doi.org/10.1016/j.gpb.2018.12.007
  72. Li L, Zang L, Zhang F et al (2017) Fat mass and obesity-associated (FTO) protein regulates adult neurogenesis. Hum Mol Genet 26, 2398-2411 https://doi.org/10.1093/hmg/ddx128
  73. Batool S, Raza H, Zaidi J, Riaz S, Hasan S and Syed NI (2019) Synapse formation: from cellular and molecular mechanisms to neurodevelopmental and neurodegenerative disorders. J Neurophysiol 121, 1381-1397 https://doi.org/10.1152/jn.00833.2018
  74. Chang M, Lv H, Zhang W et al (2017) Region-specific RNA m(6)A methylation represents a new layer of control in the gene regulatory network in the mouse brain. Open Biol 7, 170166 https://doi.org/10.1098/rsob.170166
  75. Engel M, Eggert C, Kaplick PM et al (2018) The role of m(6)A/m-RNA methylation in stress response regulation. Neuron 99, 389-403 e389 https://doi.org/10.1016/j.neuron.2018.07.009
  76. Koranda JL, Dore L, Shi H et al (2018) Mettl14 is essential for epitranscriptomic regulation of striatal function and learning. Neuron 99, 283-292 e285 https://doi.org/10.1016/j.neuron.2018.06.007
  77. Shi H, Zhang X, Weng YL et al (2018) m(6)A facilitates hippocampus-dependent learning and memory through YTHDF1. Nature 563, 249-253 https://doi.org/10.1038/s41586-018-0666-1
  78. Merkurjev D, Hong WT, Iida K et al (2018) Synaptic N(6)-methyladenosine (m(6)A) epitranscriptome reveals functional partitioning of localized transcripts. Nat Neurosci 21, 1004-1014 https://doi.org/10.1038/s41593-018-0173-6
  79. Zhang Z, Wang M, Xie D et al (2018) METTL3-mediated N(6)-methyladenosine mRNA modification enhances long-term memory consolidation. Cell Res 28, 1050-1061 https://doi.org/10.1038/s41422-018-0092-9
  80. Hou Y, Dan X, Babbar M et al (2019) Ageing as a risk factor for neurodegenerative disease. Nat Rev Neurol 15, 565-581 https://doi.org/10.1038/s41582-019-0244-7
  81. Casella G, Tsitsipatis D, Abdelmohsen K and Gorospe M (2019) mRNA methylation in cell senescence. Wiley Interdiscip Rev RNA 10, e1547
  82. Min KW, Zealy RW, Davila S et al (2018) Profiling of m6A RNA modifications identified an age-associated regulation of AGO2 mRNA stability. Aging Cell 17, e12753 https://doi.org/10.1111/acel.12753
  83. Lee MY, Leonardi A, Begley TJ and Melendez JA (2020) Loss of epitranscriptomic control of selenocysteine utilization engages senescence and mitochondrial reprogramming. Redox Biol 28, 101375 https://doi.org/10.1016/j.redox.2019.101375
  84. Weng YL, Wang X, An R et al (2018) Epitranscriptomic m(6)A regulation of axon regeneration in the adult mammalian nervous system. Neuron 97, 313-325 e316 https://doi.org/10.1016/j.neuron.2017.12.036
  85. Cumming TB and Brodtmann A (2011) Can stroke cause neurodegenerative dementia? Int J Stroke 6, 416-424 https://doi.org/10.1111/j.1747-4949.2011.00666.x
  86. Chokkalla AK, Mehta SL, Kim T, Chelluboina B, Kim J and Vemuganti R (2019) Transient focal ischemia significantly alters the m(6)A epitranscriptomic tagging of RNAs in the brain. Stroke 50, 2912-2921 https://doi.org/10.1161/STROKEAHA.119.026433
  87. Fan L, Mao C, Hu X et al (2019) New insights into the pathogenesis of Alzheimer's disease. Front Neurol 10, 1312 https://doi.org/10.3389/fneur.2019.01312
  88. Keller L, Xu W, Wang HX, Winblad B, Fratiglioni L and Graff C (2011) The obesity related gene, FTO, interacts with APOE, and is associated with Alzheimer's disease risk: a prospective cohort study. J Alzheimers Dis 23, 461-469 https://doi.org/10.3233/JAD-2010-101068
  89. Reitz C, Tosto G, Mayeux R, Luchsinger JA, Group N-LNFS and Alzheimer's disease neuroimaging I (2012) Genetic variants in the fat and obesity associated (FTO) gene and risk of Alzheimer's disease. PLoS One 7, e50354 https://doi.org/10.1371/journal.pone.0050354
