{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T05:20:30Z","timestamp":1762492830278,"version":"build-2065373602"},"reference-count":109,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T00:00:00Z","timestamp":1762300800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"crossref","award":["R01 EY025002"],"award-info":[{"award-number":["R01 EY025002"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Jules Stein Eye Institute Core Grant for Vision Research","award":["P30-EY000331"],"award-info":[{"award-number":["P30-EY000331"]}]},{"name":"Jules Stein Eye Institute unrestricted Grant from Research to Prevent Blindness, Inc."},{"name":"Patricia and Joseph Yzurdiaga Vision Research Fund"},{"name":"Daljit S. and Elaine Sarkaria Charitable Foundation"},{"name":"Research to Prevent Blindness, Inc. (RPB, New York) from the Gavin Herbert Eye Institute at the University of California, Irvine"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Stargardt disease (STGD1), the most common inherited juvenile macular degeneration, is caused by biallelic mutations in the ABCA4 gene. Currently, there is no approved treatment. In this study, we investigated early-stage epigenomic changes in the retinal pigment epithelium (RPE) of Abca4-\/- mice, a well-established model of STGD1. Reduced representation bisulfite sequencing (RRBS) revealed hypermethylation of gene regions associated with disease-related pathways, implicating methyl-CpG-binding protein 2 (MeCP2) and RE1-silencing transcription factor (REST) as potential regulators. Notably, DNA methylation of a subset of genes preceded their transcriptional change and disease phenotypes in Abca4-\/- RPE. Together with the detected age-dependent increase in MeCP2 levels in Abca4-\/- RPE, these findings suggest that early DNA methylation changes may contribute to RPE dysfunction and eventual cell loss in STGD1.<\/jats:p>","DOI":"10.3390\/ijms262110742","type":"journal-article","created":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T13:19:29Z","timestamp":1762348769000},"page":"10742","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dysregulated DNA Methylation in Abca4-\/- Retinal Pigment Epithelium: Insights into Early Stage of Stargardt Disease"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-1873-0454","authenticated-orcid":false,"given":"Arpita","family":"Dave","sequence":"first","affiliation":[{"name":"UCLA Jules Stein Eye Institute and Department of Ophthalmology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anela","family":"Tosevska","sequence":"additional","affiliation":[{"name":"Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, CA 90095, USA"},{"name":"Department of Internal Medicine 3, Division of Rheumatology, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco","family":"Morselli","sequence":"additional","affiliation":[{"name":"Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, CA 90095, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emily","family":"Tom","sequence":"additional","affiliation":[{"name":"Robert M. Brunson Center for Translational Vision Research, Department of Physiology and Biophysics, Department of Ophthalmology and Visual Sciences, School of Medicine, University of California, Irvine, CA 92697, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9355-9564","authenticated-orcid":false,"given":"Matteo","family":"Pellegrini","sequence":"additional","affiliation":[{"name":"Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, CA 90095, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5758-4225","authenticated-orcid":false,"given":"Dorota","family":"Skowronska-Krawczyk","sequence":"additional","affiliation":[{"name":"Robert M. Brunson Center for Translational Vision Research, Department of Physiology and Biophysics, Department of Ophthalmology and Visual Sciences, School of Medicine, University of California, Irvine, CA 92697, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5064-6403","authenticated-orcid":false,"given":"Roxana A.","family":"Radu","sequence":"additional","affiliation":[{"name":"UCLA Jules Stein Eye Institute and Department of Ophthalmology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1016\/j.ophtha.2015.12.009","article-title":"The natural history of the progression of atrophy secondary to Stargardt disease (ProgStar) studies: Design and baseline characteristics: ProgStar Report No. 1","volume":"123","author":"Strauss","year":"2016","journal-title":"Ophthalmology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1167\/iovs.16-20980","article-title":"Differential disease progression in atrophic age-related macular degeneration and late-onset Stargardt disease","volume":"58","author":"Lindner","year":"2017","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1093\/hmg\/ddh048","article-title":"Mutations in ABCA4 result in accumulation of lipofuscin before slowing of the retinoid cycle: A reappraisal of the human disease sequence","volume":"13","author":"Cideciyan","year":"2004","journal-title":"Hum. Mol. