RNA m⁶A modification and its function in diseases

Abstract

N⁶-methyladenosine (m⁶A) is the most common post-transcriptional RNA modification throughout the transcriptome, affecting fundamental aspects of RNA metabolism. m⁶A modification could be installed by m⁶A “writers” composed of core catalytic components (METTL3/METTL14/WTAP) and newly defined regulators and removed by m⁶A “erasers” (FTO and ALKBH5). The function of m⁶A is executed by m⁶A “readers” that bind to m⁶A directly (YTH domain-containing proteins, eIF3 and IGF2BPs) or indirectly (HNRNPA2B1). In the past few years, advances in m⁶A modulators (“writers,” “erasers,” and “readers”) have remarkably renewed our understanding of the function and regulation of m⁶A in different cells under normal or disease conditions. However, the mechanism and the regulatory network of m⁶A are still largely unknown. Moreover, investigations of the m⁶A physiological roles in human diseases are limited. In this review, we summarize the recent advances in m⁶A research and highlight the functional relevance and importance of m⁶A modification in in vitro cell lines, in physiological contexts, and in cancers.

Keywords

RNA modification / m⁶A / immunity / cancer / epigenetics

References

[1] He C. Grand challenge commentary: RNA epigenetics? Nat Chem Biol 2010; 6(12): 863–865

[2] Desrosiers R, Friderici K, Rottman F. Identification of methylated nucleosides in messenger RNA from Novikoff hepatoma cells. Proc Natl Acad Sci USA 1974; 71(10): 3971–3975

[3] Munns TW, Sims HF. Methylation and processing of transfer ribonucleic acid in mammalian and bacterial cells. J Biol Chem 1975; 250(6): 2143–2149

[4] Meyer KD, Saletore Y, Zumbo P, Elemento O, Mason CE, Jaffrey SR. Comprehensive analysis of mRNA methylation reveals enrichment in 3′ UTRs and near stop codons. Cell 2012; 149(7): 1635–1646

[5] Dominissini D, Moshitch-Moshkovitz S, Schwartz S, Salmon-Divon M, Ungar L, Osenberg S, Cesarkas K, Jacob-Hirsch J, Amariglio N, Kupiec M, Sorek R, Rechavi G. Topology of the human and mouse m⁶A RNA methylomes revealed by m⁶A-seq. Nature 2012; 485(7397): 201–206

[6] Jia G, Fu Y, Zhao X, Dai Q, Zheng G, Yang Y, Yi C, Lindahl T, Pan T, Yang YG, He C. N⁶-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat Chem Biol 2011; 7(12): 885–887

[7] Bokar JA, Rath-Shambaugh ME, Ludwiczak R, Narayan P, Rottman F. Characterization and partial purification of mRNA N⁶-adenosine methyltransferase from HeLa cell nuclei. Internal mRNA methylation requires a multisubunit complex. J Biol Chem 1994; 269(26): 17697–17704

[8] Bokar JA, Shambaugh ME, Polayes D, Matera AG, Rottman FM. Purification and cDNA cloning of the AdoMet-binding subunit of the human mRNA (N⁶-adenosine)-methyltransferase. RNA 1997; 3(11): 1233–1247

[9] Batista PJ, Molinie B, Wang J, Qu K, Zhang J, Li L, Bouley DM, Lujan E, Haddad B, Daneshvar K, Carter AC, Flynn RA, Zhou C, Lim KS, Dedon P, Wernig M, Mullen AC, Xing Y, Giallourakis CC, Chang HY. m⁶A RNA modification controls cell fate transition in mammalian embryonic stem cells. Cell Stem Cell 2014; 15(6): 707–719

[10] Wang Y, Li Y, Toth JI, Petroski MD, Zhang Z, Zhao JC. N⁶-methyladenosine modification destabilizes developmental regulators in embryonic stem cells. Nat Cell Biol 2014; 16(2): 191–198

[11] Chen T, Hao YJ, Zhang Y, Li MM, Wang M, Han W, Wu Y, Lv Y, Hao J, Wang L, Li A, Yang Y, Jin KX, Zhao X, Li Y, Ping XL, Lai WY, Wu LG, Jiang G, Wang HL, Sang L, Wang XJ, Yang YG, Zhou Q. m⁶A RNA methylation is regulated by microRNAs and promotes reprogramming to pluripotency. Cell Stem Cell 2015; 16(3): 289–301

