{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,20]],"date-time":"2025-09-20T20:23:53Z","timestamp":1758399833091,"version":"3.41.2"},"reference-count":33,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2023,11,3]],"date-time":"2023-11-03T00:00:00Z","timestamp":1698969600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Birth Defects Research"],"published-print":{"date-parts":[[2024,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Skeletal development requires precise extrinsic and intrinsic signals to regulate processes that form and maintain bone and cartilage. Notch1 is a highly conserved signaling receptor that regulates cell fate decisions by controlling the duration of transcriptional bursts. Epigenetic molecular events reversibly modify DNA and histone tails by influencing the spatial organization of chromatin and can fine\u2010tune the outcome of a Notch1 transcriptional response. Histone deacetylase 1 and 2 (HDAC1 and HDAC2) are chromatin modifying enzymes that mediate osteoblast differentiation. While an HDAC1\u2010Notch interaction has been studied <jats:italic>in vitro<\/jats:italic> and in <jats:italic>Drosophila<\/jats:italic>, its role in mammalian skeletal development and disorders is unclear. Osteosclerosis is a bone disorder with an abnormal increase in the number of osteoblasts and excessive bone formation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Here, we tested whether <jats:italic>Hdac1\/2<\/jats:italic> contribute to the pathogenesis of osteosclerosis in a murine model of the disease owing to conditionally cre\u2010activated expression of the Notch1 intracellular domain in immature osteoblasts.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Importantly, selective homozygous deletions of\u2009<jats:italic>Hdac1<\/jats:italic>\/2 in osteoblasts partially alleviate osteosclerotic phenotypes (Col2.3kb\u2010Cre; TG<jats:sup>RosaN1ICD\/+<\/jats:sup>;\u2009<jats:italic>Hdac1<\/jats:italic><jats:sup><jats:italic>flox\/flox<\/jats:italic><\/jats:sup>;\u2009<jats:italic>Hdac2<\/jats:italic><jats:sup><jats:italic>flox\/flox<\/jats:italic><\/jats:sup>) with a 40% decrease in bone volume and a 22% decrease in trabecular thickness in 4\u2009weeks old when compared to male mice with heterozygous deletions of <jats:italic>Hdac1\/2<\/jats:italic> (Col2.3\u2009kb\u2010Cre; TG<jats:sup>RosaN1ICD\/+<\/jats:sup>; <jats:italic>Hdac1<\/jats:italic><jats:sup><jats:italic>flox\/+<\/jats:italic><\/jats:sup>;\u2009<jats:italic>Hdac2<\/jats:italic><jats:sup><jats:italic>flox\/+<\/jats:italic><\/jats:sup>). Osteoblast\u2010specific deletion of <jats:italic>Hdac1\/2<\/jats:italic> in male and female mice results in no overt bone phenotype in the absence of the Notch1 gain\u2010of\u2010function (GOF) allele.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>These results provide evidence that <jats:italic>Hdac1\/2<\/jats:italic> contribute to Notch1 pathogenic signaling in the mammalian skeleton. Our study on epigenetic regulation of Notch1 GOF\u2010induced osteosclerosis may facilitate further mechanistic studies of skeletal birth defects caused by Notch\u2010related GOF mutations in human patients, such as Adams\u2010Oliver disease, congenital heart disease, and lateral meningocele syndrome.<\/jats:p><\/jats:sec>","DOI":"10.1002\/bdr2.2266","type":"journal-article","created":{"date-parts":[[2023,11,3]],"date-time":"2023-11-03T12:09:07Z","timestamp":1699013347000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["<i>Hdac1<\/i> and <i>Hdac2<\/i> positively regulate Notch1 gain\u2010of\u2010function pathogenic signaling in committed osteoblasts of male mice"],"prefix":"10.1002","volume":"116","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9912-6230","authenticated-orcid":false,"given":"Haydee M.","family":"Torres","sequence":"first","affiliation":[{"name":"Cancer Biology and Immunotherapies Group Sanford Research  Sioux Falls South Dakota USA"},{"name":"Department of Chemistry and Biochemistry South Dakota State University  Brookings South Dakota USA"},{"name":"Department of Orthopedic Surgery Mayo Clinic  Rochester Minnesota USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leetoria","family":"Hinojosa","sequence":"additional","affiliation":[{"name":"Cancer Biology and Immunotherapies Group Sanford Research  Sioux Falls South Dakota USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ashley M.","family":"VanCleave","sequence":"additional","affiliation":[{"name":"Cancer Biology and Immunotherapies Group Sanford Research  Sioux Falls South Dakota USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tania","family":"Rodezno","sequence":"additional","affiliation":[{"name":"Cancer Biology and Immunotherapies Group Sanford Research  Sioux Falls South Dakota USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer J.","family":"Westendorf","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery Mayo Clinic  Rochester Minnesota USA"},{"name":"Department of Biochemistry &amp; Molecular Biology Mayo Clinic  Rochester Minnesota USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianning","family":"Tao","sequence":"additional","affiliation":[{"name":"Cancer Biology and Immunotherapies Group Sanford Research  Sioux Falls South Dakota USA"},{"name":"Department of Chemistry and Biochemistry South Dakota State University  Brookings South Dakota USA"},{"name":"Department of Pediatrics and Biomedical Engineering University of South Dakota  Sioux Falls South Dakota USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2023,11,3]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M707000200"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00004.2015"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.121.5.1533"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.10100"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm1712"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa088"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm1716"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci124030"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2010.318"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/21.11.2672"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.148007"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2011.01.007"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1563807"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2436557100"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2011.533"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-018-0234-z"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1359\/JBMR.050813"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2014.07.011"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.8.6.707"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1009233"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1161\/jaha.112.000901"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.2009.05307.x"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.115"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2014.07.023"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13164199"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1315023111"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2020.115606"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1242\/bio.029637"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2009.06.049"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/9780470623992.ch88"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.552310"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2012.08.022"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2008-0140"}],"container-title":["Birth Defects Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/bdr2.2266","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,11]],"date-time":"2024-07-11T05:25:04Z","timestamp":1720675504000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/bdr2.2266"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,3]]},"references-count":33,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2024,1]]}},"alternative-id":["10.1002\/bdr2.2266"],"URL":"https:\/\/doi.org\/10.1002\/bdr2.2266","archive":["Portico"],"relation":{},"ISSN":["2472-1727","2472-1727"],"issn-type":[{"type":"print","value":"2472-1727"},{"type":"electronic","value":"2472-1727"}],"subject":[],"published":{"date-parts":[[2023,11,3]]},"assertion":[{"value":"2023-07-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-10-19","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-11-03","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2266"}}