{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T14:55:56Z","timestamp":1767711356069,"version":"3.48.0"},"posted":{"date-parts":[[2026,1,5]]},"group-title":"Bioengineering","reference-count":48,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T00:00:00Z","timestamp":1767571200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"National Science Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,1,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder in which a recurrent ACVR1 (R206H) mutation drives progressive heterotopic ossification (HO). While aberrant BMP hypersensitivity has been studied, how this mutation enforces a persistent pro-osteogenic state remains unclear. Here, we combined super-resolution stochastic optical reconstruction microscopy (STORM), transposase-accessible chromatin with sequencing (ATAC-Seq), and RNA sequencing (RNA-Seq) to investigate how\n                  <jats:italic>\n                    Acvr1\n                    <jats:sup>R206H<\/jats:sup>\n                  <\/jats:italic>\n                  remodels chromatin to promote osteogenic transcriptional programs. Mutant mouse embryonic fibroblasts (MEFs) exhibited globally decondensed chromatin and increased accessibility at developmental and osteogenic loci enriched for HOX, TEAD, and RUNX motifs. Integration of ATAC-Seq and RNA-Seq data identified transcriptional networks primed for osteochondrogenic gene expression, including ossification, extracellular matrix organization, and cell adhesion pathways, consistent with enhanced BMP\u2013SMAD and mechanotransduction activity. Time-course experiments revealed heightened responses to BMP ligands in Acvr1\n                  <jats:sup>R206H\/+<\/jats:sup>\n                  MEFs compared to wild-type, highlighting ligand hypersensitivity. Importantly, pharmacological modulation showed that chromatin alterations were dynamic and reversible: activation of Rho\/ROCK in wild-type cells reproduced the mutant chromatin state, while inhibition of Rho\/ROCK or BMP\u2013SMAD signaling restored condensation to wild-type levels in mutant cells. Together, these findings establish that\n                  <jats:italic>\n                    Acvr1\n                    <jats:sup>R206H<\/jats:sup>\n                  <\/jats:italic>\n                  enforces a pro-osteogenic chromatin landscape through convergent BMP\u2013SMAD and Rho\/ROCK signaling, predisposing progenitors to aberrant differentiation trajectories. Our study reframes FOP as a disorder of persistent, but reversible, chromatin states and identifies novel therapeutic opportunities to restore mesenchymal cell homeostasis and prevent pathological bone formation.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Significance Statement<\/jats:title>\n                  <jats:p>\n                    Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder in which a mutation in ACVR1\/ALK2 drives progressive heterotopic ossification. However, how this mutation enforces a persistent pro-osteogenic state is unclear. Here, we show that the\n                    <jats:italic>\n                      Acvr1\n                      <jats:sup>R206H<\/jats:sup>\n                    <\/jats:italic>\n                    mutation remodels chromatin architecture and accessibility through hyperactive BMP\u2013SMAD and Rho\/ROCK signaling, activating transcription factor networks that drive osteochondrogenic gene expression. These chromatin changes are dynamic and reversible with targeted pathway inhibition, revealing therapeutic potential to restore mesenchymal cell plasticity and prevent pathological bone formation.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.01.05.697733","type":"posted-content","created":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T22:40:13Z","timestamp":1767652813000},"source":"Crossref","is-referenced-by-count":0,"title":["Hyperactive BMP and Mechanosignaling Remodel Chromatin to Drive Aberrant Osteogenesis in FOP"],"prefix":"10.64898","author":[{"given":"Ellen Y.","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, 19104, USA"},{"name":"Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA, 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7751-7268","authenticated-orcid":false,"given":"Douglas W.","family":"Roberts","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA, 19104, USA"},{"name":"The Center for Research in FOP and Related Disorders, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sang Hyun","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, KOR"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bat-Ider","family":"Tumenbayar","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA, 19104, USA"},{"name":"Department of Genetics, University of Pennsylvania, Philadelphia, PA, 