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甲基转移酶样3及其在代谢性疾病中作用的研究进展
作者:郭文惠1 2  雷皓月1 2  潘友卓1 2  张琦2 
单位:1. 甘肃中医药大学 第一临床医学院, 甘肃 兰州 730000;
2. 甘肃省人民医院 老年医学科, 甘肃 兰州 730000
关键词:甲基转移酶样3 N6-甲基腺嘌呤 代谢性疾病 综述 
分类号:R58
出版年·卷·期(页码):2023·51·第十二期(1771-1778)
摘要:

N6-甲基腺嘌呤(m6A),是指腺苷上的N6位引入甲基的过程。m6A是真核生物中最丰富、最多样的表观遗传修饰的mRNA,可调节生物代谢、细胞分化和周期。甲基化转移酶主要包括甲基转移酶样3(METTL3) 、甲基转移酶样14(METTL14)、肾母细胞瘤1关联蛋白(WTAP)等。METTL3 因其特定的结构而成为甲基化转移酶复合体中唯一的催化亚基,METTL3介导的m6A修饰与RNA的翻译、剪接、出核和降解都有着密切联系,并且在代谢性疾病的发生发展中起着重要作用。目前,m6A修饰在代谢性疾病的作用正在得到广泛的研究。因此,本文就METTL3介导的m6A修饰及其在代谢性疾病中的作用进行综述。

参考文献:

[1] PERRY R,KELLEY D,FRIDERICI K,et al.The methylated constituents of L cell messenger RNA:evidence for an unusual cluster at the 5' terminus[J].Cell,1975,4(4):387-394.
[2] DUBIN D,TAYLOR R.The methylation state of poly A-containing messenger RNA from cultured hamster cells[J].Nucleic Acids Res,1975,2(10):1653-1668.
[3] ADAMS J,CORY S.Modified nucleosides and bizarre 5'-termini in mouse myeloma mRNA[J].Nature,1975,255(5503):28-33.
[4] DU Y,HOU G,ZHANG H,et al.SUMOylation of the m6A-RNA methyltransferase METTL3 modulates its function[J].Nucleic Acids Res,2018,46(10):5195-5208.
[5] XU C,WANG X,LIU K,et al.Corrigendum:structural basis for selective binding of m6A RNA by the YTHDC1 YTH domain[J].Nat Chem Biol,2015,11(10):815.
[6] DOMINISSINI D,MOSHITCH-MOSHKOVITZ S,SCHWARTZ S,et al.Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq[J].Nature,2012,485(7397):201-206.
[7] MEYER K,SALETORE Y,ZUMBO P,et al.Comprehensive analysis of mRNA methylation reveals enrichment in 3'UTRs and near stop codons[J].Cell,2012,149(7):1635-1646.
[8] LAN Q,LIU P,HAASE J,et al.The critical role of RNA m6A methylation in cancer[J].Cancer Res,2019,79(7):1285-1292.
[9] ZHANG C,CHEN Y,SUN B,et al.m6A modulates haematopoietic stem and progenitor cell specification[J].Nature,2017,549(7671):273-276.
[10] WANG P,DOXTADER K,NAM Y.Structural basis for cooperative function of METTL3 and METTL14 methyltransferases[J].Mol Cell,2016,63(2):306-317.
[11] FU Y,DOMINISSINI D,RECHAVI G,et al.Gene expression regulation mediated through reversible m6A RNA methylation[J].Nat Rev Genet,2014,15(5):293-306.
[12] WU L,WU D,NING J,et al.Changes of N6-methyladenosine modulators promote breast cancer progression[J].BMC Cancer,2019,19(1):326.
[13] LIN S,CHOE J,DU P,et al.The m6A methyltransferase METTL3 promotes translation in human cancer cells[J].Mol Cell,2016,62(3):335-345.
[14] VAN TRAN N,ERNST F,HAWLEY B,et al.The human 18S rRNA m6A methyltransferase METTL5 is stabilized by TRMT112[J].Nucleic Acids Res,2019,47(15):7719-7733.
[15] WARDA A,KRETSCHMER J,HACKERT P,et al.Human METTL16 is a N6-methyladenosine(m6A) methyltransferase that targets pre-mRNAs and various non-coding RNAs[J].EMBO Rep,2017,18(11):2004-2014.
