{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T21:27:47Z","timestamp":1790458067452,"version":"4.1.0"},"reference-count":58,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,6,28]],"date-time":"2023-06-28T00:00:00Z","timestamp":1687910400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:p>Myopia is one of the most common causes of vision loss globally and is significantly affected by epigenetics. Adenosine-to-inosine (A-to-I RNA) editing is an epigenetic process involved in neurological disorders, yet its role in myopia remains undetermined. We performed a transcriptome-wide analysis of A-to-I RNA editing in the retina of form-deprivation myopia mice. Our study identified 91 A-to-I RNA editing sites in 84 genes associated with myopia. Notably, at least 27 (32.1%) of these genes with myopia-associated RNA editing showed existing evidence to be associated with myopia or related ocular phenotypes in humans or animal models, such as very low-density lipoprotein receptor (<jats:italic>Vldlr<\/jats:italic>) in retinal neovascularization and hypoxia-induced factor 1 alpha (<jats:italic>Hif1a<\/jats:italic>). Moreover, functional enrichment showed that RNA editing enriched in FDM was primarily involved in response to fungicides, a potentially druggable process for myopia prevention, and epigenetic regulation. In contrast, RNA editing enriched in controls was mostly involved in post-embryonic eye morphogenesis. Our results demonstrate altered A-to-I RNA editing associated with myopia in an experimental mouse model and warrant further study on its role in myopia development.<\/jats:p>","DOI":"10.3389\/fnins.2023.1220114","type":"journal-article","created":{"date-parts":[[2023,6,28]],"date-time":"2023-06-28T08:59:54Z","timestamp":1687942794000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Epitranscriptomic investigation of myopia-associated RNA editing in the retina"],"prefix":"10.3389","volume":"17","author":[{"given":"Xu-Bin","family":"Pan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Shan","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zijing","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao-Ran","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi-Yuan","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun-Yun","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jihong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian-Huan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,6,28]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"9742","DOI":"10.1074\/jbc.M112.419960","article-title":"Dynamics of the rhomboid-like protein RHBDD2 expression in mouse retina and involvement of its human Ortholog in retinitis Pigmentosa","volume":"288","author":"Ahmedli","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"5827","DOI":"10.1167\/iovs.12-9943","article-title":"Muscarinic antagonist control of myopia: evidence for M4 and M1 receptor-based pathways in the inhibition of experimentally-induced axial myopia in the tree shrew","volume":"53","author":"Arumugam","year":"2012","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"2076","DOI":"10.1093\/hmg\/ddaa096","article-title":"The Tudor-domain protein TDRD7, mutated in congenital cataract, controls the heat shock protein HSPB1 (HSP27) and lens fiber cell morphology","volume":"29","author":"Barnum","year":"2020","journal-title":"Hum. Mol. Genet."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"859","DOI":"10.1515\/hsz-2021-0403","article-title":"TRPM3 in the eye and in the nervous system - from new findings to novel mechanisms","volume":"403","author":"Behrendt","year":"2022","journal-title":"Biol. Chem."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"2996","DOI":"10.3389\/fmed.2023.1112996","article-title":"Evidence of vascular involvement in myopia: a review","volume":"10","author":"Benavente-Perez","year":"2023","journal-title":"Front. Med."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1111\/opo.12453","article-title":"Circadian rhythms, refractive development, and myopia","volume":"38","author":"Chakraborty","year":"2018","journal-title":"Ophthalmic Physiol. Opt."},{"key":"ref7","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1007\/978-981-13-8491-2_3","article-title":"The economic and societal impact of myopia and high myopia","volume-title":"Updates on myopia: A clinical perspective","author":"Chua","year":"2020"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"e1010478","DOI":"10.1371\/journal.pgen.1010478","article-title":"Education interacts with genetic variants near GJD2, RBFOX1, LAMA2, KCNQ5 and LRRC4C to confer susceptibility to myopia","volume":"18","author":"Clark","year":"2022","journal-title":"PLoS Genet."