[12] Zhong S, Li H, Bodi Z, Button J, Vespa L, Herzog M, Fray RG. MTA is an Arabidopsis messenger RNA adenosine methylase and interacts with a homolog of a sex-specific splicing factor. Plant Cell 2008; 20(5): 1278–1288

[13] Geula S, Moshitch-Moshkovitz S, Dominissini D, Mansour AA, Kol N, Salmon-Divon M, Hershkovitz V, Peer E, Mor N, Manor YS, Ben-Haim MS, Eyal E, Yunger S, Pinto Y, Jaitin DA, Viukov S, Rais Y, Krupalnik V, Chomsky E, Zerbib M, Maza I, Rechavi Y, Massarwa R, Hanna S, Amit I, Levanon EY, Amariglio N, Stern-Ginossar N, Novershtern N, Rechavi G, Hanna JH. m⁶A mRNA methylation facilitates resolution of naïve pluripotency toward differentiation. Science 2015; 347(6225): 1002–1006

[14] Schwartz S, Agarwala SD, Mumbach MR, Jovanovic M, Mertins P, Shishkin A, Tabach Y, Mikkelsen TS, Satija R, Ruvkun G, Carr SA, Lander ES, Fink GR, Regev A. High-resolution mapping reveals a conserved, widespread, dynamic mRNA methylation program in yeast meiosis. Cell 2013; 155(6): 1409–1421

[15] Licatalosi DD, Mele A, Fak JJ, Ule J, Kayikci M, Chi SW, Clark TA, Schweitzer AC, Blume JE, Wang X, Darnell JC, Darnell RB. HITS-CLIP yields genome-wide insights into brain alternative RNA processing. Nature 2008; 456(7221): 464–469

[16] Ke S, Pandya-Jones A, Saito Y, Fak JJ, Vågbø CB, Geula S, Hanna JH, Black DL, Darnell JE Jr, Darnell RB. m⁶A mRNA modifications are deposited in nascent pre-mRNA and are not required for splicing but do specify cytoplasmic turnover. Genes Dev 2017; 31(10): 990–1006

[17] Knuckles P, Carl SH, Musheev M, Niehrs C, Wenger A, Bühler M. RNA fate determination through cotranscriptional adenosine methylation and microprocessor binding. Nat Struct Mol Biol 2017; 24(7): 561–569

[18] Slobodin B, Han R, Calderone V, Vrielink JA, Loayza-Puch F, Elkon R, Agami R. Transcription impacts the efficiency of mRNA translation via co-transcriptional N⁶-adenosine methylation. Cell 2017; 169(2):326–337.e12

[19] Xiang Y, Laurent B, Hsu CH, Nachtergaele S, Lu Z, Sheng W, Xu C, Chen H, Ouyang J, Wang S, Ling D, Hsu PH, Zou L, Jambhekar A, He C, Shi Y. RNA m⁶A methylation regulates the ultraviolet-induced DNA damage response. Nature 2017; 543(7646): 573–576

[20] Liu J, Yue Y, Han D, Wang X, Fu Y, Zhang L, Jia G, Yu M, Lu Z, Deng X, Dai Q, Chen W, He C. A METTL3-METTL14 complex mediates mammalian nuclear RNA N⁶-adenosine methylation. Nat Chem Biol 2014; 10(2): 93–95

[21] Schwartz S, Mumbach MR, Jovanovic M, Wang T, Maciag K, Bushkin GG, Mertins P, Ter-Ovanesyan D, Habib N, Cacchiarelli D, Sanjana NE, Freinkman E, Pacold ME, Satija R, Mikkelsen TS, Hacohen N, Zhang F, Carr SA, Lander ES, Regev A. Perturbation of m⁶A writers reveals two distinct classes of mRNA methylation at internal and 5′ sites. Cell Reports 2014; 8(1): 284–296

[22] Śledź P, Jinek M. Structural insights into the molecular mechanism of the m⁶A writer complex. eLife 2016; 5: e1843

[23] Wang P, Doxtader KA, Nam Y. Structural basis for cooperative function of Mettl3 and Mettl14 methyltransferases. Mol Cell 2016; 63(2): 306–317

[24] Wang X, Feng J, Xue Y, Guan Z, Zhang D, Liu Z, Gong Z, Wang Q, Huang J, Tang C, Zou T, Yin P. Structural basis of N⁶-adenosine methylation by the METTL3-METTL14 complex. Nature 2016; 534(7608): 575–578