  90. Li H, Ren Y, Mao K et al (2018) FTO is involved in Alzheimer's disease by targeting TSC1-mTOR-Tau signaling. Biochem Biophys Res Commun 498, 234-239 https://doi.org/10.1016/j.bbrc.2018.02.201
  91. Liu X, Meng P, Yang G, Zhang M, Peng S and Zhai MZ (2020) Genome-wide identification and transcript profiles of walnut heat stress transcription factor involved in abiotic stress. BMC Genomics 21, 474 https://doi.org/10.1186/s12864-020-06879-2
  92. Westmark CJ, Maloney B, Alisch RS, Sokol DK and Lahiri DK (2020) FMRP regulates the nuclear export of Adam9 and Psen1 mRNAs: secondary analysis of an N(6)-methyladenosine dataset. Sci Rep 10, 10781 https://doi.org/10.1038/s41598-020-66394-y
  93. Boza-Serrano A, Yang Y, Paulus A and Deierborg T (2018) Innate immune alterations are elicited in microglial cells before plaque deposition in the Alzheimer's disease mouse model 5xFAD. Sci Rep 8, 1550 https://doi.org/10.1038/s41598-018-19699-y
  94. Balestrino R and Schapira AHV (2020) Parkinson disease. Eur J Neurol 27, 27-42 https://doi.org/10.1111/ene.14108
  95. Chen X, Yu C, Guo M et al (2019) Down-regulation of m6A mRNA methylation is involved in dopaminergic neuronal death. ACS Chem Neurosci 10, 2355-2363 https://doi.org/10.1021/acschemneuro.8b00657
  96. Hess ME, Hess S, Meyer KD et al (2013) The fat mass and obesity associated gene (Fto) regulates activity of the dopaminergic midbrain circuitry. Nat Neurosci 16, 1042-1048 https://doi.org/10.1038/nn.3449
  97. Peng S, Xiao W, Ju D et al (2019) Identification of entacapone as a chemical inhibitor of FTO mediating metabolic regulation through FOXO1. Sci Transl Med 11, eaau7116 https://doi.org/10.1126/scitranslmed.aau7116
  98. Vissers LE, Gilissen C and Veltman JA (2016) Genetic studies in intellectual disability and related disorders. Nat Rev Genet 17, 9-18 https://doi.org/10.1038/nrg3999
  99. Iwase S, Berube NG, Zhou Z et al (2017) Epigenetic etiology of intellectual disability. J Neurosci 37, 10773-10782 https://doi.org/10.1523/JNEUROSCI.1840-17.2017
  100. Zhang F, Kang Y, Wang M et al (2018) Fragile X mental retardation protein modulates the stability of its m6A-marked messenger RNA targets. Hum Mol Genet 27, 3936-3950
  101. Ignatova VV, Stolz P, Kaiser S et al (2020) The rRNA m(6)A methyltransferase METTL5 is involved in pluripotency and developmental programs. Genes Dev 34, 715-729 https://doi.org/10.1101/gad.333369.119
  102. Richard EM, Polla DL, Assir MZ et al (2019) Bi-allelic variants in METTL5 cause autosomal-recessive intellectual disability and microcephaly. Am J Hum Genet 105, 869-878 https://doi.org/10.1016/j.ajhg.2019.09.007
  103. de Brouwer APM, Abou Jamra R, Kortel N et al (2018) Variants in PUS7 cause intellectual disability with speech delay, microcephaly, short stature, and aggressive behavior. Am J Hum Genet 103, 1045-1052 https://doi.org/10.1016/j.ajhg.2018.10.026
  104. Bykhovskaya Y, Casas K, Mengesha E, Inbal A and Fischel-Ghodsian N (2004) Missense mutation in pseudouridine synthase 1 (PUS1) causes mitochondrial myopathy and sideroblastic anemia (MLASA). Am J Hum Genet 74, 1303-1308 https://doi.org/10.1086/421530
  105. Cao M, Dona M, Valentino ML et al (2016) Clinical and molecular study in a long-surviving patient with MLASA syndrome due to novel PUS1 mutations. Neurogenetics 17, 65-70 https://doi.org/10.1007/s10048-015-0465-x
  106. Abbasi-Moheb L, Mertel S, Gonsior M et al (2012) Mutations in NSUN2 cause autosomal-recessive intellectual disability. Am J Hum Genet 90, 847-855 https://doi.org/10.1016/j.ajhg.2012.03.021