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.ajo.2019.02.007","article-title":"Correlation of outer retinal degeneration and choriocapillaris loss in Stargardt disease using en face optical coherence tomography and optical coherence tomography angiography","volume":"202","author":"Alabduljalil","year":"2019","journal-title":"Am. J. Ophthalmol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1038\/ng0397-236","article-title":"A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Starqardt macular dystrophy","volume":"15","author":"Allikmets","year":"1997","journal-title":"Nat. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Wang, L., Shah, S.M., Mangwani-Mordani, S., and Gregori, N.Z. (2023). Updates on emerging interventions for autosomal recessive ABCA4-associated Stargardt disease. J. Clin. Med., 12.","DOI":"10.3390\/jcm12196229"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Zaydon, Y.A., and Tsang, S.H. (2024). The ABCs of Stargardt disease: The latest advances in precision medicine. Cell Biosci., 14.","DOI":"10.1186\/s13578-024-01272-y"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1038\/ng0997-15","article-title":"Stargardt\u2019s ABCR is localized to the disc membrane of retinal rod outer segments","volume":"17","author":"Sun","year":"1997","journal-title":"Nat. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"10303","DOI":"10.1074\/jbc.272.15.10303","article-title":"The 220-kDa rim protein of retinal rod outer segments is a member of the ABC transporter superfamily","volume":"272","author":"Illing","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"E11120","DOI":"10.1073\/pnas.1802519115","article-title":"Expression of ABCA4 in the retinal pigment epithelium and its implications for Stargardt macular degeneration","volume":"115","author":"Lenis","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1167\/tvst.11.3.33","article-title":"Assessing Variant Causality and Severity Using Retinal Pigment Epithelial Cells Derived from Stargardt Disease Patients","volume":"11","author":"Matynia","year":"2022","journal-title":"Transl. Vis. Sci. Technol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Ng, E.S.Y., Kady, N., Hu, J., Dave, A., Jiang, Z., Pei, J., Gorin, M.B., Matynia, A., and Radu, R.A. (2022). Membrane Attack Complex Mediates Retinal Pigment Epithelium Cell Death in Stargardt Macular Degeneration. Cells, 11.","DOI":"10.3390\/cells11213462"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2438","DOI":"10.1016\/j.stemcr.2022.10.001","article-title":"Cell-autonomous lipid-handling defects in Stargardt iPSC-derived retinal pigment epithelium cells","volume":"17","author":"Farnoodian","year":"2022","journal-title":"Stem Cell Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1038\/77004","article-title":"ABCR expression in foveal cone photoreceptors and its role in Stargardt macular dystrophy","volume":"25","author":"Molday","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"7154","DOI":"10.1073\/pnas.130110497","article-title":"Biosynthesis of a major lipofuscin fluorophore in mice and humans with ABCR-mediated retinal and macular degeneration","volume":"97","author":"Mata","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/S0092-8674(00)80602-9","article-title":"Insights into the function of Rim protein in photoreceptors and etiology of Stargardt\u2019s disease from the phenotype in abcr knockout mice","volume":"98","author":"Weng","year":"1999","journal-title":"Cell"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Zhao, J., Kim, H.J., Ueda, K., Zhang, K., Montenegro, D., Dunaief, J.L., and Sparrow, J.R. (2021). A vicious cycle of bisretinoid formation and oxidation relevant to recessive Stargardt disease. J. Biol. Chem., 296.","DOI":"10.1016\/j.jbc.2021.100259"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e23720","DOI":"10.1096\/fj.202400210RR","article-title":"Impaired cathepsin D in retinal pigment epithelium cells mediates Stargardt disease pathogenesis","volume":"38","author":"Ng","year":"2024","journal-title":"FASEB J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"18593","DOI":"10.1074\/jbc.M110.191866","article-title":"Complement system dysregulation and inflammation in the retinal pigment epithelium of a mouse model for Stargardt macular degeneration","volume":"286","author":"Radu","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1101\/gad.2037511","article-title":"CpG islands and the regulation of transcription","volume":"25","author":"Deaton","year":"2011","journal-title":"Genes Dev."