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Among NBIA subtypes, beta-propeller-protein-associated neurodegeneration (BPAN) is associated with mutations in the autophagy gene WDR45 (WD repeat domain 45). Previously, we demonstrated that WDR45 mutations in BPAN cellular models impaired autophagy, iron metabolism, and cell bioenergetics. In addition, antioxidant supplementation partially improved cell physiopathology; however, autophagy and cell bioenergetics remained affected. In this work, we explored the possibility of expressing the normal WDR45 allele present in the inactive chromosome X (Xi) of BPAN cells through treatment with epigenetic modulators. The aim of this study was to demonstrate whether biotin, an epigenetic nutrient, was able to restore the expression levels of WDR45 by a mechanism involving Xi reactivation and, consequently, correct BPAN defects. Our study demonstrated that biotin supplementation increases histone biotinylation and allows for the transcription of the WDR45 allele in Xi. Consequently, all physiopathological alterations in BPAN cells were notably corrected. The reactivation of Xi by epigenetic modulators can be a promising approach for the treatment of BPAN and other X-linked diseases.<\/jats:p>","DOI":"10.3390\/ijms26031315","type":"journal-article","created":{"date-parts":[[2025,2,4]],"date-time":"2025-02-04T05:55:22Z","timestamp":1738648522000},"page":"1315","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Biotin Induces Inactive Chromosome X Reactivation and Corrects Physiopathological Alterations in Beta-Propeller-Protein-Associated Neurodegeneration"],"prefix":"10.3390","volume":"26","author":[{"given":"Diana","family":"Reche-L\u00f3pez","sequence":"first","affiliation":[{"name":"Centro Andaluz de Biolog\u00eda del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), 41013 Sevilla, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Romero-Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Centro Andaluz de Biolog\u00eda del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), 41013 Sevilla, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00f3nica","family":"\u00c1lvarez-C\u00f3rdoba","sequence":"additional","affiliation":[{"name":"Centro Andaluz de Biolog\u00eda del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), 41013 Sevilla, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandra","family":"Su\u00e1rez-Carrillo","sequence":"additional","affiliation":[{"name":"Centro Andaluz de Biolog\u00eda del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), 41013 Sevilla, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula","family":"Cilleros-Holgado","sequence":"additional","affiliation":[{"name":"Centro Andaluz de Biolog\u00eda del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), 41013 Sevilla, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roc\u00edo","family":"Pi\u00f1ero-P\u00e9rez","sequence":"additional","affiliation":[{"name":"Centro Andaluz de Biolog\u00eda del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), 41013 Sevilla, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"G\u00f3mez-Fern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Centro Andaluz de Biolog\u00eda del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), 41013 Sevilla, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Manuel","family":"Romero-Dom\u00ednguez","sequence":"additional","affiliation":[{"name":"Centro Andaluz de Biolog\u00eda del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), 41013 Sevilla, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5906-1662","authenticated-orcid":false,"given":"Alejandra","family":"L\u00f3pez-Cabrera","sequence":"additional","affiliation":[{"name":"Centro Andaluz de Biolog\u00eda del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), 41013 Sevilla, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1531-550X","authenticated-orcid":false,"given":"Susana","family":"Gonz\u00e1lez-Granero","sequence":"additional","affiliation":[{"name":"Laboratory of Comparative Neurobiology, Cavanilles Institute of Biodiversity and Evolutionary Biology, University of Valencia and CIBERNED-ISCIII, 46980 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9872-6499","authenticated-orcid":false,"given":"Jos\u00e9 Manuel","family":"Garc\u00eda-Verdugo","sequence":"additional","affiliation":[{"name":"Laboratory of Comparative Neurobiology, Cavanilles Institute of Biodiversity and Evolutionary Biology, University of Valencia and CIBERNED-ISCIII, 46980 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9705-1469","authenticated-orcid":false,"given":"Jos\u00e9 A.","family":"S\u00e1nchez-Alc\u00e1zar","sequence":"additional","affiliation":[{"name":"Centro Andaluz de Biolog\u00eda del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), 41013 Sevilla, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1721","DOI":"10.1152\/physrev.00008.2013","article-title":"Systemic iron homeostasis","volume":"93","author":"Ganz","year":"2013","journal-title":"Physiol. 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