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We hypothesized that the lysine demethylase UTY (ubiquitously transcribed tetratricopeptide repeat containing Y-linked) decreases methylation uniquely in male VICs responding to nanoscale extracellular matrix cues to promote an osteoblast-like cell phenotype. Here, we describe a hydrogel biomaterial cell culture platform to interrogate how nanoscale cues modulate sex-specific methylation states in VICs activating to myofibroblasts and osteoblast-like cells. We found that UTY modulates the osteoblast-like cell phenotype in response to nanoscale cues uniquely in male VICs. Overall, we reveal a previously unidentified role of UTY in the regulation of calcification processes in males during AVS progression.<\/jats:p>","DOI":"10.1126\/sciadv.ads5717","type":"journal-article","created":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T13:58:57Z","timestamp":1741787937000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":19,"title":["Y chromosome\u2013linked UTY modulates sex differences in valvular fibroblast methylation in response to nanoscale extracellular matrix cues"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3386-7674","authenticated-orcid":true,"given":"Rayyan M.","family":"Gorashi","sequence":"first","affiliation":[{"name":"Shu Chien-Gene Lay Department of Bioengineering, University of California San Diego, La Jolla, CA 92093, USA."},{"name":"Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5317-8203","authenticated-orcid":true,"given":"Talia","family":"Baddour","sequence":"additional","affiliation":[{"name":"Shu Chien-Gene Lay Department of Bioengineering, University of California San Diego, La Jolla, CA 92093, USA."},{"name":"Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4083-0829","authenticated-orcid":true,"given":"Sarah J.","family":"Chittle","sequence":"additional","affiliation":[{"name":"Shu Chien-Gene Lay Department of Bioengineering, University of California San Diego, La Jolla, CA 92093, USA."},{"name":"Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3637-1992","authenticated-orcid":true,"given":"Nicole E.","family":"F\u00e9lix V\u00e9lez","sequence":"additional","affiliation":[{"name":"Shu Chien-Gene Lay Department of Bioengineering, University of California San Diego, La Jolla, CA 92093, USA."},{"name":"Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michaela A.","family":"Wenning","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biological Engineering, University of Colorado Boulder, Boulder, CO 80303, USA."},{"name":"BioFrontiers Institute, University of Colorado Boulder, Boulder, CO 80309, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5725-5691","authenticated-orcid":true,"given":"Kristi S.","family":"Anseth","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biological Engineering, University of Colorado Boulder, Boulder, CO 80303, USA."},{"name":"BioFrontiers Institute, University of Colorado Boulder, Boulder, CO 80309, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1116-2286","authenticated-orcid":true,"given":"Luisa","family":"Mestroni","sequence":"additional","affiliation":[{"name":"Division of Cardiology, School of Medicine, Cardiovascular Institute, University of Colorado Denver Anschutz Medical Campus, 12700 E.19th Avenue, Bldg. 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