[25] Agarwala SD, Blitzblau HG, Hochwagen A, Fink GR. RNA methylation by the MIS complex regulates a cell fate decision in yeast. PLoS Genet 2012; 8(6): e1002732

[26] Ping XL, Sun BF, Wang L, Xiao W, Yang X, Wang WJ, Adhikari S, Shi Y, Lv Y, Chen YS, Zhao X, Li A, Yang Y, Dahal U, Lou XM, Liu X, Huang J, Yuan WP, Zhu XF, Cheng T, Zhao YL, Wang X, Rendtlew Danielsen JM, Liu F, Yang YG. Mammalian WTAP is a regulatory subunit of the RNA N⁶-methyladenosine methyltransferase. Cell Res 2014; 24(2): 177–189

[27] Hilfiker A, Amrein H, Dübendorfer A, Schneiter R, Nöthiger R. The gene virilizer is required for female-specific splicing controlled by Sxl, the master gene for sexual development in Drosophila. Development 1995; 121(12): 4017–4026

[28] Granadino B, Penalva LO, Sánchez L. The gene fl(2)d is needed for the sex-specific splicing of transformer pre-mRNA but not for double-sex pre-mRNA in Drosophila melanogaster. Mol Gen Genet 1996; 253(1-2): 26–31

[29] Patil DP, Chen CK, Pickering BF, Chow A, Jackson C, Guttman M, Jaffrey SR. m⁶A RNA methylation promotes XIST-mediated transcriptional repression. Nature 2016; 537(7620): 369–373

[30] Pendleton KE, Chen B, Liu K, Hunter OV, Xie Y, Tu BP, Conrad NK. The U6 snRNA m⁶A methyltransferase METTL16 regulates SAM synthetase intron retention. Cell 2017; 169(5): 824–835.e14

[31] Jia G, Yang CG, Yang S, Jian X, Yi C, Zhou Z, He C. Oxidative demethylation of 3-methylthymine and 3-methyluracil in single-stranded DNA and RNA by mouse and human FTO. FEBS Lett 2008; 582(23-24): 3313–3319

[32] Dina C, Meyre D, Gallina S, Durand E, Körner A, Jacobson P, Carlsson LM, Kiess W, Vatin V, Lecoeur C, Delplanque J, Vaillant E, Pattou F, Ruiz J, Weill J, Levy-Marchal C, Horber F, Potoczna N, Hercberg S, Le Stunff C, Bougnères P, Kovacs P, Marre M, Balkau B, Cauchi S, Chèvre JC, Froguel P. Variation in FTO contributes to childhood obesity and severe adult obesity. Nat Genet 2007; 39(6): 724–726

[33] Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM, Perry JR, Elliott KS, Lango H, Rayner NW, Shields B, Harries LW, Barrett JC, Ellard S, Groves CJ, Knight B, Patch AM, Ness AR, Ebrahim S, Lawlor DA, Ring SM, Ben-Shlomo Y, Jarvelin MR, Sovio U, Bennett AJ, Melzer D, Ferrucci L, Loos RJ, Barroso I, Wareham NJ, Karpe F, Owen KR, Cardon LR, Walker M, Hitman GA, Palmer CN, Doney AS, Morris AD, Smith GD, Hattersley AT, McCarthy MI. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 2007; 316(5826): 889–894

[34] Scuteri A, Sanna S, Chen WM, Uda M, Albai G, Strait J, Najjar S, Nagaraja R, Orrú M, Usala G, Dei M, Lai S, Maschio A, Busonero F, Mulas A, Ehret GB, Fink AA, Weder AB, Cooper RS, Galan P, Chakravarti A, Schlessinger D, Cao A, Lakatta E, Abecasis GR. Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits. PLoS Genet 2007; 3(7): e115

[35] Li Z, Weng H, Su R, Weng X, Zuo Z, Li C, Huang H, Nachtergaele S, Dong L, Hu C, Qin X, Tang L, Wang Y, Hong GM, Huang H, Wang X, Chen P, Gurbuxani S, Arnovitz S, Li Y, Li S, Strong J, Neilly MB, Larson RA, Jiang X, Zhang P, Jin J, He C, Chen J. FTO plays an oncogenic role in acute myeloid leukemia as a N⁶-methyladenosine RNA demethylase. Cancer Cell 2017; 31(1): 127–141

