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2025年5月11日 7:00 星期日
首页 > 过刊浏览>2023年第39卷第1期 >45-59. DOI:10.13345/j.cjb.220236
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N6-甲基化腺嘌呤RNA甲基化修饰在中枢神经系统中的作用研究进展
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国家自然科学基金(82060234);云南省基础研究计划(202101BE070001-065, 202102AA100053);云南省科技厅科技人才与平台计划(202005AE160019)


Role of N6-methyladenosine RNA methylation in central nervous system: a review
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    摘要:

    mRNA存在多种转录后修饰，这些修饰调控mRNA的稳定和剪接、翻译、转运等多个过程，进而影响细胞发育、机体免疫、学习认知等重要生理功能。其中m6A修饰是转录后修饰中最丰富的一种，广泛存在于mRNA中，调控mRNA的代谢活动，影响基因表达。m6A修饰的稳态对神经系统的发育和功能维持至关重要。近年研究发现，在神经退行性疾病、精神疾病和脑肿瘤中均存在m6A修饰的身影。因此本文对近几年m6A甲基化修饰在中枢神经系统发育、功能及相关疾病中的作用进行总结，为神经系统疾病提供潜在的临床治疗靶点。

    Abstract:

    There are a variety of post-transcriptional modifications in mRNA, which regulate the stability, splicing, translation, transport and other processes of mRNA, followed by affecting cell development, body immunity, learning and cognition and other important physiological functions. m6A modification is one of the most abundant post-transcriptional modifications widely existing in mRNA, regulating the metabolic activities of RNA and affecting gene expression. m6A modified homeostasis is critical for the development and maintenance of the nervous system. In recent years, m6A modification has been found in neurodegenerative diseases, mental diseases and brain tumors. This review summarizes the role of m6A methylation modification in the development, function and related diseases of the central nervous system in recent years, providing potential clinical therapeutic targets for neurological diseases.

    参考文献
    [1] Allis CD, Jenuwein T. The molecular hallmarks of epigenetic control[J]. Nature Reviews Genetics, 2016, 17(8):487-500.
    [2] YAO B, CHRISTIAN KM, HE C, JIN P, MING GL, SONG HJ. Epigenetic mechanisms in neurogenesis[J]. Nature Reviews Neuroscience, 2016, 17(9):537-549.
    [3] BOCCALETTO P, STEFANIAK F, RAY A, CAPPANNINI A, MUKHERJEE S, PURTA E, KURKOWSKA M, SHIRVANIZADEH N, DESTEFANIS E, GROZA P, AVŞAR G, ROMITELLI A, PIR P, DASSI E, CONTICELLO SG, AGUILO F, BUJNICKI JM. MODOMICS:a database of RNA modification pathways. 2021 update[J]. Nucleic Acids Research, 2022, 50(D1):D231-D235.
    [4] ZACCARA S, RIES RJ, JAFFREY SR. Reading, writing and erasing mRNA methylation[J]. Nature Reviews Molecular Cell Biology, 2019, 20(10):608-624.
    [5] DESROSIERS R, FRIDERICI K, ROTTMAN F. Identification of methylated nucleosides in messenger RNA from Novikoff hepatoma cells[J]. Proceedings of the National Academy of Sciences of the United States of America, 1974, 71(10):3971-3975.
    [6] 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[J]. RNA:New York, N Y, 1997, 3(11):1233-1247.
    [7] CLANCY MJ, SHAMBAUGH ME, TIMPTE CS, BOKAR JA. Induction of sporulation in Saccharomyces cerevisiae leads to the formation of N6-methyladenosine in mRNA:a potential mechanism for the activity of the IME4 gene[J]. Nucleic Acids Research, 2002, 30(20):4509-4518.
    [8] ZHONG SL, LI HY, 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[J]. The Plant Cell, 2008, 20(5):1278-1288.
    [9] 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[J]. Cell, 2012, 149(7):1635-1646.
    [10] DOMINISSINID, 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[J]. Nature, 2012, 485(7397):201-206.
    [11] HUANG JB, DONG X, GONG Z, QIN LY, YANG S, ZHU YL, WANG X, ZHANG DL, ZOU TT, YIN P, TANG C. Solution structure of the RNA recognition domain of METTL3-METTL14 N6-methyladenosine methyltransferase[J]. Protein & Cell, 2019, 10(4):272-284.
