RNA m6A modification and its function in diseases

Jiyu Tong1, Richard A. Flavell2, Hua Bing Li1
1Shanghai Institute of Immunology, Department of Microbiology and Immunology, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, 200025, China
2Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA

Tóm tắt

Từ khóa


Tài liệu tham khảo

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

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

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

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

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

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

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

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

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

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

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 micro RNAs and promotes reprogramming to pluripotency. Cell Stem Cell 2015; 16(3): 289–301

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

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

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

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

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

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

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

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 ultravioletinduced DNA damage response. Nature 2017; 543(7646): 573–576

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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