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Bird, A. (1993). Functions for DNA methylation in vertebrates. Cold Spring Harbor Symposia on Quantitative Biology, Cold Spring Harbor Laboratory Press.","DOI":"10.1101\/SQB.1993.058.01.033"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1007\/s13237-021-00367-y","article-title":"DNA methylation and regulation of gene expression: Guardian of our health","volume":"64","author":"Dhar","year":"2021","journal-title":"Nucleus"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1038\/npp.2012.112","article-title":"DNA methylation and its basic function","volume":"38","author":"Moore","year":"2013","journal-title":"Neuropsychopharmacology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.preteyeres.2018.03.002","article-title":"Epigenetic control of gene regulation during development and disease: A view from the retina","volume":"65","author":"Jaeger","year":"2018","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3353","DOI":"10.1074\/jbc.M007224200","article-title":"DNA recognition by the methyl-CpG binding domain of MeCP2","volume":"276","author":"Free","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1038\/13810","article-title":"Rett syndrome is caused by mutations in X-linked MeCP2, encoding methyl-CpG-binding protein 2","volume":"23","author":"Amir","year":"1999","journal-title":"Nat. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"5085","DOI":"10.1093\/nar\/20.19.5085","article-title":"Characterization of MeCP2, a vertebrate DNA binding protein with affinity for methylated DNA","volume":"20","author":"Meehan","year":"1992","journal-title":"Nucleic Acids Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1224","DOI":"10.1126\/science.1153252","article-title":"MeCP2, a key contributor to neurological disease, activates and represses transcription","volume":"320","author":"Chahrour","year":"2008","journal-title":"Science"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2431","DOI":"10.1093\/hmg\/ddp181","article-title":"Mouse models of MeCP2 disorders share gene expression changes in the cerebellum and hypothalamus","volume":"18","author":"Chahrour","year":"2009","journal-title":"Hum. Mol. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1007\/s12031-015-0597-3","article-title":"Involvement of MeCP2 in regulation of myelin-related gene expression in cultured rat oligodendrocytes","volume":"57","author":"Sharma","year":"2015","journal-title":"J. Mol. Neurosci."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Cheng, T.-L., Chen, J., Wan, H., Tang, B., Tian, W., Liao, L., and Qiu, Z. (2017). Regulation of mRNA splicing by MeCP2 via epigenetic modifications in the brain. Sci. Rep., 7.","DOI":"10.1038\/srep42790"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4035","DOI":"10.1074\/jbc.M210256200","article-title":"The methyl-CpG-binding protein MeCP2 links DNA methylation to histone methylation","volume":"278","author":"Fuks","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2679","DOI":"10.1093\/hmg\/ddh282","article-title":"Mild overexpression of MeCP2 causes a progressive neurological disorder in mice","volume":"13","author":"Collins","year":"2004","journal-title":"Hum. Mol. Genet."},{"key":"ref_34","unstructured":"Mann, I. (1928). The Development of the Human Eye, The University Press."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/1756-8935-7-17","article-title":"DNA methylation reader MECP2: Cell type-and differentiation stage-specific protein distribution","volume":"7","author":"Song","year":"2014","journal-title":"Epigenet. Chromatin"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"9420","DOI":"10.1111\/jcmm.15602","article-title":"MeCP2-421-mediated RPE epithelial-mesenchymal transition and its relevance to the pathogenesis of proliferative vitreoretinopathy","volume":"24","author":"Li","year":"2020","journal-title":"J. Cell. Mol. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"5579","DOI":"10.1167\/iovs.14-16258","article-title":"Inhibition of DNA methylation and methyl-CpG-binding protein 2 suppresses RPE transdifferentiation: Relevance to proliferative vitreoretinopathy","volume":"56","author":"He","year":"2015","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e31429","DOI":"10.1002\/jcp.31429","article-title":"Critical role of apoptosis in MeCP2-mediated epithelial\u2013mesenchymal transition of ARPE-19 cells","volume":"239","author":"Zhang","year":"2024","journal-title":"J. Cell. Physiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"47964","DOI":"10.1021\/acsomega.3c06610","article-title":"MeCP2-Induced Alternations of Transcript Levels and m6A Methylation in Human Retinal Pigment Epithelium Cells","volume":"8","author":"Zhao","year":"2023","journal-title":"ACS Omega"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"AMD104","DOI":"10.1167\/iovs.18-24132","article-title":"A role for \u03b2A3\/A1-crystallin in type 2 EMT of RPE cells occurring in dry age-related macular degeneration","volume":"59","author":"Ghosh","year":"2018","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e10270","DOI":"10.15252\/emmm.201910270","article-title":"MECP2 mutations affect ciliogenesis: A novel perspective for Rett syndrome and related disorders","volume":"12","author":"Frasca","year":"2020","journal-title":"EMBO Mol. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"9084","DOI":"10.1111\/jcmm.16882","article-title":"Primary cilia in retinal pigment epithelium development and diseases","volume":"25","author":"Sun","year":"2021","journal-title":"J. Cell. Mol. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"5602","DOI":"10.1167\/iovs.13-11688","article-title":"Fundus autofluorescence in the Abca4\u2212\/\u2212 mouse model of Stargardt disease\u2014Correlation with accumulation of A2E, retinal function, and histology","volume":"54","author":"Issa","year":"2013","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3821","DOI":"10.1167\/iovs.07-1470","article-title":"Accelerated accumulation of lipofuscin pigments in the RPE of a mouse model for ABCA4-mediated retinal dystrophies following Vitamin A supplementation","volume":"49","author":"Radu","year":"2008","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1038\/nprot.2010.190","article-title":"Preparation of reduced representation bisulfite sequencing libraries for genome-scale DNA methylation profiling","volume":"6","author":"Gu","year":"2011","journal-title":"Nat. Protoc."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Zhong, H., and Sun, X. (2022). Contribution of interleukin-17A to retinal degenerative diseases. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.847937"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"505","DOI":"10.2174\/156720506779025297","article-title":"A role for TGF-\u03b2 signaling in neurodegeneration: Evidence from genetically engineered models","volume":"3","author":"Tesseur","year":"2006","journal-title":"Curr. Alzheimer Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/1750-1326-4-20","article-title":"Calcium signaling in neurodegeneration","volume":"4","author":"Marambaud","year":"2009","journal-title":"Mol. Neurodegener."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Guti\u00e9rrez-Vargas, J.A., Castro-\u00c1lvarez, J.F., Zapata-Berruecos, J.F., Abdul-Rahim, K., and Arteaga-Noriega, A. (2022). Neurodegeneration and convergent factors contributing to the deterioration of the cytoskeleton in Alzheimer\u2019s disease, cerebral ischemia and multiple sclerosis. Biomed. Rep., 16.","DOI":"10.3892\/br.2022.1510"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Lionaki, E., Ploumi, C., and Tavernarakis, N. (2022). One-carbon metabolism: Pulling the strings behind aging and neurodegeneration. Cells, 11.","DOI":"10.3390\/cells11020214"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"e163359","DOI":"10.1172\/jci.insight.163359","article-title":"Blocking IL-6 signaling prevents astrocyte-induced neurodegeneration in an iPSC-based model of Parkinson\u2019s disease","volume":"9","author":"Baruffi","year":"2024","journal-title":"JCI Insight"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"W212","DOI":"10.1093\/nar\/gkz446","article-title":"ChEA3: Transcription factor enrichment analysis by orthogonal omics integration","volume":"47","author":"Keenan","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1006\/bbrc.1999.1130","article-title":"The DNA-binding and transcriptional activities of MAZ, a myc-associated zinc finger protein, are regulated by casein kinase II","volume":"262","author":"Tsutsui","year":"1999","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"29583","DOI":"10.1074\/jbc.274.42.29583","article-title":"Context-dependent transcriptional regulation","volume":"274","author":"Fry","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.cyto.2010.12.019","article-title":"The CCAAT\/enhancer (C\/EBP) family of basic-leucine zipper (bZIP) transcription factors is a multifaceted highly-regulated system for gene regulation","volume":"54","author":"Tsukada","year":"2011","journal-title":"Cytokine"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Zheng, D., Zhao, K., and Mehler, M.F. (2009). Profiling RE1\/REST-mediated histone modifications in the human genome. Genome Biol., 10.","DOI":"10.1186\/gb-2009-10-1-r9"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"110626","DOI":"10.1016\/j.celrep.2022.110626","article-title":"CTCF functions as an insulator for somatic genes and a chromatin remodeler for pluripotency genes during reprogramming","volume":"39","author":"Song","year":"2022","journal-title":"Cell Rep."