[16] MELSTROM L,CHEN J.RNA N6-methyladenosine modification in solid tumors:new therapeutic frontiers[J].Cancer Gene Ther,2020,27(9):625-633.
[17] MA H,WANG X,CAI J,et al.N6-methyladenosine methyltransferase ZCCHC4 mediates ribosomal RNA methylation[J].Nat Chem Biol,2019,15(1):88-94.
[18] LED P,JINEK M.Structural insights into the molecular mechanism of the m6A writer complex[J].Elife,2016,13(5):13-15.
[19] LIANG Y,ZHAN G,CHANG K,et al.The roles of m6A RNA modifiers in human cancer[J].J Chin Med Assoc,2020,83(3):221-226.
[20] CUI Q,SHI H,YE P,et al.M6A RNA methylation regulates the self-renewal and tumorigenesis of glioblastoma stem cells[J].Cell Rep,2017,18(11):2622-2634.
[21] BOKAR J,SHAMBAUGH M,POLAYES D,et al.Purification and cDNA cloning of the AdoMet-binding subunit of the human mRNA(N6-adenosine)-methyltransferase[J].RNA,1997,3(11):1233-1247.
[22] PING X,SUN B,WANG L,et al.Mammalian WTAP is a regulatory subunit of the RNA N6methyladenosine methyltransferase[J].Cell Res,2014,24(2):177-189.
[23] LIU J,YUE Y,HAN D,et al.A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation[J].Nat Chem Biol,2014,10(2):93-95.
[24] WANG Y,LI Y,TOTH J,et al.N6-methyladenosine modification destabilizes developmental regulators in embryonic stem cells[J].Nat Cell Biol,2014,16(2):191-198.
[25] JONES D.Protein secondary structure prediction based on position-specific scoring matrices[J].Mol Biol,1999,292(2):195-202.
[26] WARD J,MCGUFFIN L,BRYSON K,et al.The DISOPRED server for the prediction of protein disorder[J].Bioinformatics,2004,20(13):2138-2139.
[27] WANG X,FENG J,XUE Y,et al.Structural basis of N6-adenosine methylation by the METTL3-METTL14 complex[J].Nature,2016,534(7608):575-578.
[28] LIU S,ZHUO L,WANG J,et al.METTL3 plays multiple functions in biological processes[J].Cancer Res,2020,10(6):1631-1646.
[29] SCHÖLLER E,WEICHMANN F,TREIBER T,et al.Interactions,localization,and phosphorylation of the m6A generating METTL3-METTL14-WTAP complex[J].RNA,2018,24(4):499-512.
[30] AGUILO F,ZHANG F,SANCHO A,et al.Coordination of m6A mRNA methylation and gene transcription by ZFP217 regulates pluripotency and reprogramming[J].Cell Stem Cell,2015,17(6):689-704.
[31] HESS M,HESS S,MEYER K,et al.The fat mass and obesity associated gene(Fto) regulates activity of the dopaminergic midbrain circuitry[J].Nat Neurosci,2013,16(8):1042-1048.
[32] XU K,YANG Y,FENG G,et al.METTL3-mediated m6A regulates spermatogonial differentiation and meiosis initiation[J].Cell Res,2017,27(9):1100-1114.
[33] LI H,TONG J,ZHU S,et al.M6A mRNA methylation controls T cell homeostasis by targeting the IL-7/STAT5/SOCS pathways[J].Nature,2017,548(7667):338-342.
[34] YAO Y,BI Z,WU R,et al.METTL3 inhibits BMSC adipogenic differentiation by targeting the JAK1/STAT5/C/EBPβ pathway via an m6A-YTHDF2-dependent manner[J].FASEB J,2019,33(6):7529-7544.
[35] TIAN C,HUANG Y,LI Q,et al.METTL3 regulates osteogenic differentiation and alternative splicing of vegfa in bone marrow mesenchymal stem cells[J].Int J Mol Sci,2019,20(3):551.
[36] MIAO W,CHEN J,JIA L,et al.The m6A methyltransferase METTL3 promotes osteosarcoma progression by regulating the m6A level of LEF1[J].Biochem Bioph Res Co,2019,516(3):719-725.
