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Foundation","award":["Research grant"],"award-info":[{"award-number":["Research grant"]}]},{"name":"National Institutes of Health (NIH)\/National Institute of General Medical Sciences","award":["T32GM136577"],"award-info":[{"award-number":["T32GM136577"]}]},{"name":"Johns Hopkins University","award":["Bloomberg Distinguished Professorship to Carol W Greider"],"award-info":[{"award-number":["Bloomberg Distinguished Professorship to Carol W Greider"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,1,9]]},"abstract":"<jats:p>\n                    Weaver syndrome is a Mendelian disorder of the epigenetic machinery (MDEM) caused by germline pathogenic variants in\n                    <jats:italic>EZH2<\/jats:italic>\n                    , which encodes the predominant H3K27 methyltransferase and key enzymatic component of Polycomb repressive complex 2 (PRC2). Weaver syndrome is characterized by striking overgrowth and advanced bone age, intellectual disability, and distinctive facies. We generated a mouse model for the most common Weaver syndrome missense variant, EZH2 p.R684C.\n                    <jats:italic>\n                      Ezh2\n                      <jats:sup>R684C\/R684C<\/jats:sup>\n                    <\/jats:italic>\n                    mouse embryonic fibroblasts (MEFs) showed global depletion of H3K27me3.\n                    <jats:italic>\n                      Ezh2\n                      <jats:sup>R684C\/+<\/jats:sup>\n                    <\/jats:italic>\n                    mice had abnormal bone parameters, indicative of skeletal overgrowth, and\n                    <jats:italic>\n                      Ezh2\n                      <jats:sup>R684C\/+<\/jats:sup>\n                    <\/jats:italic>\n                    osteoblasts showed increased osteogenic activity. RNA-Seq comparing osteoblasts differentiated from\n                    <jats:italic>\n                      Ezh2\n                      <jats:sup>R684C\/+<\/jats:sup>\n                    <\/jats:italic>\n                    , and\n                    <jats:italic>\n                      Ezh2\n                      <jats:sup>+\/+<\/jats:sup>\n                    <\/jats:italic>\n                    BM-mesenchymal stem cells (BM-MSCs) indicated collective dysregulation of the BMP pathway and osteoblast differentiation. Inhibition of the opposing H3K27 demethylases KDM6A and KDM6B substantially reversed the excessive osteogenesis in\n                    <jats:italic>\n                      Ezh2\n                      <jats:sup>R684C\/+<\/jats:sup>\n                    <\/jats:italic>\n                    cells both at the transcriptional and phenotypic levels. This supports both the ideas that writers and erasers of histone marks exist in a fine balance to maintain epigenome state and that epigenetic modulating agents have therapeutic potential for the treatment of MDEMs.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.173392","type":"journal-article","created":{"date-parts":[[2023,11,28]],"date-time":"2023-11-28T12:00:47Z","timestamp":1701172847000},"source":"Crossref","is-referenced-by-count":21,"title":["A mouse model of Weaver syndrome displays overgrowth and excess osteogenesis reversible with KDM6A\/6B inhibition"],"prefix":"10.1172","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2298-2239","authenticated-orcid":true,"given":"Christine W.","family":"Gao","sequence":"first","affiliation":[{"name":"Department of Genetic Medicine,"},{"name":"Department of Molecular Biology and Genetics, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"WanYing","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Genetic Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7265-6939","authenticated-orcid":true,"given":"Ryan C.","family":"Riddle","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA."},{"name":"Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, Maryland, USA."},{"name":"Research and Development Service, Baltimore Veterans Administration Medical Center, Baltimore, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priyanka","family":"Kushwaha","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leandros","family":"Boukas","sequence":"additional","affiliation":[{"name":"Department of Genetic Medicine,"},{"name":"Department of Biostatistics, Johns Hopkins University School of Public Health, Baltimore, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6635-6753","authenticated-orcid":true,"given":"Hans T.","family":"Bj\u00f6rnsson","sequence":"additional","affiliation":[{"name":"Department of Genetic Medicine,"},{"name":"Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA."},{"name":"Faculty of Medicine, University of Iceland, Reykjav\u00edk, Iceland."},{"name":"Landsp\u00edtali University Hospital, Reykjav\u00edk, Iceland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0086-0687","authenticated-orcid":true,"given":"Kasper D.","family":"Hansen","sequence":"additional","affiliation":[{"name":"Department of Genetic Medicine,"},{"name":"Department of Biostatistics, Johns Hopkins University School of Public Health, Baltimore, Maryland, USA."},{"name":"Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5506-8780","authenticated-orcid":true,"given":"Jill A.","family":"Fahrner","sequence":"additional","affiliation":[{"name":"Department of Genetic Medicine,"},{"name":"Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2024,1,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-genom-090613-094245"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddz174"},{"key":"B3","doi-asserted-by":"crossref","unstructured":"Harris JR, et al. 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