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At the cellular level, quiescent valve interstitial cells (qVICs) activate to myofibroblasts (aVICs) that persist within the valve tissue. Given the persistence of myofibroblasts in AVS, epigenetic mechanisms have been implicated. Here, we studied changes that occur in VICs during myofibroblast activation by using a hydrogel matrix to recapitulate different stiffnesses in the valve leaflet during fibrosis. We first compared the chromatin landscape of qVICs cultured on soft hydrogels and aVICs cultured on stiff hydrogels, representing the native and diseased phenotypes respectively. Using assay for transposase\u2010accessible chromatin sequencing (ATAC\u2010Seq), we found that open chromatin regions in aVICs were enriched for transcription factor binding motifs associated with mechanosensing pathways compared to qVICs. Next, we used RNA\u2010Seq to show that the open chromatin regions in aVICs correlated with pro\u2010fibrotic gene expression, as aVICs expressed higher levels of contractile fiber genes, including myofibroblast markers such as alpha smooth muscle actin (\u03b1SMA), compared to qVICs. In contrast, chromatin remodeling genes were downregulated in aVICs compared to qVICs, indicating qVICs may be protected from myofibroblast activation through epigenetic mechanisms. Small molecule inhibition of one of these remodelers, CREB Binding Protein (CREBBP), prevented qVICs from activating to aVICs. Notably, CREBBP is more abundant in valves from healthy patients compared to fibrotic valves. Our findings reveal the role of mechanical regulation in chromatin remodeling during VIC activation and quiescence and highlight one potential therapeutic target for treating AVS.<\/jats:p>","DOI":"10.1002\/btm2.10394","type":"journal-article","created":{"date-parts":[[2022,8,12]],"date-time":"2022-08-12T02:03:20Z","timestamp":1660269800000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["Extracellular matrix stiffness controls cardiac valve myofibroblast activation through epigenetic remodeling"],"prefix":"10.1002","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2449-0334","authenticated-orcid":false,"given":"Cierra J.","family":"Walker","sequence":"first","affiliation":[{"name":"Materials Science and Engineering Program University of Colorado Boulder  Boulder Colorado USA"},{"name":"BioFrontiers Institute, University of Colorado Boulder  Boulder Colorado 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