[37] FENG Z,LI Q,MENG R,et al.METTL3 regulates alternative splicing of MyD88 upon the lipopolysaccharide-induced inflammatory response in human dental pulp cells[J].J Cell Mol Med,2018,22(5):2558-2568.
[38] LITTLE N,HASTIE N,DAVIES R.Identification of WTAP,a novel Wilms' tumour 1-associating protein[J].Hum Mol Genet,2000,9(15):2231-2239.
[39] HAN D,LONGHINI A,ZHANG X,et al.Dynamic assembly of the mRNA m6A methyltransferase complex is regulated by METTL3 phase separation[J].PLoS Biol,2022,20(2):e3001535.
[40] SCHWARTZ S,MUMBACH M,JOVANOVIC M,et al.Perturbation of m6A writers reveals two distinct classes of mRNA methylation at internal and 5' sites[J].Cell Rep,2014,8(1):284-296.
[41] GEULA S,MOSHITCH-MOSHKOVITZ S,DOMINISSINI D,et al.Stem cells.m6A mRNA methylation facilitates resolution of nave pluripotency toward differentiation[J].Science,2015,347(6225):1002-1006.
[42] CHOE J,LIN S,ZHANG W,et al.mRNA circularization by METTL3-eIF3h enhances translation and promotes oncogenesis[J].Nature,2018,561(7724):556-560.
[43] ZHENG R,ZHANG K,TAN S,et al.Exosomal circLPAR1 functions in colorectal cancer diagnosis and tumorigenesis through suppressing BRD4 via METTL3-eIF3h interaction[J].Mol Cancer,2022,21(1):49.
[44] JIN D,GUO J,WU Y,et al.M6A mRNA methylation initiated by METTL3 directly promotes YAP translation and increases YAP activity by regulating the MALAT1-miR-1914-3p-YAP axis to induce NSCLC drug resistance and metastasis[J].J Hematol Oncol,2019,12(1):135.
[45] WANG H,HU X,HUANG M,et al.METTL3-mediated mRNA m6A methylation promotes dendritic cell activation[J].Nat Commun,2019,10(1):1898.
[46] POH H,MIRZA A,PICKERING B,et al.Alternative splicing of METTL3 explains apparently METTL3-independent m6A modifications in mRNA[J].PLoS Biol,2022,20(7):e3001683.
[47] ROUNDTREE I,LUO G,ZHANG Z,et al.YTHDC1 mediates nuclear export of N6-methyladenosine methylated mRNAs[J].Elife,2017,6:e31311.
[48] LEE Y,CHOE J,PARK O,et al.Molecular mechanisms driving mRNA degradation by m6A modification[J].Trends Genet,2020,36(3):177-188.
[49] WU J,BOSTRÖM P,SPARKS L,et al.Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human[J].Cell,2012,150(2):366-376.
[50] LOWELL B,SPIEGELMAN B.Towards a molecular understanding of adaptive thermogenesis[J].Nature,2000,404(6778):652-660.
[51] WANG Y,GAO M,ZHU F,et al.METTL3 is essential for postnatal development of brown adipose tissue and energy expenditure in mice[J].Nat Commun,2020,11(1):1648.
[52] AMBROS V.MicroRNA pathways in flies and worms:growth,death,fat,stress,and timing[J].Cell,2003,113(6):673-676.
[53] ALARCóN C,LEE H,GOODARZI H,et al.N6-methyladenosine marks primary microRNAs for processing[J].Nature,2015,519(7544):482-485.
[54] MA J,YANG F,ZHOU C,et al.METTL14 suppresses the metastatic potential of hepatocellular carcinoma by modulating N6-methyladenosine-dependent primary microRNA processing[J].Hepatology,2017,65(2):529-543.
[55] LI X,JIANG Y,SUN X,et al.METTL3 is required for maintaining β-cell function[J].Metabolism,2021,3(116):154702.
[56] WANG Y,SUN J,LIN Z,et al.M6A mRNA methylation controls functional maturation in neonatal murine β-Cells[J].Diabetes,2020,69(8):1708-1722.