  107. Martinez FJ, Lee JH, Lee JE et al (2012) Whole exome sequencing identifies a splicing mutation in NSUN2 as a cause of a Dubowitz-like syndrome. J Med Genet 49, 380-385 https://doi.org/10.1136/jmedgenet-2011-100686
  108. Khan MA, Rafiq MA, Noor A et al (2012) Mutation in NSUN2, which encodes an RNA methyltransferase, causes autosomal-recessive intellectual disability. Am J Hum Genet 90, 856-863 https://doi.org/10.1016/j.ajhg.2012.03.023
  109. Willems P, Vits L, Buntinx I, Raeymaekers P, Van Broeckhoven C and Ceulemans B (1993) Localization of a gene responsible for nonspecific mental retardation (MRX9) to the pericentromeric region of the X chromosome. Genomics 18, 290-294 https://doi.org/10.1006/geno.1993.1468
  110. Hamel BC, Smits AP, van den Helm B et al (1999) Four families (MRX43, MRX44, MRX45, MRX52) with nonspecific X-linked mental retardation: clinical and psychometric data and results of linkage analysis. Am J Med Genet 85, 290-304 https://doi.org/10.1002/(SICI)1096-8628(19990730)85:3<290::AID-AJMG21>3.0.CO;2-H
  111. Dai L, Xing L, Gong P et al (2008) Positive association of the FTSJ1 gene polymorphisms with nonsyndromic Xlinked mental retardation in young Chinese male subjects. J Hum Genet 53, 592-597 https://doi.org/10.1007/s10038-008-0287-x
  112. Wang R, Lei T, Fu F et al (2019) Application of chromosome microarray analysis in patients with unexplained developmental delay/intellectual disability in South China. Pediatr Neonatol 60, 35-42 https://doi.org/10.1016/j.pedneo.2018.03.006
  113. Giorda R, Bonaglia MC, Beri S et al (2009) Complex segmental duplications mediate a recurrent dup(X)(p11. 22-p11.23) associated with mental retardation, speech delay, and EEG anomalies in males and females. Am J Hum Genet 85, 394-400 https://doi.org/10.1016/j.ajhg.2009.08.001
  114. Zhang X, Wang F, Wang Z et al (2020) ALKBH5 promotes the proliferation of renal cell carcinoma by regulating AURKB expression in an m(6)A-dependent manner. Ann Transl Med 8, 646 https://doi.org/10.21037/atm-20-3079
  115. Jensen LR, Garrett L, Holter SM et al (2019) A mouse model for intellectual disability caused by mutations in the X-linked 2'Omethyltransferase Ftsj1 gene. Biochim Biophys Acta Mol Basis Dis 1865, 2083-2093 https://doi.org/10.1016/j.bbadis.2018.12.011
  116. Bai L, Tang Q, Zou Z et al (2018) m6A demethylase FTO regulates dopaminergic neurotransmission deficits caused by arsenite. Toxicol Sci 165, 431-446 https://doi.org/10.1093/toxsci/kfy172
  117. Choudhry Z, Sengupta SM, Grizenko N et al (2013) Association between obesity-related gene FTO and ADHD. Obesity (Silver Spring) 21, E738-744 https://doi.org/10.1002/oby.20444
  118. Oldmeadow C, Mossman D, Evans TJ et al (2014) Combined analysis of exon splicing and genome wide polymorphism data predict schizophrenia risk loci. J Psychiatr Res 52, 44-49 https://doi.org/10.1016/j.jpsychires.2014.01.011
  119. Yoon KJ, Ming GL and Song H (2018) Epitranscriptomes in the adult mammalian brain: dynamic changes regulate behavior. Neuron 99, 243-245 https://doi.org/10.1016/j.neuron.2018.07.019
  120. Barbon A and Magri C (2020) RNA editing and modifications in mood disorders. Genes (Basel) 11, 872 https://doi.org/10.3390/genes11080872
  121. Du T, Rao S, Wu L 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
  122. Bian J, Zhuo Z, Zhu J et al (2020) Association between METTL3 gene polymorphisms and neuroblastoma susceptibility: A nine-centre case-control study. J Cell Mol Med 24, 9280-9286 https://doi.org/10.1111/jcmm.15576
  123. Zhuo Z, Lu H, Zhu J et al (2020) METTL14 gene polymorphisms confer neuroblastoma susceptibility: an eightcenter case-control study. Mol Ther Nucleic Acids 22, 17-26 https://doi.org/10.1016/j.omtn.2020.08.009