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"e030460","DOI":"10.1161\/JAHA.123.030460","article-title":"Stroke causes DNA methylation at Ncx1 heart promoter in the brain via DNMT1\/MeCP2\/REST epigenetic complex","volume":"13","author":"Guida","year":"2024","journal-title":"J. Am. Heart Assoc."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1016\/j.conb.2005.08.015","article-title":"The many faces of REST oversee epigenetic programming of neuronal genes","volume":"15","author":"Ballas","year":"2005","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1016\/j.tins.2012.05.004","article-title":"Cell fate determination in the vertebrate retina","volume":"35","author":"Bassett","year":"2012","journal-title":"Trends Neurosci."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"\u00c1lvarez-Barrios, A., \u00c1lvarez, L., S\u00e1enz de Santa Mar\u00eda, P., Garc\u00eda, M., \u00c1lvarez-Buylla, J.R., Pereiro, R., and Gonz\u00e1lez-Iglesias, H. (2025). Dysregulated lipid metabolism in a retinal pigment epithelial cell model and serum of patients with age-related macular degeneration. BMC Biol., 23.","DOI":"10.1186\/s12915-025-02198-8"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"100037","DOI":"10.1194\/jlr.TR120000972","article-title":"Sphingolipids as critical players in retinal physiology and pathology","volume":"62","author":"Simon","year":"2021","journal-title":"J. Lipid Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1091\/mbc.e14-05-1028","article-title":"Cholesterol-mediated activation of acid sphingomyelinase disrupts autophagy in the retinal pigment epithelium","volume":"26","author":"Toops","year":"2015","journal-title":"Mol. Biol. Cell"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"5572","DOI":"10.1111\/jcmm.16569","article-title":"RNA-seq analysis of ageing human retinal pigment epithelium: Unexpected up-regulation of visual cycle gene transcription","volume":"25","author":"Butler","year":"2021","journal-title":"J. Cell. Mol. Med."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1712","DOI":"10.1016\/j.ophtha.2019.07.010","article-title":"Highly variable disease courses in siblings with Stargardt disease","volume":"126","author":"Valkenburg","year":"2019","journal-title":"Ophthalmology"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1016\/j.ajo.2025.07.024","article-title":"The Visual Acuity course in Stargardt Disease","volume":"279","author":"Pas","year":"2025","journal-title":"Am. J. Ophthalmol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.14336\/AD.2019.1126","article-title":"An Updated Review of the Epigenetic Mechanism Underlying the Pathogenesis of Age-related Macular Degeneration","volume":"11","author":"Li","year":"2020","journal-title":"Aging Dis."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Hamid, M.A., Moustafa, M.T., Nashine, S., Costa, R.D., Schneider, K., Atilano, S.R., Kuppermann, B.D., and Kenney, M.C. (2021). Anti-VEGF Drugs Influence Epigenetic Regulation and AMD-Specific Molecular Markers in ARPE-19 Cells. Cells, 10.","DOI":"10.3390\/cells10040878"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1407","DOI":"10.1038\/eye.2014.225","article-title":"The role of epigenetics in age-related macular degeneration","volume":"28","author":"Gemenetzi","year":"2014","journal-title":"Eye"},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Zibetti, C. (2025). Molecular Determinants of the Human Retinal Pigment Epithelium Cell Fate and Potential Pharmacogenomic Targets for Precision Medicine. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26125817"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1038\/nri3459-c1","article-title":"A role for IL-17 in age-related macular degeneration","volume":"13","author":"Shin","year":"2013","journal-title":"Nat. Rev. Immunol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1016\/j.celrep.2012.10.013","article-title":"Hypomethylation of the IL17RC promoter associates with age-related macular degeneration","volume":"2","author":"Wei","year":"2012","journal-title":"Cell Rep."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"2089","DOI":"10.1167\/iovs.11-8449","article-title":"DNA methylation is associated with altered gene expression in AMD","volume":"53","author":"Hunter","year":"2012","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/s13148-019-0608-2","article-title":"Whole-genome methylation profiling of the retinal pigment epithelium of individuals with age-related macular degeneration reveals differential methylation of the SKI, GTF2H4, and TNXB genes","volume":"11","author":"Porter","year":"2019","journal-title":"Clin. Epigenet."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"107525","DOI":"10.1016\/j.celrep.2020.107525","article-title":"Genome-wide profiling identifies DNA methylation signatures of aging in rod photoreceptors associated with alterations in energy metabolism","volume":"31","author":"Gentry","year":"2020","journal-title":"Cell Rep."