BAO Sijie,LI Pengfei,KANG Lihua,et al.Research progress in the effect of ribonucleic acid methylation N6-methyladenosine modification on eye diseases[J].Recent Advances in Ophthalmology,2023,43(5):401-406.[doi:10.13389/j.cnki.rao.2023.0081]





Research progress in the effect of ribonucleic acid methylation N6-methyladenosine modification on eye diseases
22600 江苏省南通市,南通大学附属医院眼科,南通大学医学院
BAO SijieLI PengfeiKANG LihuaWANG CongyuWANG SiwenGUAN Huaijin
Department of Ophthalmology,the Affiliated Hospital of Nantong University,Nantong 226001,Jiangsu Province,China
ribonucleic acid methylation N6-methyladenosine modification eye diseases
N6-methyladenosine (m6A) refers to the methylation modification that occurs at the 6th N site of adenine, and the modification is completed by methyltransferases, demethylases and recognition enzymes. The m6A ribonucleic acid (RNA) methylation modification can regulate the messenger ribonucleic acid (mRNA) metabolism, such as alternative splicing, nuclear export, translation and stability of mRNA. Meanwhile, it can participate in various cellular biological processes, such as embryonic development, immune regulation, fat metabolism, and biological rhythms, which subsequently affect the occurrence and development of diseases. This paper was to summarize the recent research progress of m6A RNA methylation modification in eye diseases, including ocular surface diseases, glaucoma, cataracts, retinal diseases, uveal diseases, Graves eye diseases, and ocular tumors.


[1] WANG S,L W,LI T,ZHANG S,WANG H,LI X,et al.Dynamic regulation and functions of mRNA m6A modification[J].Cancer Cell Int,2022,22(1):48.
[2] MEYER K D,SALETORE Y,ZUMBO P,ELEMENTO O,MASON C E,JAFFREY S R.Comprehensive analysis of mRNA methylation reveals enrichment in 3’ UTRs and near stop codons[J].Cell,2012,149(7):1635-1646.
[3] CSEPANY T,LIN A,BALDICK C J J R,BEEMON K.Sequence specificity of mRNA N6-adenosine methyltransferase[J].J Biol Chem,1990,265(33):20117-20122.
[4] BI Z,LIU Y,ZHAO Y,YAO Y,WU R,LIU Q,et al.A dynamic reversible RNA N(6)-methyladenosine modification:current status and perspectives[J].J Cell Physiol,2019,234(6):7948-7956.
[5] WU Y,ZHOU C,YUAN Q.Role of DNA and RNA N6-Adenine methylation in regulating stem cell fate[J].Curr Stem Cell Res Ther,2018,13(1):31-38.
[6] WINKLER R,GILLIS E,LASMAN L,SAFRA M,GEULA S,SOYRIS C,et al.M(6)A modification controls the innate immune response to infection by targeting type I interferons[J].Nat Immunol,2019,20(2):173-182.
[7] LIU Z X,LI L M,SUN H L,LIU S M.Link between m6A modification and cancers[J].Front Bioeng Biotechnol,2018,6:89.
[8] CHURCH C,MOIR L,MCMURRAY F,GIRARD C,BANKS G T,TEBOUL L,et al.Overexpression of FTO leads to increased food intake and results in obesity[J].Nat Genet,2010,42(12):1086-1092.
[9] GAO J F,ZHANG L.The role of N6-methyladenosine (m6A) in eye diseases[J].Mol Biol Rep,2021,48(8):6145-6150.
[10] WANG P,DOXTADER K A,NAM Y.Structural basis for cooperative function of METTL3 and METTL4 Methyltransferases[J].Mol Cell,2016,63(2):306-317.
[11] LIU J,YUE Y,HAN D,WANG X,FU Y,ZHANG L,et al.A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation[J].Nat Chem Biol,2014,10(2):93-95.
[12] HORIUCHI K,KAWAMURA T,IWANARI H,OHASHI R,NAITO M,KODAMA T,et al.Identification of Wilms’ tumor 1-associating protein complex and its role in alternative splicing and the cell cycle[J].J Biol Chem,2013,288(46):33292-33302.
[13] KNUCKLES P,LENCE T,HAUSSMANN I U,JACOB D,KREIM N,CARL S H,et al.Zc3h13/Flacc is required for adenosine methylation by bridging the mRNA-binding factor Rbm15/Spenito to the m(6)A machinery component Wtap/Fl(2)d[J].Genes Dev,2018,32(5-6):415-429.
[14] YANG C,HU Y,ZHOU B,BAO Y,LI Z,GONG C,et al.The role of m(6)A modification in physiology and disease[J].Cell Death Dis,2020,11(11):960.