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"e1009497","DOI":"10.1371\/journal.pgen.1009497","article-title":"Genetic variation affects morphological retinal phenotypes extracted from UK biobank optical coherence tomography images","volume":"17","author":"Currant","year":"2021","journal-title":"PLoS Genet."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"11.14.1","DOI":"10.1002\/0471250953.bi1114s51","article-title":"Mapping RNA-seq reads with STAR","volume":"51","author":"Dobin","year":"2015","journal-title":"Curr. Protoc. Bioinformatics"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1002\/path.4926","article-title":"SMARCA4 inactivating mutations cause concomitant coffin\u2013Siris syndrome, microphthalmia and small-cell carcinoma of the ovary hypercalcaemic type","volume":"243","author":"Errichiello","year":"2017","journal-title":"J. Pathol."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"100113","DOI":"10.1016\/j.xops.2022.100113","article-title":"Genome-wide association study of axial length in population-based cohorts in Japan","volume":"2","author":"Fuse","year":"2022","journal-title":"Ophthalmol Sci."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"e5048","DOI":"10.7717\/peerj.5048","article-title":"Pathway analysis identifies altered mitochondrial metabolism, neurotransmission, structural pathways and complement cascade in retina\/RPE\/choroid in chick model of form-deprivation myopia","volume":"6","author":"Giummarra","year":"2018","journal-title":"PeerJ"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"8200","DOI":"10.1523\/JNEUROSCI.2550-21.2022","article-title":"Progressively decreased HCN1 channels results in cone morphological defects in diabetic retinopathy","volume":"42","author":"Han","year":"2022","journal-title":"J. Neurosci."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"1036","DOI":"10.1016\/j.ophtha.2016.01.006","article-title":"Global prevalence of myopia and high myopia and temporal trends from 2000 through 2050","volume":"123","author":"Holden","year":"2016","journal-title":"Ophthalmology"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1167\/iovs.07-0870","article-title":"Expression of VLDLR in the retina and evolution of subretinal neovascularization in the knockout mouse model\u2019s retinal angiomatous proliferation","volume":"49","author":"Hu","year":"2008","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1111\/j.1460-9568.2011.07944.x","article-title":"Profound defects in pupillary responses to light in TRPM-channel null mice: a role for TRPM channels in non-image forming photoreception","volume":"35","author":"Hughes","year":"2012","journal-title":"Eur. J. Neurosci."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1038\/s41588-020-0599-0","article-title":"Meta-analysis of 542,934 subjects of European ancestry identifies new genes and mechanisms predisposing to refractive error and myopia","volume":"52","author":"Hysi","year":"2020","journal-title":"Nat. Genet."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"349","DOI":"10.3109\/13816810.2014.886266","article-title":"Pediatric cone-rod dystrophy with high myopia and Nystagmus suggests recessive PROM1 mutations","volume":"36","author":"Khan","year":"2015","journal-title":"Ophthalmic Genet."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"e1003299","DOI":"10.1371\/journal.pgen.1003299","article-title":"Genome-wide analysis points to roles for extracellular matrix remodeling, the visual cycle, and neuronal development in myopia","volume":"9","author":"Kiefer","year":"2013","journal-title":"PLoS Genet."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"568","DOI":"10.1101\/gr.129684.111","article-title":"VarScan 2: somatic mutation and copy number alteration discovery in cancer by exome sequencing","volume":"22","author":"Koboldt","year":"2012","journal-title":"Genome Res."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"2078","DOI":"10.1093\/bioinformatics\/btp352","article-title":"The sequence alignment\/map format and SAMtools","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"1014031","DOI":"10.3389\/fgene.2022.1014031","article-title":"RNA-sequencing analysis reveals the long noncoding RNA profile in the mouse myopic retina","volume":"13","author":"Li","year":"2022","journal-title":"Front. Genet."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3892\/ijmm.2022.5162","article-title":"Silencing of circular RNA-ZYG11B exerts a neuroprotective effect against retinal neurodegeneration","volume":"50","author":"Ma","year":"2022","journal-title":"Int. J. Mol. Med."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"D1012","DOI":"10.1093\/nar\/gkaa916","article-title":"REDIportal: millions of novel A-to-I RNA editing events from thousands of RNAseq experiments","volume":"49","author":"Mansi","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1186\/s13059-016-0974-4","article-title":"The Ensembl variant effect predictor","volume":"17","author":"McLaren","year":"2016","journal-title":"Genome Biol."