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jaeun","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, 19104, USA"},{"name":"Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA, 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Loreilys Mej\u00edas","family":"Rivera","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA, 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5885-2754","authenticated-orcid":false,"given":"Inkyung","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, KOR"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert L.","family":"Mauck","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, 19104, USA"},{"name":"Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA, 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eileen M.","family":"Shore","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA, 19104, USA"},{"name":"Department of Genetics, University of Pennsylvania, Philadelphia, PA, 19104, USA"},{"name":"The Center for Research in FOP and Related Disorders, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2771-5076","authenticated-orcid":false,"given":"Su Chin","family":"Heo","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, 19104, USA"},{"name":"Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA, 19104, USA"},{"name":"Department of Dentistry, College of Dentistry, Kyung Hee University, Seoul, KOR"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026010606550661000_2026.01.05.697733v1.1","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.berh.2007.11.007","article-title":"Fibrodysplasia ossificans progressiva","volume":"22","year":"2008","journal-title":"Best Practice & Research Clinical Rheumatology"},{"key":"2026010606550661000_2026.01.05.697733v1.2","doi-asserted-by":"crossref","first-page":"779","DOI":"10.3390\/biomedicines12040779","article-title":"Cellular and Molecular Mechanisms of Heterotopic Ossification in Fibrodysplasia Ossificans Progressiva","volume":"12","year":"2024","journal-title":"Biomedicines"},{"key":"2026010606550661000_2026.01.05.697733v1.3","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1172-6-80"},{"key":"2026010606550661000_2026.01.05.697733v1.4","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.2728"},{"key":"2026010606550661000_2026.01.05.697733v1.5","doi-asserted-by":"crossref","first-page":"2422","DOI":"10.1016\/j.gim.2022.08.013","article-title":"The natural history of fibrodysplasia ossificans progressiva: A prospective, global 36-month study","volume":"24","year":"2022","journal-title":"Genetics in Medicine"},{"key":"2026010606550661000_2026.01.05.697733v1.6","doi-asserted-by":"publisher","DOI":"10.1038\/ng1783"},{"key":"2026010606550661000_2026.01.05.697733v1.7","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20868"},{"key":"2026010606550661000_2026.01.05.697733v1.8","doi-asserted-by":"publisher","DOI":"10.1359\/jbmr.071030"},{"key":"2026010606550661000_2026.01.05.697733v1.9","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M801681200"},{"key":"2026010606550661000_2026.01.05.697733v1.10","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1091\/mbc.E18-05-0311","article-title":"ACVR1R206H FOP mutation alters mechanosensing and tissue stiffness during heterotopic ossification","volume":"30","year":"2019","journal-title":"MBoC"},{"key":"2026010606550661000_2026.01.05.697733v1.11","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.3760"},{"key":"2026010606550661000_2026.01.05.697733v1.12","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-02872-2"},{"key":"2026010606550661000_2026.01.05.697733v1.13","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2297"},{"key":"2026010606550661000_2026.01.05.697733v1.14","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-023-00918-9"},{"key":"2026010606550661000_2026.01.05.697733v1.15","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2012.191"},{"key":"2026010606550661000_2026.01.05.697733v1.16","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkr572"},{"key":"2026010606550661000_2026.01.05.697733v1.17","doi-asserted-by":"publisher","DOI":"10.1101\/gr.092114.109"},{"key":"2026010606550661000_2026.01.05.697733v1.18","doi-asserted-by":"crossref","first-page":"e53761","DOI":"10.7554\/eLife.53761","article-title":"Fibrodysplasia ossificans progressiva mutant ACVR1 signals by multiple modalities in the developing zebrafish","volume":"9","year":"2020","journal-title":"eLife"},{"key":"2026010606550661000_2026.01.05.697733v1.19","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.1637"},{"key":"2026010606550661000_2026.01.05.697733v1.20","doi-asserted-by":"publisher","DOI":"10.1038\/nrg.2016.59"},{"key":"2026010606550661000_2026.01.05.697733v1.21","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1038\/s41551-020-00678-6","article-title":"Epigenetic regulation of