[15] FEDELES B I,SINGH V,DELANEY J C,LI D,ESSIGMANN J M.The AlkB family of Fe(II)/alpha-ketoglutarate-dependent dioxygenases:repairing nucleic acid alkylation damage and beyond[J].J Biol Chem,2015,290(34):20734-20742.
[16] TOH J D W,CROSSLEY S W M,BRUEMMER K J,GE E J,HE D,IOVAN D A,et al.Distinct RNA N-demethylation pathways catalyzed by nonheme iron ALKBH5 and FTO enzymes enable regulation of formaldehyde release rates[J].Proc Natl Acad Sci U S A,2020,117(41):25284-25292.
[17] XU C,LIU K,AHMED H,LOPPNAU P,SCHAPIRA M,MIN J.Structural basis for the discriminative recognition of N6-Methyladenosine RNA by the human YT521-B homology domain family of proteins[J].J Biol Chem,2015,290(41):24902-24913.
[18] SHI H,WANG X,LU Z,ZHAO B S,MA H,HSU P J,et al.YTHDF3 facilitates translation and decay of N(6)-methyladenosine-modified RNA[J].Cell Res,2017,27(3):315-328.
[19] WU R,LI A,SUN B,SUN J G,ZHANG J,ZHANG T,et al.A novel m(6)A reader Prrc2a controls oligodendroglial specification and myelination[J].Cell Res,2019,29(1):23-41.
[20] LIU N,DAI Q,ZHENG G,HE C,PARISIEN M,PAN T.N(6)-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions[J].Nature,2015,518(7540):560-564.
[21] HUANG H,WENG H,SUN W,QIN X,SHI H,WU H,et al.Recognition of RNA N(6)-methyladenosine by IGF2BP proteins enhances mRNA stability and translation[J].Nat Cell Biol,2018,20(3):285-295.
[22] FLORCRUZ N V,EVANS J R.Medical interventions for fungal keratitis[J].Cochrane Database Syst Rev,2015,(4):CD004241.
[23] HU J,LIN Y.Fusarium infection alters the m(6)A-modified transcript landscape in the cornea[J].Exp Eye Res,2020,200:108216.
[24] KE L,YANG Y,LI JW,WANG B,WANG Y,YANG W,et al.Modulation of corneal FAK/PI3K/Akt signaling expression and of Metalloproteinase-2 and Metalloproteinase-9 during the development of herpes simplex keratitis[J].Biomed Res Int,2019,2019:4143981.
[25] QIN X H,MA X,FANG S F,ZHANG Z Z,LU J M.IL-17 produced by Th17 cells alleviates the severity of fungal keratitis by suppressing CX43 expression in corneal peripheral vascular endothelial cells[J].Cell Cycle,2019,18(3):274-287.
[26] CHEN J,MAQSOOD S,KAYE S,TEY A,AHMAD S.Pterygium:are we any closer to the cause?[J].Br J Ophthalmol,2014,98(4):423-424.
[27] JIANG Y,ZHANG X,ZHANG X,ZHAO K,ZHANG J,YANG C,et al.Comprehensive analysis of the transcriptome-wide m6A methylome in pterygium by MeRIP sequencing[J].Front Cell Dev Biol,2021,9:670528.
[28] GONZALEZ G,SASAMOTO Y,KSANDER B R,FRANK M H,FRANK N Y.Limbal stem cells:identity,developmental origin,and therapeutic potential[J].Wiley Interdiscip Rev Dev Biol,2018,7(2):10.1002/wdev.303.
[29] DAI Y,CHENG M,ZHANG S,LING R,WEN J,CHENG Y,et al.METTL3-mediated m(6)A RNA modification regulates corneal injury repair[J].Stem Cells Int,2021,2021:5512153.
[30] LIM H J,KIM J,PARK C H,LEE S A,LEE M R,KIM K S,et al.Regulation of c-Myc expression by ahnak promotes induced pluripotent stem cell generation[J].J Biol Chem,2016,291(2):752-761.
[31] MARTIN S K,FITTER S,DUTTA A K,MATTHEWS M P,WALKLEY C R,HALL M N,et al.Brief report:the differential roles of mTORC1 and mTORC2 in mesenchymal stem cell differentiation[J].Stem Cells,2015,33(4):1359-1365.
[32] DIAS M S,LUO X,RIBAS V T,PETRS-SILVA H,KOCH J C.The role of axonal transport in glaucoma[J].Int J Mol Sci,2022,23(7):3935.
[33] NIU F,HAN P,ZHANG J,SHE Y,YANG L,YU J,et al.The m(6)A reader YTHDF2 is a negative regulator for dendrite development and maintenance of retinal ganglion cells[J].Elife,2022,11:e75827.
[34] LIU Y,GU C,LI X,WANG T,YU L.Involvement of METTL3/m(6)Adenosine and TGFbeta/Smad3 signaling on Tenon’s fibroblasts and in a rabbit model of glaucoma surgery[J].J Mol Histol,2021,52(6):1129-1144.