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Liu, Z., Jiang, R., Yuan, S., Wang, N., Feng, Y., Hu, G., Zhu, X., Huang, K., Ma, J., and Xu, G. (2014). Integrated analysis of DNA methylation and RNA transcriptome during in vitro differentiation of human pluripotent stem cells into retinal pigment epithelial cells. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0091416"},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Dvoriantchikova, G., Seemungal, R.J., and Ivanov, D. (2019). The epigenetic basis for the impaired ability of adult murine retinal pigment epithelium cells to regenerate retinal tissue. Sci. Rep., 9.","DOI":"10.1038\/s41598-019-40262-w"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.gendis.2018.01.002","article-title":"DNA methylation in human diseases","volume":"5","author":"Jin","year":"2018","journal-title":"Genes Dis."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/j.bbrc.2007.03.135","article-title":"Epigenetic regulation of clusterin\/apolipoprotein J expression in retinal pigment epithelial cells","volume":"357","author":"Suuronen","year":"2007","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"100302","DOI":"10.1016\/j.xgen.2023.100302","article-title":"A systems biology approach uncovers novel disease mechanisms in age-related macular degeneration","volume":"3","author":"Orozco","year":"2023","journal-title":"Cell Genom."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"8415","DOI":"10.1073\/pnas.1506960112","article-title":"Rescue of the Stargardt phenotype in Abca4 knockout mice through inhibition of vitamin A dimerization","volume":"112","author":"Barnard","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"8179","DOI":"10.1167\/iovs.15-17629","article-title":"Monoallelic ABCA4 mutations appear insufficient to cause retinopathy: A quantitative autofluorescence study","volume":"56","author":"Gliem","year":"2015","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1086\/303100","article-title":"Simple and complex ABCR: Genetic predisposition to retinal disease","volume":"67","author":"Allikmets","year":"2000","journal-title":"Am. J. Hum. Genet."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1038\/ejhg.2017.13","article-title":"Genotypic spectrum and phenotype correlations of ABCA4-associated disease in patients of south Asian descent","volume":"25","author":"Lee","year":"2017","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"e156154","DOI":"10.1172\/jci.insight.156154","article-title":"A genotype-phenotype correlation matrix for ABCA4 disease based on long-term prognostic outcomes","volume":"7","author":"Lee","year":"2022","journal-title":"JCI Insight"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1086\/303079","article-title":"Mutations in the ABCA4 (ABCR) gene are the major cause of autosomal recessive cone-rod dystrophy","volume":"67","author":"Maugeri","year":"2000","journal-title":"Am. J. Hum. Genet."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1002\/humu.23165","article-title":"In silico functional meta-analysis of 5,962 ABCA4 variants in 3,928 retinal dystrophy cases","volume":"38","author":"Cornelis","year":"2017","journal-title":"Hum. Mutat."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1007\/s00018-019-03421-w","article-title":"Epigenetics in age-related macular degeneration: New discoveries and future perspectives","volume":"77","author":"Gemenetzi","year":"2020","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Kwon, W., and Freeman, S.A. (2020). Phagocytosis by the Retinal Pigment Epithelium: Recognition, Resolution, Recycling. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.604205"},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Hu, J., Pauer, G.J., Hagstrom, S.A., Bok, D., DeBenedictis, M.J., Bonilha, V.L., Hollyfield, J.G., and Radu, R.A. (2020). Evidence of complement dysregulation in outer retina of Stargardt disease donor eyes. Redox Biol., 37.","DOI":"10.1016\/j.redox.2020.101787"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1016\/j.cell.2005.03.013","article-title":"REST and its corepressors mediate plasticity of neuronal gene chromatin throughout neurogenesis","volume":"121","author":"Ballas","year":"2005","journal-title":"Cell"},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Hall, A.M., Short, A.K., Singh-Taylor, A., Daglian, J., Mishina, T., Schmidt, W.K., Kouji, H., and Baram, T.Z. (2018). NRSF\u2013mediated repression of neuronal genes in developing brain persists in the absence of NRSF-Sin3 interaction. bioRxiv.","DOI":"10.1101\/245993"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/j.celrep.2015.03.020","article-title":"TET3 is recruited by REST for context-specific hydroxymethylation and induction of gene expression","volume":"11","author":"Perera","year":"2015","journal-title":"Cell Rep."