    [12] WANG P, DOXTADER KA, NAM Y. Structural basis for cooperative function of Mettl3 and Mettl14 methyltransferases[J]. Molecular Cell, 2016, 63(2):306-317.
    [13] PING XL, SUN BF, WANG L, XIAO W, YANG X, WANG WJ, ADHIKARI S, SHI Y, Lü Y, CHEN YS, ZHAO X, LI A, YANG Y, DAHAL U, LOU XM, LIU X, HUANG J, YUAN WP, ZHU XF, CHENG T, et al. Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase[J]. Cell Research, 2014, 24(2):177-189.
    [14] 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[J]. Cell Reports, 2014, 8(1):284-296.
    [15] YUE YN, LIU J, CUI XL, CAO J, LUO GZ, ZHANG ZZ, CHENG T, GAO MS, SHU X, MA HH, WANG FQ, WANG XX, SHEN B, WANG YZ, FENG XH, HE C, LIU JZ. VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation[J]. Cell Discovery, 2018, 4:10.
    [16] FU Y, JIA GF, PANG XQ, WANG RN, WANG X, LI CJ, SMEMO S, DAI Q, BAILEY KA, NOBREGA MA, HAN KL, CUI Q, HE C. FTO-mediated formation of N6-hydroxymethyladenosine and N6-formyladenosine in mammalian RNA[J]. Nature Communications, 2013, 4:1798.
    [17] WEI JB, LIU FG, LU ZK, FEI QL, AI YX, HE PC, SHI HL, CUI XL, SU R, KLUNGLAND A, JIA GF, CHEN JJ, HE C. Differential m6A, m6Am, and m1A demethylation mediated by FTO in the cell nucleus and cytoplasm[J]. Molecular Cell, 2018, 71(6):973-985.e5.
    [18] ZHENG GQ, DAHL JA, NIU YM, FEDORCSAK P, HUANG CM, LI CJ, VÅGBØ CB, SHI Y, WANG WL, SONG SH, LU ZK, BOSMANS RPG, DAI Q, HAO YJ, YANG X, ZHAO WM, TONG WM, WANG XJ, BOGDAN F, FURU KR, et al. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility[J]. Molecular Cell, 2013, 49(1):18-29.
    [19] SHI HL, WEI JB, HE C. Where, when, and how:context-dependent functions of RNA methylation writers, readers, and erasers[J]. Molecular Cell, 2019, 74(4):640-650.
    [20] WU R, LI A, SUN BF, SUN JG, ZHANG JH, ZHANG T, CHEN YS, XIAO YJ, GAO YH, ZHANG QY, MA J, YANG X, LIAO YJ, LAI WY, QI XL, WANG SK, SHU YS, WANG HL, WANG FC, YANG YG, et al. A novel m6A reader Prrc2a controls oligodendroglial specification and myelination[J]. Cell Research, 2019, 29(1):23-41.
    [21] WANG X, ZHAO BS, ROUNDTREE IA, LU ZK, HAN DL, MA HH, WENG XC, CHEN K, SHI HL, HE C. N6-methyladenosine modulates messenger RNA translation efficiency[J]. Cell, 2015, 161(6):1388-1399.
    [22] DU H, ZHAO Y, HE JQ, ZHANG Y, XI HR, LIU MF, MA JB, WU LG. YTHDF2 destabilizes m6A-containing RNA through direct recruitment of the CCR4-NOT deadenylase complex[J]. Nature Communications, 2016, 7:12626.
    [23] XU C, WANG X, LIU K, ROUNDTREE IA, TEMPEL W, LI YJ, LU ZK, HE C, MIN JR. Structural basis for selective binding of m6A RNA by the YTHDC1 YTH domain[J]. Nature Chemical Biology, 2014, 10(11):927-929.
    [24] 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, et al. Nuclear m6A reader YTHDC1 regulates mRNA splicing[J]. Molecular Cell, 2016, 61(4):507-519.
    [25] ROUNDTREE IA, LUO GZ, ZHANG ZJ, WANG X, ZHOU T, CUI Y, SHA JH, HUANG XX, GUERRERO L, XIE P, HE E, SHEN B, HE C. YTHDC1 mediates nuclear export of N6-methyladenosine methylated mRNAs[J]. eLife, 2017, 6:e31311.