mechanotransduction","volume":"5","year":"2021","journal-title":"Nat Biomed Eng"},{"key":"2026010606550661000_2026.01.05.697733v1.22","doi-asserted-by":"crossref","first-page":"026127","DOI":"10.1063\/5.0271050","article-title":"Epigenetic regulation and mechanobiological adaptation in tenocytes during maturation","volume":"9","year":"2025","journal-title":"APL Bioengineering"},{"key":"2026010606550661000_2026.01.05.697733v1.23","doi-asserted-by":"publisher","DOI":"10.1016\/S0003-3472(69)80023-0"},{"key":"2026010606550661000_2026.01.05.697733v1.24","doi-asserted-by":"publisher","DOI":"10.1042\/bcj20200036"},{"key":"2026010606550661000_2026.01.05.697733v1.25","doi-asserted-by":"publisher","DOI":"10.7554\/elife.67312"},{"key":"2026010606550661000_2026.01.05.697733v1.26","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1038\/s41413-018-0018-7","article-title":"YAP promotes osteogenesis and suppresses adipogenic differentiation by regulating \u03b2-catenin signaling","volume":"6","year":"2018","journal-title":"Bone Res"},{"key":"2026010606550661000_2026.01.05.697733v1.27","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2211947120"},{"key":"2026010606550661000_2026.01.05.697733v1.28","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aav3262"},{"key":"2026010606550661000_2026.01.05.697733v1.29","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0062721"},{"key":"2026010606550661000_2026.01.05.697733v1.30","doi-asserted-by":"publisher","DOI":"10.1038\/nrg.2017.57"},{"key":"2026010606550661000_2026.01.05.697733v1.31","doi-asserted-by":"crossref","first-page":"1364","DOI":"10.1002\/jbmr.4869","article-title":"Reduced GS domain serine\/threonine requirements of Fibrodysplasia Ossificans Progressiva mutant type I BMP receptor ACVR1 in the zebrafish","volume":"38","year":"2023","journal-title":"J Bone Miner Res"},{"key":"2026010606550661000_2026.01.05.697733v1.32","doi-asserted-by":"crossref","first-page":"ar73","DOI":"10.1091\/mbc.E22-12-0543","article-title":"Microenvironmental mechanoactivation through Yap\/Taz suppresses chondrogenic gene expression","volume":"34","year":"2023","journal-title":"Mol Biol Cell"},{"key":"2026010606550661000_2026.01.05.697733v1.33","first-page":"177","article-title":"Aberrant chromatin reorganization in cells from diseased fibrous connective tissue in response to altered chemomechanical cues. Nat","volume":"7","year":"2023","journal-title":"Biomed. Eng"},{"key":"2026010606550661000_2026.01.05.697733v1.34","doi-asserted-by":"crossref","first-page":"ziaf123","DOI":"10.1093\/jbmrpl\/ziaf123","article-title":"An inducible knock-in mouse model of fibrodysplasia ossificans progressiva shows spontaneous formation of heterotopic ossification","volume":"9","year":"2025","journal-title":"JBMR Plus"},{"key":"2026010606550661000_2026.01.05.697733v1.35","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu170"},{"key":"2026010606550661000_2026.01.05.697733v1.36","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts635"},{"key":"2026010606550661000_2026.01.05.697733v1.37","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btt656"},{"key":"2026010606550661000_2026.01.05.697733v1.38","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"key":"2026010606550661000_2026.01.05.697733v1.39","doi-asserted-by":"publisher","DOI":"10.18129\/B9.bioc.EnhancedVolcano"},{"key":"2026010606550661000_2026.01.05.697733v1.40","doi-asserted-by":"publisher","DOI":"10.1089\/omi.2011.0118"},{"key":"2026010606550661000_2026.01.05.697733v1.41","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.1923"},{"key":"2026010606550661000_2026.01.05.697733v1.42","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp352"},{"key":"2026010606550661000_2026.01.05.697733v1.43","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2008-9-9-r137"},{"key":"2026010606550661000_2026.01.05.697733v1.44","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btq033"},{"key":"2026010606550661000_2026.01.05.697733v1.45","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2010.05.004"},{"key":"2026010606550661000_2026.01.05.697733v1.46","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aax5083"},{"key":"2026010606550661000_2026.01.05.697733v1.47","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.01.054"},{"key":"2026010606550661000_2026.01.05.697733v1.48","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkz593"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.01.05.697733","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T14:55:17Z","timestamp":1767711317000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.01.05.697733"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,5]]},"references-count":48,"URL":"https:\/\/doi.org\/10.64898\/2026.01.05.697733","relation":{},"subject":[],"published":{"date-parts":[[2026,1,5]]},"subtype":"preprint"}}