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1038\/s41419-018-0473-5","article-title":"REST, regulated by RA through miR-29a and the proteasome pathway, plays a crucial role in RPC proliferation and differentiation","volume":"9","author":"Wang","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1805","DOI":"10.1126\/science.277.5333.1805","article-title":"Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration","volume":"277","author":"Allikmets","year":"1997","journal-title":"Science"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"3987","DOI":"10.1073\/pnas.1620299114","article-title":"Complement modulation in the retinal pigment epithelium rescues photoreceptor degeneration in a mouse model of Stargardt disease","volume":"114","author":"Lenis","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1742","DOI":"10.1016\/j.ophtha.2008.03.021","article-title":"Inflammation, complement factor h, and age-related macular degeneration: The Multi-ethnic Study of Atherosclerosis","volume":"115","author":"Klein","year":"2008","journal-title":"Ophthalmology"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1007\/s004170050209","article-title":"Patterns of increased in vivo fundus autofluorescence in the junctional zone of geographic atrophy of the retinal pigment epithelium associated with age-related macular degeneration","volume":"237","author":"Holz","year":"1999","journal-title":"Graefe\u2019s Arch. Clin. Exp. Ophthalmol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"39625","DOI":"10.1074\/jbc.M007049200","article-title":"The lipofusion component N-retinyl-N-retinylidene ethanolamine detaches proapoptotic proteins from mitochondria and induces apoptosis in mammalian retinal pigment epithelial cells","volume":"275","author":"Suter","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1086\/303018","article-title":"Further evidence for an association of ABCR alleles with age-related macular degeneration","volume":"67","author":"Allikmets","year":"2000","journal-title":"Am. J. Hum. Genet."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"5928","DOI":"10.1073\/pnas.0308302101","article-title":"Light exposure stimulates formation of A2E oxiranes in a mouse model of Stargardt\u2019s macular degeneration","volume":"101","author":"Radu","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"giab033","DOI":"10.1093\/gigascience\/giab033","article-title":"BiSulfite Bolt: A bisulfite sequencing analysis platform","volume":"10","author":"Farrell","year":"2021","journal-title":"GigaScience"},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"M\u00fcller, F., Scherer, M., Assenov, Y., Lutsik, P., Walter, J., Lengauer, T., and Bock, C. (2019). RnBeads 2.0: Comprehensive analysis of DNA methylation data. Genome Biol., 20.","DOI":"10.1186\/s13059-019-1664-9"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"e47","DOI":"10.1093\/nar\/gkv007","article-title":"limma powers differential expression analyses for RNA-sequencing and microarray studies","volume":"43","author":"Ritchie","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"2381","DOI":"10.1093\/bioinformatics\/btx183","article-title":"Annotatr: Genomic regions in context","volume":"33","author":"Cavalcante","year":"2017","journal-title":"Bioinformatics"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"e585","DOI":"10.1002\/cpz1.585","article-title":"Exploring epigenomic datasets by ChIPseeker","volume":"2","author":"Wang","year":"2022","journal-title":"Curr. Protoc."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"3292","DOI":"10.1038\/s41596-024-01020-z","article-title":"Using clusterProfiler to characterize multiomics data","volume":"19","author":"Xu","year":"2024","journal-title":"Nat. Protoc."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1038\/s41467-019-09234-6","article-title":"Metascape provides a biologist-oriented resource for the analysis of systems-level datasets","volume":"10","author":"Zhou","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"3220","DOI":"10.1093\/hmg\/ddv073","article-title":"Protein misfolding and the pathogenesis of ABCA4-associated retinal degenerations","volume":"24","author":"Zhang","year":"2015","journal-title":"Hum. Mol. Genet."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/21\/10742\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T05:18:26Z","timestamp":1762492706000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/21\/10742"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,5]]},"references-count":109,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["ijms262110742"],"URL":"https:\/\/doi.org\/10.3390\/ijms262110742","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2025,11,5]]}}}