{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:34:45Z","timestamp":1790814885858,"version":"4.1.0"},"reference-count":69,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2023,12,14]],"date-time":"2023-12-14T00:00:00Z","timestamp":1702512000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["R01EY022161"],"award-info":[{"award-number":["R01EY022161"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["P30EY030413"],"award-info":[{"award-number":["P30EY030413"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100018576","name":"Harrington Discovery Institute, University Hospitals","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100018576","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001818","name":"Research to Prevent Blindness","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001818","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Late-onset Fuchs\u2019 endothelial corneal dystrophy (FECD) is a degenerative disease of cornea and the leading indication for corneal transplantation. Genetically, FECD patients can be categorized as with (RE+) or without (RE-) the CTG trinucleotide repeat expansion in the transcription factor 4 gene. The molecular mechanisms underlying FECD remain unclear, though there are plausible pathogenic models proposed for RE+ FECD.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Method<\/jats:title>\n<jats:p>In this study, we performed a meta-analysis on RNA sequencing datasets of FECD corneal endothelium including 3 RE+ datasets and 2 RE- datasets, aiming to compare the transcriptomic profiles of RE+ and RE- FECD. Gene differential expression analysis, co-expression networks analysis, and pathway analysis were conducted.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>There was a striking similarity between RE+ and RE- transcriptomes. There were 1,184 genes significantly upregulated and 1,018 genes significantly downregulated in both RE+ and RE- cases. Pathway analysis identified multiple biological processes significantly enriched in both\u2014mitochondrial functions, energy-related processes, ER-nucleus signaling pathway, demethylation, and RNA splicing were negatively enriched, whereas small GTPase mediated signaling, actin-filament processes, extracellular matrix organization, stem cell differentiation, and neutrophil mediated immunity were positively enriched. The translational initiation process was downregulated in the RE+ transcriptomes. Gene co-expression analysis identified modules with relatively distinct biological processes enriched including downregulation of mitochondrial respiratory chain complex assembly. The majority of oxidative phosphorylation (OXPHOS) subunit genes, as well as their upstream regulator gene estrogen-related receptor alpha (<jats:italic>ESRRA<\/jats:italic>), encoding ERR\u03b1, were downregulated in both RE+ and RE- cases, and the expression level of <jats:italic>ESRRA<\/jats:italic> was correlated with that of OXPHOS subunit genes.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>Meta-analysis increased the power of detecting differentially expressed genes. Integrating differential expression analysis with co-expression analysis helped understand the underlying molecular mechanisms. FECD RE+ and RE- transcriptomic profiles are much alike with the hallmark of downregulation of genes in pathways related to ERR\u03b1-mediated OXPHOS.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0295542","type":"journal-article","created":{"date-parts":[[2023,12,14]],"date-time":"2023-12-14T18:40:25Z","timestamp":1702579225000},"page":"e0295542","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":10,"title":["Transcriptomic meta-analysis reveals ERR\u03b1-mediated oxidative phosphorylation is downregulated in Fuchs\u2019 endothelial corneal dystrophy"],"prefix":"10.1371","volume":"18","author":[{"given":"Xunzhi","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashwani","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adwait A.","family":"Sathe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V. Vinod","family":"Mootha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1838-0502","authenticated-orcid":true,"given":"Chao","family":"Xing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,12,14]]},"reference":[{"key":"pone.0295542.ref001","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/S1542-0124(12)70232-X","article-title":"Fuchs endothelial corneal dystrophy","volume":"8","author":"H Elhalis","year":"2010","journal-title":"Ocul Surf"},{"key":"pone.0295542.ref002","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1146\/annurev-vision-091718-014852","article-title":"Fuchs Endothelial Corneal Dystrophy: Clinical, Genetic, Pathophysiologic, and Therapeutic Aspects","volume":"5","author":"M Matthaei","year":"2019","journal-title":"Annu Rev Vis Sci"},{"key":"pone.0295542.ref003","doi-asserted-by":"crossref","first-page":"2036","DOI":"10.1001\/archopht.1978.03910060424004","article-title":"Corneal endothelial dystrophy. 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