[36] Su R, Dong L, Li C, Nachtergaele S, Wunderlich M, Qing Y, Deng X, Wang Y, Weng X, Hu C, Yu M, Skibbe J, Dai Q, Zou D, Wu T, Yu K, Weng H, Huang H, Ferchen K, Qin X, Zhang B, Qi J, Sasaki AT, Plas DR, Bradner JE, Wei M, Marcucci G, Jiang X, Mulloy JC, Jin J, He C, Chen J. R-2HG exhibits anti-tumor activity by targeting FTO/m⁶A/MYC/CEBPA signaling. Cell 2018; 172(1-2): 90–105.e23

[37] Hess ME, Hess S, Meyer KD, Verhagen LA, Koch L, Brönneke HS, Dietrich MO, Jordan SD, Saletore Y, Elemento O, Belgardt BF, Franz T, Horvath TL, Rüther U, Jaffrey SR, Kloppenburg P, Brüning JC. The fat mass and obesity associated gene (Fto) regulates activity of the dopaminergic midbrain circuitry. Nat Neurosci 2013; 16(8): 1042–1048

[38] Mauer J, Luo X, Blanjoie A, Jiao X, Grozhik AV, Patil DP, Linder B, Pickering BF, Vasseur JJ, Chen Q, Gross SS, Elemento O, Debart F, Kiledjian M, Jaffrey SR. Reversible methylation of m⁶Am in the 5′ cap controls mRNA stability. Nature 2017; 541(7637): 371–375

[39] Zhao B, Nachtergaele S, Roundtree IA, He C. Our views of dynamic N⁶-methyladenosine RNA methylation. RNA 2018; 24(3): 268–272

[40] Zheng G, Dahl JA, Niu Y, Fedorcsak P, Huang CM, Li CJ, Vågbø CB, Shi Y, Wang WL, Song SH, Lu Z, Bosmans RP, Dai Q, Hao YJ, Yang X, Zhao WM, Tong WM, Wang XJ, Bogdan F, Furu K, Fu Y, Jia G, Zhao X, Liu J, Krokan HE, Klungland A, Yang YG, He C. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol Cell 2013; 49(1): 18–29

[41] Linder B, Grozhik AV, Olarerin-George AO, Meydan C, Mason CE, Jaffrey SR. Single-nucleotide-resolution mapping of m6A and m⁶Am throughout the transcriptome. Nat Methods 2015; 12(8): 767–772

[42] Zhang S, Zhao BS, Zhou A, Lin K, Zheng S, Lu Z, Chen Y, Sulman EP, Xie K, Bogler O, Majumder S, He C, Huang S. m⁶A demethylase ALKBH5 maintains tumorigenicity of glioblastoma stem-like cells by sustaining FOXM1 expression and cell proliferation program. Cancer Cell, 2017; 31(4):591–606.e6

[43] Meyer KD, Patil DP, Zhou J, Zinoviev A, Skabkin MA, Elemento O, Pestova TV, Qian SB, Jaffrey SR. 5′ UTR m⁶A promotes cap-independent translation. Cell 2015; 163(4): 999–1010

[44] Zhou J, Wan J, Gao X, Zhang X, Jaffrey SR, Qian SB. Dynamic m⁶A mRNA methylation directs translational control of heat shock response. Nature 2015; 526(7574): 591–594

[45] Luo S, Tong L. Molecular basis for the recognition of methylated adenines in RNA by the eukaryotic YTH domain. Proc Natl Acad Sci USA 2014; 111(38): 13834–13839

[46] Theler D, Dominguez C, Blatter M, Boudet J, Allain FH. Solution structure of the YTH domain in complex with N⁶-methyladenosine RNA: a reader of methylated RNA. Nucleic Acids Res 2014; 42(22): 13911–13919

[47] Xu C, Wang X, Liu K, Roundtree IA, Tempel W, Li Y, Lu Z, He C, Min J. Structural basis for selective binding of m⁶A RNA by the YTHDC1 YTH domain. Nat Chem Biol 2014; 10(11): 927–929

[48] König J, Zarnack K, Rot G, Curk T, Kayikci M, Zupan B, Turner DJ, Luscombe NM, Ule J. iCLIP reveals the function of hnRNP particles in splicing at individual nucleotide resolution. Nat Struct Mol Biol 2010; 17(7): 909–915

[49] Wang X, Zhao BS, Roundtree IA, Lu Z, Han D, Ma H, Weng X, Chen K, Shi H, He C. N⁶-methyladenosine modulates messenger RNA translation efficiency. Cell 2015; 161(6): 1388–1399