  124. Cheng J, Xu L, Deng L et al (2020) RNA N(6)-methyladenosine modification is required for miR-98/MYCN axismediated inhibition of neuroblastoma progression. Sci Rep 10, 13624 https://doi.org/10.1038/s41598-020-64682-1
  125. Wang Z, Cheng H, Xu H, Yu X and Sui D (2020) A five-gene signature derived from m6A regulators to improve prognosis prediction of neuroblastoma. Cancer Biomark 28, 275-284 https://doi.org/10.3233/CBM-191196
  126. Louis DN, Ohgaki H, Wiestler OD et al (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114, 97-109 https://doi.org/10.1007/s00401-007-0243-4
  127. Stupp R, Roila F and Group EGW (2009) Malignant glioma: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 20 Suppl 4, 126-128
  128. Xi Z, Xue Y, Zheng J, Liu X, Ma J and Liu Y (2016) WTAP expression predicts poor prognosis in malignant glioma patients. J Mol Neurosci 60, 131-136 https://doi.org/10.1007/s12031-016-0788-6
  129. Sundar SJ, Hsieh JK, Manjila S, Lathia JD and Sloan A (2014) The role of cancer stem cells in glioblastoma. Neurosurg Focus 37, E6
  130. Cui Q, Shi H, Ye P et al (2017) m(6)A RNA methylation regulates the self-renewal and tumorigenesis of glioblastoma stem cells. Cell Rep 18, 2622-2634 https://doi.org/10.1016/j.celrep.2017.02.059
  131. Zhang S, Zhao BS, Zhou A 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, 591-606 e596 https://doi.org/10.1016/j.ccell.2017.02.013
  132. Visvanathan A, Patil V, Arora A et al (2018) Essential role of METTL3-mediated m(6)A modification in glioma stem-like cells maintenance and radioresistance. Oncogene 37, 522-533 https://doi.org/10.1038/onc.2017.351
  133. Zang L, Kondengaden SM, Che F, Wang L and Heng X (2018) Potential epigenetic-based therapeutic targets for glioma. Front Mol Neurosci 11, 408 https://doi.org/10.3389/fnmol.2018.00408
  134. Ge L, Zhang N, Chen Z et al (2020) Level of N6- methyladenosine in peripheral blood RNA: a novel predictive biomarker for gastric cancer. Clin Chem 66, 342-351 https://doi.org/10.1093/clinchem/hvz004
  135. Strick A, von Hagen F, Gundert L et al (2020) The N(6)-methyladenosine (m(6) A) erasers alkylation repair homologue 5 (ALKBH5) and fat mass and obesity-associated protein (FTO) are prognostic biomarkers in patients with clear cell renal carcinoma. BJU Int 125, 617-624 https://doi.org/10.1111/bju.15019
  136. Wang W, Li J, Lin F, Guo J and Zhao J (2020) Identification of N(6)-methyladenosine-related lncRNAs for patients with primary glioblastoma. Neurosurg Rev [Online ahead of print]
  137. Tu Z, Wu L, Wang P et al (2020) N6-methylandenosine-related lncRNAs are potential biomarkers for predicting the overall survival of lower-grade glioma patients. Front Cell Dev Biol 8, 642 https://doi.org/10.3389/fcell.2020.00642
  138. Xiao L, Li X, Mu Z et al (2020) FTO inhibition enhances the anti-tumor effect of temozolomide by targeting MYCmiR-155/23a cluster-MXI1 feedback circuit in glioma. Cancer Res 80, 3945-3958 https://doi.org/10.1158/0008-5472.can-20-0132
  139. Malacrida A, Rivara M, Di Domizio A et al (2020) 3D proteome-wide scale screening and activity evaluation of a new ALKBH5 inhibitor in U87 glioblastoma cell line. Bioorg Med Chem 28, 115300 https://doi.org/10.1016/j.bmc.2019.115300
  140. Garcia-Campos MA, Edelheit S, Toth U et al (2019) Deciphering the "m(6)A code" via antibody-independent quantitative profiling. Cell 178, 731-747 e716 https://doi.org/10.1016/j.cell.2019.06.013
  141. Sas-Chen A, Thomas JM, Matzov D et al (2020) Dynamic RNA acetylation revealed by quantitative cross-evolutionary mapping. Nature 583, 638-643 https://doi.org/10.1038/s41586-020-2418-2