    [26] HSU PJ, ZHU YF, MA HH, GUO YS, SHI XD, LIU YY, QI MJ, LU ZK, SHI HL, WANG JY, CHENG YW, LUO GZ, DAI Q, LIU MX, GUO XJ, SHA JH, SHEN B, HE C. Ythdc2 is an N6-methyladenosine binding protein that regulates mammalian spermatogenesis[J]. Cell Research, 2017, 27(9):1115-1127.
    [27] LIU N, ZHOU KI, PARISIEN M, DAI Q, DIATCHENKO L, PAN T. N6-methyladenosine alters RNA structure to regulate binding of a low-complexity protein[J]. Nucleic Acids Research, 2017, 45(10):6051-6063.
    [28] ALARCÓN CR, GOODARZI H, LEE H, LIU XH, TAVAZOIE S, TAVAZOIE SF. HNRNPA2B1 is a mediator of m6A-dependent nuclear RNA processing events[J]. Cell, 2015, 162(6):1299-1308.
    [29] HUANG HL, WENG HY, SUN WJ, QIN X, SHI HL, WU HZ, ZHAO BS, MESQUITA A, LIU C, YUAN CL, HU YC, HÜTTELMAIER S, SKIBBE JR, SU R, DENG XL, DONG L, SUN M, LI CY, NACHTERGAELE S, WANG YG, et al. Recognition of RNA N6-methyladenosine by IGF2BP proteins enhances mRNA stability and translation[J]. Nature Cell Biology, 2018, 20(3):285-295.
    [30] WANG J, SHA YQ, SUN T. m6A modifications play crucial roles in glial cell development and brain tumorigenesis[J]. Frontiers in Oncology, 2021, 11:611660.
    [31] YEN YP, CHEN JN. The m6A epitranscriptome on neural development and degeneration[J]. Journal of Biomedical Science, 2021, 28(1):40.
    [32] SILBEREIS JC, POCHAREDDY S, ZHU Y, LI MF, SESTAN N. The cellular and molecular landscapes of the developing human central nervous system[J]. Neuron, 2016, 89(2):248-268.
    [33] YOON KJ, RINGELING FR, VISSERS C, JACOB F, POKRASS M, JIMENEZ-CYRUS D, SU YJ, KIM NS, ZHU YH, ZHENG L, KIM S, WANG XY, DORÉ LC, JIN P, REGOT S, ZHUANG XX, CANZAR S, HE C, MING GL, SONG HJ. Temporal control of mammalian cortical neurogenesis by m6A methylation[J]. Cell, 2017, 171(4):877-889.e17.
    [34] CHEN JC, ZHANG YC, HUANG CM, SHEN H, SUN BF, CHENG XJ, ZHANG YJ, YANG YG, SHU Q, YANG Y, LI XK. m6A regulates neurogenesis and neuronal development by modulating histone methyltransferase Ezh2[J]. Genomics, Proteomics & Bioinformatics, 2019, 17(2):154-168.
    [35] GAO H, CHENG XJ, CHEN JC, JI C, GUO HF, QU WZ, DONG XX, CHEN YY, MA LH, SHU Q, LI XK. Fto-modulated lipid niche regulates adult neurogenesis through modulating adenosine metabolism[J]. Human Molecular Genetics, 2020, 29(16):2775-2787.
    [36] MA CH, CHANG MQ, Lü HY, ZHANG ZW, ZHANG WL, HE X, WU GL, ZHAO SL, ZHANG Y, WANG D, TENG XF, LIU CY, LI Q, KLUNGLAND A, NIU YM, SONG SH, TONG WM. RNA m6A methylation participates in regulation of postnatal development of the mouse cerebellum[J]. Genome Biology, 2018, 19(1):68.
    [37] DU TF, LI GX, YANG JL, MA KL. RNA demethylase Alkbh5 is widely expressed in neurons and decreased during brain development[J]. Brain Research Bulletin, 2020, 163:150-159.