[50] Kennedy EM, Bogerd HP, Kornepati AV, Kang D, Ghoshal D, Marshall JB, Poling BC, Tsai K, Gokhale NS, Horner SM, Cullen BR. Posttranscriptional m⁶A editing of HIV-1 mRNAs enhances viral gene expression. Cell Host Microbe 2016; 19(5): 675–685

[51] Du H, Zhao Y, He J, Zhang Y, Xi H, Liu M, Ma J, Wu L. YTHDF2 destabilizes m⁶A-containing RNA through direct recruitment of the CCR4-NOT deadenylase complex. Nat Commun 2016; 7: 12626

[52] Gokhale NS, McIntyre ABR, McFadden MJ, Roder AE, Kennedy EM, Gandara JA, Hopcraft SE, Quicke KM, Vazquez C, Willer J, Ilkayeva OR, Law BA, Holley CL, Garcia-Blanco MA, Evans MJ, Suthar MS, Bradrick SS, Mason CE, Horner SM. N⁶-methyladenosine in flaviviridae viral RNA genomes regulates infection. Cell Host Microbe 2016; 20(5): 654–665

[53] Lichinchi G, Zhao BS, Wu Y, Lu Z, Qin Y, He C, Rana TM. Dynamics of human and viral RNA methylation during Zika virus infection. Cell Host Microbe 2016; 20(5): 666–673

[54] Tirumuru N, Zhao BS, Lu W, Lu Z, He C, Wu L. N⁶-methyladenosine of HIV-1 RNA regulates viral infection and HIV-1 Gag protein expression. eLife 2016; 5: e15528

[55] Tanabe A, Tanikawa K, Tsunetomi M, Takai K, Ikeda H, Konno J, Torigoe T, Maeda H, Kutomi G, Okita K, Mori M, Sahara H. RNA helicase YTHDC2 promotes cancer metastasis via the enhancement of the efficiency by which HIF-1α mRNA is translated. Cancer Lett 2016; 376(1): 34–42

[56] Alarcón CR, Goodarzi H, Lee H, Liu X, Tavazoie S, Tavazoie SF. HNRNPA2B1 is a mediator of m⁶A-dependent nuclear RNA processing events. Cell 2015; 162(6): 1299–1308

[57] Spitale RC, Flynn RA, Zhang QC, Crisalli P, Lee B, Jung JW, Kuchelmeister HY, Batista PJ, Torre EA, Kool ET, Chang HY. Structural imprints in vivo decode RNA regulatory mechanisms. Nature 2015; 519(7544): 486–490

[58] Degrauwe N, Suvà ML, Janiszewska M, Riggi N, Stamenkovic I. IMPs: an RNA-binding protein family that provides a link between stem cell maintenance in normal development and cancer. Genes Dev 2016; 30(22): 2459–2474

[59] Huang H, Weng H, Sun W, Qin X, Shi H, Wu H, Zhao BS, Mesquita A, Liu C, Yuan CL, Hu YC, Hüttelmaier S, Skibbe JR, Su R, Deng X, Dong L, Sun M, Li C, Nachtergaele S, Wang Y, Hu C, Ferchen K, Greis KD, Jiang X, Wei M, Qu L, Guan JL, He C, Yang J, Chen J. Recognition of RNA N⁶-methyladenosine by IGF2BP proteins enhances mRNA stability and translation. Nat Cell Biol 2018; 20(3): 285–295

[60] Sommer S, Lavi U, Darnell JE Jr. The absolute frequency of labeled N⁶-methyladenosine in HeLa cell messenger RNA decreases with label time. J Mol Biol 1978; 124(3): 487–499

[61] Li HB, Tong J, Zhu S, Batista PJ, Duffy EE, Zhao J, Bailis W, Cao G, Kroehling L, Chen Y, Wang G, Broughton JP, Chen YG, Kluger Y, Simon MD, Chang HY, Yin Z, Flavell RA. m⁶A mRNA methylation controls T cell homeostasis by targeting the IL-7/STAT5/SOCS pathways. Nature 2017; 548(7667): 338–342

[62] Tong J, Cao G, Zhang T, Sefik E, Amezcua Vesely MC, Broughton JP, Zhu S, Li H, Li B, Chen L, Chang HY, Su B, Flavell RA, Li HB. m⁶A mRNA methylation sustains Treg suppressive functions. Cell Res 2018; 28(2): 253–256