[57] LI H,ZHU X,ZHANG J,et al.MicroRNA-25 inhibits high glucose-induced apoptosis in renal tubular epithelial cells via PTEN/AKT pathway[J].Biomed Pharmacother,2017,96(4):471-479.
[58] ZHA X,XI X,FAN X,et al.Overexpression of METTL3 attenuates high-glucose induced RPE cell pyroptosis by regulating miR-25-3p/PTEN/Akt signaling cascade through DGCR8[J].Aging,2020,12(9):8137-8150.
[59] HUANG Y,ZHENG Y,JIA L,et al.Long noncoding RNA H19 promotes osteoblast differentiation via TGF-β1/Smad3/HDAC signaling pathway by deriving miR-675[J].Stem Cells(Dayton,Ohio),2015,33(12):3481-3492.
[60] WANG C,LIAO Z,XIAO H,et al.LncRNA KCNQ1OT1 promoted BMP2 expression to regulate osteogenic differentiation by sponging miRNA-214[J].Exp Mol Pathol,2019,107:77-84.
[61] LIN T,GIBON E,LOI F,et al.Decreased osteogenesis in mesenchymal stem cells derived from the aged mouse is associated with enhanced NF-κB activity[J].J Orthop Res,2017,35(2):281-288.
[62] YU J,SHEN L,LIU Y,et al.The m6A methyltransferase METTL3 cooperates with demethylase ALKBH5 to regulate osteogenic differentiation through NF-κB signaling[J].Mol Cell Biochem,2020,463(4):203-210.
[63] WU Y,XIE L,WANG M,et al.METTL3-mediated m6A RNA methylation regulates the fate of bone marrow mesenchymal stem cells and osteoporosis[J].Nat Commun,2018,9(1):4772.
[64] LIU J,CHEN M,MA L,et al.piRNA-36741 regulates BMP2-mediated osteoblast differentiation via METTL3 controlled m6A modification[J].Aging,2021,13(19):23361-23375.
[65] WU T,TANG H,YANG J,et al.METTL3-m6A methylase regulates the osteogenic potential of bone marrow mesenchymal stem cells in osteoporotic rats via the Wnt signalling pathway[J].Cell Prolif,2022,55(5):e13234.
[66] YOUNOSSI Z,KOENIG A,ABDELATIF D,et al.Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence,incidence,and outcomes[J].Hepatology(Baltimore,Md),2016,64(1):73-84.
[67] ADAMS L,LYMP J,ST SAUVER J,et al.The natural history of nonalcoholic fatty liver disease:a population-based cohort study[J].Gastroenterology,2005,129(1):113-121.
[68] WHITE D,KANWAL F,EL-SERAG H.Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer,based on systematic review[J].Clin Gastroenterol Hepatol,2012,10(12):1342-1359.e2.
[69] HAUKELAND J,DAMåS J,KONOPSKI Z,et al.Systemic inflammation in nonalcoholic fatty liver disease is characterized by elevated levels of CCL2[J].J Hepatol,2006,44(6):1167-1174.
[70] MIURA K,YANG L,VAN ROOIJEN N,et al.Hepatic recruitment of macrophages promotes nonalcoholic steatohepatitis through CCR2[J].Am J Physiol Gastrointest Liver Physiol,2012,302(11):G1310-1321.
[71] BAECK C,WEHR A,KARLMARK K,et al.Pharmacological inhibition of the chemokine CCL2(MCP-1) diminishes liver macrophage infiltration and steatohepatitis in chronic hepatic injury[J].Gut,2012,61(3):416-426.
[72] LEFEBVRE E,MOYLE G,RESHEF R,et al.Antifibrotic effects of the dual CCR2/CCR5 antagonist cenicriviroc in animal models of liver and kidney fibrosis[J].PLoS One,2016,11(6):e0158156.
[73] LI X,YUAN B,LU M,et al.The methyltransferase METTL3 negatively regulates nonalcoholic steatohepatitis(NASH) progression[J].Nat Commun,2021,12(1):7213.
[74] DOU X,XIA Y,CHEN J,et al.Rectification of impaired adipose tissue methylation status and lipolytic response contributes to hepatoprotective effect of betaine in a mouse model of alcoholic liver disease[J].Br J Pharmacol,2014,171(17):4073-4086.

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