    [38] SHI HL, ZHANG XL, WENG YL, LU ZY, LIU YJ, LU ZK, LI JN, HAO PL, ZHANG Y, ZHANG F, WU Y, DELGADO JY, SU YJ, PATEL MJ, CAO XH, SHEN B, HUANG XX, MING GL, ZHUANG XX, SONG HJ, et al. m6A facilitates hippocampus-dependent learning and memory through YTHDF1[J]. Nature, 2018, 563(7730):249-253.
    [39] ZHANG ZY, WANG M, XIE DF, HUANG ZH, ZHANG LS, YANG Y, MA DX, LI WG, ZHOU Q, YANG YG, WANG XJ. METTL3-mediated N6-methyladenosine mRNA modification enhances long-term memory consolidation[J]. Cell Research, 2018, 28(11):1050-1061.
    [40] LI MM, ZHAO X, WANG W, SHI HL, PAN QF, LU ZK, PEREZ SP, SUGANTHAN R, HE C, BJØRÅS M, KLUNGLAND A. Ythdf2-mediated m6A mRNA clearance modulates neural development in mice[J]. Genome Biology, 2018, 19(1):69.
    [41] ROWITCH DH, KRIEGSTEIN AR. Developmental genetics of vertebrate glial-cell specification[J]. Nature, 2010, 468(7321):214-222.
    [42] ZHOU H, WANG B, SUN H, XU XS, WANG YX. Epigenetic regulations in neural stem cells and neurological diseases[J]. Stem Cells International, 2018, 2018:6087143.
    [43] XU H, DZHASHIASHVILI Y, SHAH A, KUNJAMMA RB, WENG YL, ELBAZ B, FEI QL, JONES JS, LI YI, ZHUANG XX, MING GL, HE C, POPKO B. m6A mRNA methylation is essential for oligodendrocyte maturation and CNS myelination[J]. Neuron, 2020, 105(2):293-309.e5.
    [44] KORANDA JL, DORE L, SHI HL, PATEL MJ, VAASJO LO, RAO MN, CHEN K, LU ZK, YI YT, CHI WH, HE C, ZHUANG XX. Mettl14 is essential for epitranscriptomic regulation of striatal function and learning[J]. Neuron, 2018, 99(2):283-292.e5.
    [45] CHEN XC, YU CY, GUO MJ, ZHENG XT, ALI S, HUANG H, ZHANG LH, WANG SS, HUANG YH, QIE SY, WANG J. Down-regulation of m6A mRNA methylation is involved in dopaminergic neuronal death[J]. ACS Chemical Neuroscience, 2019, 10(5):2355-2363.
    [46] QIU XH, HE HH, HUANG YN, WANG J, XIAO YS. Genome-wide identification of m6A-associated single-nucleotide polymorphisms in Parkinson's disease[J]. Neuroscience Letters, 2020, 737:135315.
    [47] HAN M, LIU Z, XU YY, LIU XT, WANG DW, LI F, WANG Y, BI JZ. Abnormality of m6A mRNA methylation is involved in Alzheimer's disease[J]. Frontiers in Neuroscience, 2020, 14:98.
    [48] HUANG H, CAMATS-PERNA J, MEDEIROS R, ANGGONO V, WIDAGDO J. Altered expression of the m6A methyltransferase METTL3 in Alzheimerʼs disease[J]. eNeuro, 2020, 7(5):ENEURO.0125- ENEURO.0120.2020.
    [49] SHEN J, YANG L, WEI WS. Role of Fto on CaMKII/CREB signaling pathway of hippocampus in depressive-like behaviors induced by chronic restraint stress mice[J]. Behavioural Brain Research, 2021, 406:113227.
    [50] CUI Q, SHI HL, YE P, LI L, QU QH, SUN GQ, SUN GH, LU ZK, HUANG Y, YANG CG, RIGGS AD, HE C, SHI YH. m6A RNA methylation regulates the self-renewal and tumorigenesis of glioblastoma stem cells[J]. Cell Reports, 2017, 18(11):2622-2634.
    [51] LI F, ZHANG C, ZHANG GF. m6A RNA methylation controls proliferation of human glioma cells by influencing cell apoptosis[J]. Cytogenetic and Genome Research, 2019, 159(3):119-125.