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"7983","DOI":"10.1167\/iovs.12-10409","article-title":"A genome-wide association study provides evidence for association of chromosome 8p23 (MYP10) and 10q21.1 (MYP15) with high myopia in the French population","volume":"53","author":"Meng","year":"2012","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1016\/j.preteyeres.2017.09.004","article-title":"The epidemics of myopia: Aetiology and prevention","volume":"62","author":"Morgan","year":"2018","journal-title":"Prog. Retin. Eye Res."},{"key":"ref29","first-page":"1019","article-title":"Temporal changes of novel transcripts in the chicken retina following imposed defocus","volume":"10","author":"Ohngemach","year":"2004","journal-title":"Mol. Vis."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1038\/ng.3570","article-title":"Detection and interpretation of shared genetic influences on 42 human traits","volume":"48","author":"Pickrell","year":"2016","journal-title":"Nat. Genet."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"1065","DOI":"10.1007\/s11010-021-04305-z","article-title":"HIF-1\u03b1 aggravates pathologic myopia through the miR-150-5p\/LAMA4\/p38 MAPK signaling axis","volume":"477","author":"Ren","year":"2022","journal-title":"Mol. Cell. Biochem."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"e0214791","DOI":"10.1371\/journal.pone.0214791","article-title":"In-utero epigenetic factors are associated with early-onset myopia in young children","volume":"14","author":"Seow","year":"2019","journal-title":"PLoS One"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"881","DOI":"10.1007\/s00439-018-1942-8","article-title":"Genome-wide association studies for corneal and refractive astigmatism in UK biobank demonstrate a shared role for myopia susceptibility loci","volume":"137","author":"Shah","year":"2018","journal-title":"Hum. Genet."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1186\/s40246-020-00258-4","article-title":"TRPM3_miR-204: a complex locus for eye development and disease","volume":"14","author":"Shiels","year":"2020","journal-title":"Hum. Genomics"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"4779","DOI":"10.1167\/iovs.16-19310","article-title":"Development of experimental myopia in chicks in a natural environment","volume":"57","author":"Stone","year":"2016","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1016\/j.advms.2021.02.005","article-title":"Variants in FLRT3 and SLC35E2B identified using exome sequencing in seven high myopia families from Central Europe","volume":"66","author":"Swierkowska","year":"2021","journal-title":"Adv. Med. Sci."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1167\/iovs.63.9.31","article-title":"Decreased levels of DNA methylation in the PCDHA gene cluster as a risk factor for early-onset high myopia in Young children","volume":"63","author":"Swierkowska","year":"2022","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"D605","DOI":"10.1093\/nar\/gkaa1074","article-title":"The STRING database in 2021: customizable protein\u2013protein networks, and functional characterization of user-uploaded gene\/measurement sets","volume":"49","author":"Szklarczyk","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"12","DOI":"10.3389\/fgene.2021.680548","article-title":"Transcriptome-wide identification of G-to-a RNA editing in chronic social defeat stress mouse models","volume":"12","author":"Tao","year":"2021","journal-title":"Front. Genet."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"M89","DOI":"10.1167\/iovs.18-25965","article-title":"IMI \u2013 myopia genetics report","volume":"60","author":"Tedja","year":"2019","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"834","DOI":"10.1038\/s41588-018-0127-7","article-title":"Genome-wide association meta-analysis highlights light-induced signaling as a driver for refractive error","volume":"50","author":"Tedja","year":"2018","journal-title":"Nat. Genet."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"601","DOI":"10.1001\/jamaophthalmol.2021.0497","article-title":"Evaluation of shared genetic susceptibility to high and low myopia and hyperopia","volume":"139","author":"Tideman","year":"2021","journal-title":"JAMA Ophthalmol."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"11.10.1","DOI":"10.1002\/0471250953.bi1110s43","article-title":"From FastQ data to high confidence variant calls: the genome analysis toolkit best practices pipeline","volume":"43","author":"Van der Auwera","year":"2013","journal-title":"Curr. Protoc. Bioinformatics"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"494","DOI":"10.1016\/j.tips.2018.02.004","article-title":"Chemical diversity in the G protein-coupled receptor superfamily","volume":"39","author":"Vass","year":"2018","journal-title":"Trends Pharmacol. Sci."