[63] Liu N, Pan T. Probing RNA modification status at single-nucleotide resolution in total RNA. Methods Enzymol 2015; 560: 149–159

[64] Xiao W, Adhikari S, Dahal U, Chen YS, Hao YJ, Sun BF, Sun HY, Li A, Ping XL, Lai WY, Wang X, Ma HL, Huang CM, Yang Y, Huang N, Jiang GB, Wang HL, Zhou Q, Wang XJ, Zhao YL, Yang YG. Nuclear m⁶A reader YTHDC1 regulates mRNA splicing. Mol Cell 2016; 61(4): 507–519

[65] Haussmann IU, Bodi Z, Sanchez-Moran E, Mongan NP, Archer N, Fray RG, Soller M. m⁶A potentiates Sxl alternative pre-mRNA splicing for robust Drosophila sex determination. Nature 2016; 540(7632): 301–304

[66] Lence T, Akhtar J, Bayer M, Schmid K, Spindler L, Ho CH, Kreim N, Andrade-Navarro MA, Poeck B, Helm M, Roignant JY. m⁶A modulates neuronal functions and sex determination in Drosophila. Nature 2016; 540(7632): 242–247

[67] Kan L, Grozhik AV, Vedanayagam J, Patil DP, Pang N, Lim KS, Huang YC, Joseph B, Lin CJ, Despic V, Guo J, Yan D, Kondo S, Deng WM, Dedon PC, Jaffrey SR, Lai EC. The m⁶A pathway facilitates sex determination in Drosophila. Nat Commun 2017; 8: 15737

[68] Vu LP, Pickering BF, Cheng Y, Zaccara S, Nguyen D, Minuesa G, Chou T, Chow A, Saletore Y, MacKay M, Schulman J, Famulare C, Patel M, Klimek VM, Garrett-Bakelman FE, Melnick A, Carroll M, Mason CE, Jaffrey SR, Kharas MG. The N⁶-methyladenosine (m⁶A)-forming enzyme METTL3 controls myeloid differentiation of normal hematopoietic and leukemia cells. Nat Med 2017; 23(11): 1369–1376

[69] Barbieri I, Tzelepis K, Pandolfini L, Shi J, Millán-Zambrano G, Robson SC, Aspris D, Migliori V, Bannister AJ, Han N, De Braekeleer E, Ponstingl H, Hendrick A, Vakoc CR, Vassiliou GS, Kouzarides T. Promoter-bound METTL3 maintains myeloid leukaemia by m⁶A-dependent translation control. Nature 2017; 552(7683): 126–131

[70] Chen M, Wei L, Law CT, Tsang FH, Shen J, Cheng CL, Tsang LH, Ho DW, Chiu DK, Lee CC JM, Wong IO, Ng CM, Wong . RNA N⁶-methyladenosine methyltransferase METTL3 promotes liver cancer progression through YTHDF2 dependent post-transcriptional silencing of SOCS2. Hepatology 2018; 67(6):2254–2270

[71] Cui Q, Shi H, Ye P, Li L, Qu Q, Sun G, Sun G, Lu Z, Huang Y, Yang CG, Riggs AD, He C, Shi Y. m⁶A RNA methylation regulates the self-renewal and tumorigenesis of glioblastoma stem cells. Cell Reports 2017; 18(11): 2622–2634

[72] Zhao BS, Wang X, Beadell AV, Lu Z, Shi H, Kuuspalu A, Ho RK, He C. m⁶A-dependent maternal mRNA clearance facilitates zebrafish maternal-to-zygotic transition. Nature 2017; 542(7642): 475–478

Acknowledgements

We thank the members of the Flavell laboratory and the Li laboratory for discussions and technical support. This work was supported by the National Natural Science Foundation of China (No. 91753141 to Hua-Bing Li), the Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning (Hua-Bing Li), the start-up fund from the Shanghai Jiao Tong University School of Medicine (Hua-Bing Li), and the Howard Hughes Medical Institute (Richard A. Flavell).

Compliance with ethics guidelines

Jiyu Tong, Richard A. Flavell, and Hua-Bing Li declare that they have no conflict of interest. This manuscript is a review article and does not require an approved research protocol by the relevant institutional review board of ethics committee.

Open Access

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the appropriate credit is given to the original author(s) and the source, and a link is provided to the Creative Commons license, which indicates if changes are made.

RIGHTS & PERMISSIONS

2018 The Author(s) 2018. This article is published with open access at link.springer.com and journal.hep.com.cn