    [52] ZHANG SC, ZHAO BS, ZHOU AD, LIN KY, ZHENG SP, LU ZK, CHEN YH, SULMAN EP, XIE KP, BÖGLER O, MAJUMDER S, HE C, HUANG SY. m6A demethylase ALKBH5 maintains tumorigenicity of glioblastoma stem-like cells by sustaining FOXM1 expression and cell proliferation program[J]. Cancer Cell, 2017, 31(4):591-606.e6.
    [53] JANKOVIC J, TAN EK. Parkinson's disease:etiopathogenesis and treatment[J]. Journal of Neurology, Neurosurgery, and Psychiatry, 2020, 91(8):795-808.
    [54] ASCHERIO A, SCHWARZSCHILD MA. The epidemiology of Parkinson's disease:risk factors and prevention[J]. The Lancet Neurology, 2016, 15(12):1257-1272.
    [55] SORIA LOPEZ JA, GONZÁLEZ HM, LÉGER GC. Alzheimer's disease[A]//Handbook of Clinical Neurology[M]. Amsterdam:Elsevier, 2019:231-255.
    [56] BALMIK AA, CHINNATHAMBI S. Methylation as a key regulator of Tau aggregation and neuronal health in Alzheimer's disease[J]. Cell Communication and Signaling:CCS, 2021, 19(1):51.
    [57] REITZ C, TOSTO G, MAYEUX R, LUCHSINGER JA, GROUP NL FS, INITIATIVE ADN. Genetic variants in the Fat and Obesity Associated (FTO) gene and risk of Alzheimer's disease[J]. PLoS One, 2012, 7(12):e50354.
    [58] CORREALE J, GAITÁN MI, YSRRAELIT MC, FIOL MP. Progressive multiple sclerosis:from pathogenic mechanisms to treatment[J]. Brain, 2017, 140(3):527-546.
    [59] ZHANG N, DING CH, ZUO YX, PENG Y, ZUO LL. N6-methyladenosine and neurological diseases[J]. Molecular Neurobiology, 2022, 59(3):1925-1937.
    [60] SCHRAMM E, KLEIN DN, ELSAESSER M, FURUKAWA TA, DOMSCHKE K. Review of dysthymia and persistent depressive disorder:history, correlates, and clinical implications[J]. The Lancet Psychiatry, 2020, 7(9):801-812.
    [61] LI M, FU XY, XIE W, GUO WX, LI BJ, CUI RJ, YANG W. Effect of early life stress on the epigenetic profiles in depression[J]. Frontiers in Cell and Developmental Biology, 2020, 8:867.
    [62] RIVERA M, COHEN-WOODS S, KAPUR K, BREEN G, NG MY, BUTLER AW, CRADDOCK N, GILL M, KORSZUN A, MAIER W, MORS O, OWEN MJ, PREISIG M, BERGMANN S, TOZZI F, RICE J, RIETSCHEL M, RUCKER J, SCHOSSER A, AITCHISON KJ, et al. Depressive disorder moderates the effect of the FTO gene on body mass index[J]. Molecular Psychiatry, 2012, 17(6):604-611.
    [63] FARMER A, KORSZUN A, OWEN MJ, CRADDOCK N, JONES L, JONES I, GRAY J, WILLIAMSON RJ, MCGUFFIN P. Medical disorders in people with recurrent depression[J]. The British Journal of Psychiatry:the Journal of Mental Science, 2008, 192(5):351-355.
    [64] LOUIS DN, PERRY A, REIFENBERGER G, von DEIMLING A, FIGARELLA-BRANGER D, CAVENEE WK, OHGAKI H, WIESTLER OD, KLEIHUES P, ELLISON DW. The 2016 World Health Organization classification of tumors of the central nervous system:a summary[J]. Acta Neuropathologica, 2016, 131(6):803-820.
    [65] ZHANG YH, GENG XC, LI Q, XU JL, TAN YL, XIAO ML, SONG J, LIU FL, FANG C, WANG H. m6A modification in RNA:biogenesis, functions and roles in gliomas[J]. Journal of Experimental & Clinical Cancer Research, 2020, 39(1):192.
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王万莹,罗富成. N6-甲基化腺嘌呤RNA甲基化修饰在中枢神经系统中的作用研究进展[J]. 生物工程学报, 2023, 39(1): 45-59

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  • 收稿日期:2022-03-29
  • 最后修改日期:2022-07-20
  • 在线发布日期: 2023-02-01
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