},{"key":"ref45","doi-asserted-by":"publisher","first-page":"E7091","DOI":"10.1073\/pnas.1721443115","article-title":"Scleral hypoxia is a target for myopia control","volume":"115","author":"Wu","year":"2018","journal-title":"Proc. Natl. Acad. Sci."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1038\/s41433-018-0139-7","article-title":"Update in myopia and treatment strategy of atropine use in myopia control","volume":"33","author":"Wu","year":"2019","journal-title":"Eye"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"6572","DOI":"10.1167\/iovs.10-7082","article-title":"The role of Vldlr in Intraretinal angiogenesis in mice","volume":"52","author":"Xia","year":"2011","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref48","doi-asserted-by":"publisher","first-page":"109342","DOI":"10.1016\/j.exer.2022.109342","article-title":"Trio-based exome sequencing broaden the genetic spectrum in keratoconus","volume":"226","author":"Xu","year":"2023","journal-title":"Exp. Eye Res."},{"key":"ref49","doi-asserted-by":"publisher","first-page":"2908","DOI":"10.1172\/JCI35891","article-title":"Mutant prominin 1 found in patients with macular degeneration disrupts photoreceptor disk morphogenesis in mice","volume":"118","author":"Yang","year":"2008","journal-title":"J. Clin. Invest."},{"key":"ref50","doi-asserted-by":"publisher","first-page":"999","DOI":"10.1080\/15476286.2020.1867797","article-title":"Adenosine-to-inosine RNA editing in neurological development and disease","volume":"18","author":"Yang","year":"","journal-title":"RNA Biol."},{"key":"ref51","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1186\/s40662-021-00248-0","article-title":"Intravitreal brimonidine inhibits form-deprivation myopia in guinea pigs","volume":"8","author":"Yang","year":"","journal-title":"Eye Vis (Lond)"},{"key":"ref52","doi-asserted-by":"publisher","first-page":"4755","DOI":"10.3390\/ijms20194755","article-title":"Proteomic biomarkers of retinal inflammation in diabetic retinopathy","volume":"20","author":"Youngblood","year":"2019","journal-title":"Int. J. Mol. Sci."},{"key":"ref53","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1016\/s1350-9462(00)00027-6","article-title":"Oxygen distribution and consumption within the retina in vascularised and avascular retinas and in animal models of retinal disease","volume":"20","author":"Yu","year":"2001","journal-title":"Prog. Retin. Eye Res."},{"key":"ref54","doi-asserted-by":"publisher","first-page":"102878","DOI":"10.1016\/j.ebiom.2020.102878","article-title":"Scleral HIF-1\u03b1 is a prominent regulatory candidate for genetic and environmental interactions in human myopia pathogenesis","volume":"57","author":"Zhao","year":"2020","journal-title":"EBioMedicine"},{"key":"ref55","doi-asserted-by":"publisher","first-page":"e21288","DOI":"10.1096\/fj.202002037R","article-title":"Mutation of the TRPM3 cation channel underlies progressive cataract development and lens calcification associated with pro-fibrotic and immune cell responses","volume":"35","author":"Zhou","year":"2021","journal-title":"FASEB J."},{"key":"ref56","first-page":"1312","article-title":"Experimental murine myopia induces collagen type I\u03b11 (COL1A1) DNA methylation and altered COL1A1 messenger RNA expression in sclera","volume":"18","author":"Zhou","year":"2012","journal-title":"Mol. Vis."},{"key":"ref57","doi-asserted-by":"publisher","first-page":"814814","DOI":"10.3389\/fphar.2022.814814","article-title":"Alteration of EIF2 signaling, glycolysis, and dopamine secretion in form-deprived myopia in response to 1% atropine treatment: evidence from interactive iTRAQ-MS and SWATH-MS proteomics using a Guinea pig model","volume":"13","author":"Zhu","year":"2022","journal-title":"Front. Pharmacol."},{"key":"ref58","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1002\/wsbm.10","article-title":"Adenosine-to-inosine RNA editing","volume":"1","author":"Zinshteyn","year":"2009","journal-title":"Wiley Interdiscip. Rev. Syst. Biol. Med."}],"container-title":["Frontiers in Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2023.1220114\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,6,28]],"date-time":"2023-06-28T09:00:02Z","timestamp":1687942802000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2023.1220114\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,28]]},"references-count":58,"alternative-id":["10.3389\/fnins.2023.1220114"],"URL":"https:\/\/doi.org\/10.3389\/fnins.2023.1220114","relation":{},"ISSN":["1662-453X"],"issn-type":[{"value":"1662-453X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,28]]},"article-number":"1220114"}}