[35] GBD 2019 BLINDNESS AND VISION IMPAIRMENT COLLABORATORS,VISION LOSS EXPERT GROUP OF THE GLOBAL BURDEN OF DISEASE S.Causes of blindness and vision impairment in 2020 and trends over 30 years,and prevalence of avoidable blindness in relation to vision 2020:the right to sight:an analysis for the global burden of disease study[J].Lancet Glob Health,2021,9(2):e144-e160.
[36] LI P,YU H,ZHANG G,KANG L,QIN B,CAO Y,et al.Identification and characterization of N6-methyladenosine circRNAs and methyltransferases in the lens epithelium cells from age-related cataract[J].Invest Ophthalmol Vis Sci,2020,61(10):13.
[37] WONG T Y,SUN J,KAWASAKI R,RUAMVIBOONSUK P,GUPTA N,LANSINGH V C,et al.Guidelines on diabetic eye care:the international council of ophthalmology recommendations for screening,follow-up,referral,and treatment based on resource settings[J].Ophthalmology,2018,125(10):1608-1622.
[38] YANG J,LIU J,ZHAO S,TIAN F.N(6)-methyladenosine METTL3 modulates the proliferation and apoptosis of lens epithelial cells in diabetic cataract[J].Mol Ther Nucleic Acids,2020,20:111-116.
[39] PAN C W,BOEY P Y,CHENG C Y,SAW S M,TAY W T,WANG J J,et al.Myopia,axial length,and age-related cataract:the Singapore Malay eye study[J].Invest Ophthalmol Vis Sci,2013,54(7):4498-4502.
[40] ZHU X,LI D,DU Y,HE W,LU Y.DNA hypermethylation-mediated downregulation of antioxidant genes contributes to the early onset of cataracts in highly myopic eyes[J].Redox Biol,2018,19:179-189.
[41] YAN L,DENG Y,ZHOU J,ZHAO H,WANG G.Serum YKL-40 as a biomarker for liver fibrosis in chronic hepatitis B patients with normal and mildly elevated ALT[J].Infection,2018,46(3):385-393.
[42] WEN K,ZHANG Y,LI Y,WANG Q,SUN J.Comprehensive analysis of transcriptome-wide m(6)A methylome in the anterior capsule of the lens of high myopia patients[J].Epigenetics,2021,16(9):955-968.
[43] LEE J,KIM K E,CHOI D K,JANG J Y,JUNG J J,KIYONARI H,et al.Angiopoietin-1 guides directional angiogenesis through integrin alphavbeta5 signaling for recovery of ischemic retinopathy[J].Sci Transl Med,2013,5(203):203ra127.
[44] YAO M D,JIANG Q,MA Y,LIU C,ZHU C Y,SUN Y N,et al.Role of METTL3-dependent N(6)-methyladenosine mRNA modification in the promotion of gngiogenesis[J].Mol Ther,2020,28(10):2191-2202.
[45] CHEUNG N,MITCHELL P,WONG T Y.Diabetic retinopathy[J].Lancet,2010,376(9735):124-136.
[46] HUANG H.Pericyte-endothelial interactions in the retinal microvasculature[J].Int J Mol Sci,2020,21(19):7413.
[47] SUO L,LIU C,ZHANG Q Y,YAO M D,MA Y,YAO J,et al.METTL3-mediated N(6)-methyladenosine modification governs pericyte dysfunction during diabetes-induced retinal vascular complication[J].Theranostics,2022,12(1):277-289.
[48] QI Y,YAO R,ZHANG W,CUI Q.KAT1 triggers YTHDF2-mediated ITGB1 mRNA instability to alleviate the progression of diabetic retinopathy[J].Pharmacol Res,2021,170:105713.
[49] CHEN T,ZHU W,WANG C,DONG X,YU F,SU Y,et al.ALKBH5-mediated m(6)A modification of A20 regulates microglia polarization in diabetic retinopathy[J].Front Immunol,2022,13:813979.
[50] KWON W,FREEMAN S A.Phagocytosis by the retinal pigment epithelium:recognition,resolution,recycling[J].Front Immunol,2020,11:604205.
[51] NEWTON F,MEGAW R.Mechanisms of photoreceptor death in retinitis pigmentosa[J].Genes (Basel),2020,11(10):1120.
[52] YIN L,MA C,HOU S,MA X.Methyltransferase-like (METTL)14-mediated N6-methyladenosine modification modulates retinal pigment epithelial (RPE) activity by regulating the methylation of microtubule-associated protein (MAP)2[J].Bioengineered,2022,13(3):4773-4785.
[53] HOU S,LI N,LIAO X,KIJLSTRA A,YANG P.Uveitis genetics[J].Exp Eye Res,2020,190:107853.
[54] ZHOU H,XU Z,LIAO X,TANG S,LI N,HOU S.Low expression of YTH domain-containing 1 promotes microglial M1 polarization by reducing the stability of Sirtuin 1 mRNA[J].Front Cell Neurosci,2021,15:774305.
[55] WANG H,LIU C,HAN M,CHENG C,ZHANG D.TRAM1 promotes microglia M1 polarization[J].J Mol Neurosci,2016,58(2):287-296.
[56] MADEIRA M H,BOIA R,SANTOS P F,AMBROSIO A F,SANTIAGO A R.Contribution of microglia-mediated neuroinflammation to retinal degenerative diseases[J].Mediators Inflamm,2015,2015:673090.
[57] RATHNASAMY G,FOULDS W S,LING E A,KAUR C.Retinal microglia-a key player in healthy and diseased retina[J].Prog Neurobiol,2019,173:18-40.
[58] CHEN X,CHEN C,FAN S,WU S,YANG F,FANG Z,et al.Omega-3 polyunsaturated fatty acid attenuates the inflammatory response by modulating microglia polarization through SIRT1-mediated deacetylation of the HMGB1/NF-kappaB pathway following experimental traumatic brain injury[J].J Neuroinflammation,2018,15(1):116.
[59] BAHN R S.Graves’ ophthalmopathy[J].N Engl J Med,2010,362(8):726-738.
[60] ZHU L,LI S,HE S,TONG Q,WANG L,LI X,et al.The critical role of m(6)A methylation in the pathogenesis of Graves’ ophthalmopathy[J].Eye Vis (Lond),2020,7(1):55.
[61] ROMERO-KUSABARA I L,FILHO J V,SCALISSI N M,MELO K C,DEMARTINO G,LONGUI C A,et al.Distinct inflammatory gene expression in extraocular muscle and fat from patients with Graves’ orbitopathy[J].Eur J Endocrinol,2017,176(4):481-488.
[62] ARONOW M E,TOPHAM A K,SINGH A D.Uveal melanoma:5-year update on incidence,treatment,and survival (SEER 1973-2013)[J].Ocul Oncol Pathol,2018,4(3):145-151.
[63] TANG J,WAN Q,LU J.The prognostic values of m6A RNA methylation regulators in uveal melanoma[J].BMC Cancer,2020,20(1):674.
[64] JIA R,CHAI P,WANG S,SUN B,XU Y,YANG Y,et al.M(6)A modification suppresses ocular melanoma through modulating HINT2 mRNA translation[J].Mol Cancer,2019,18(1):161.
[65] HAO L,YIN J,YANG H,LI C,ZHU L,LIU L,et al.ALKBH5-mediated m(6)A demethylation of FOXM1 mRNA promotes progression of uveal melanoma[J].Aging (Albany NY),2021,13(3):4045-4062.
[66] YU J,CHAI P,XIE M,GE S,RUAN J,FAN X,et al.Histone lactylation drives oncogenesis by facilitating m(6)A reader protein YTHDF2 expression in ocular melanoma[J].Genome Biol,2021,22(1):85.
[67] LUO G,XU W,ZHAO Y,JIN S,WANG S,LIU Q,et al.RNA m(6) A methylation regulates uveal melanoma cell proliferation,migration,and invasion by targeting c-Met[J].J Cell Physiol,2020,235(10):7107-7119.
[68] HE F,YU J,YANG J,WANG S,ZHUANG A,SHI H,et al.M(6)A RNA hypermethylation-induced BACE2 boosts intracellular calcium release and accelerates tumorigenesis of ocular melanoma[J].Mol Ther,2021,29(6):2121-2133.
[69] MALLIPATNA A,MARINO M,SINGH A D.Genetics of retinoblastoma[J].Asia Pac J Ophthalmol (Phila),2016,5(4):260-264.
[70] RAJESHUNI N,WHITTEMORE A S,LUDWIG C A,MRUTHYUNJAYA P,MOSHFEGHI D M.Racial,ethnic,and socioeconomic disparities in retinoblastoma enucleation:a population-based study,SEER 18 2000-2014[J].Am J Ophthalmol,2019,207:215-223.
[71] ZHANG H,ZHANG P,LONG C,MA X,HUANG H,KUANG X,et al.M(6)A methyltransferase METTL3 promotes retinoblastoma progression via PI3K/AKT/mTOR pathway[J].J Cell Mol Med,2020,24(21):12368-12378.


 ZHAO Ya,MA Yan,YAO Mudi,et al.Advances in epigenetic modification and its regulation in retinal neurodegenerative diseases[J].Recent Advances in Ophthalmology,2022,42(5):551.[doi:10.13389/j.cnki.rao.2022.0113]


更新日期/Last Update: 2023-05-05