dc.contributor.author |
Gao, Christine W. |
dc.contributor.author |
Lin, Wan Ying |
dc.contributor.author |
Riddle, Ryan C. |
dc.contributor.author |
Kushwaha, Priyanka |
dc.contributor.author |
Boukas, Leandros |
dc.contributor.author |
Björnsson, Hans Tómas |
dc.contributor.author |
Hansen, Kasper D. |
dc.contributor.author |
Fahrner, Jill A. |
dc.date.accessioned |
2024-01-30T01:06:50Z |
dc.date.available |
2024-01-30T01:06:50Z |
dc.date.issued |
2024-01-09 |
dc.identifier.citation |
Gao , C W , Lin , W Y , Riddle , R C , Kushwaha , P , Boukas , L , Björnsson , H T , Hansen , K D & Fahrner , J A 2024 , ' A mouse model of Weaver syndrome displays overgrowth and excess osteogenesis reversible with KDM6A/6B inhibition ' , JCI insight , vol. 9 , no. 1 , e173392 . https://doi.org/10.1172/jci.insight.173392 |
dc.identifier.issn |
2379-3708 |
dc.identifier.other |
216439447 |
dc.identifier.other |
ff92193d-29b2-4b2d-8e2f-539be8cb9d1d |
dc.identifier.other |
85182016880 |
dc.identifier.other |
38015625 |
dc.identifier.uri |
https://hdl.handle.net/20.500.11815/4693 |
dc.description |
Publisher Copyright: © 2024 American Society for Clinical Investigation. All rights reserved. |
dc.description.abstract |
Weaver syndrome is a Mendelian disorder of the epigenetic machinery (MDEM) caused by germline pathogenic variants in EZH2, 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. Ezh2R684C/R684C mouse embryonic fibroblasts (MEFs) showed global depletion of H3K27me3. Ezh2R684C/+ mice had abnormal bone parameters, indicative of skeletal overgrowth, and Ezh2R684C/+ osteoblasts showed increased osteogenic activity. RNA-Seq comparing osteoblasts differentiated from Ezh2R684C/+, and Ezh2+/+ 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 Ezh2R684C/+ 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. |
dc.format.extent |
1467611 |
dc.format.extent |
|
dc.language.iso |
en |
dc.relation.ispartofseries |
JCI insight; 9(1) |
dc.rights |
info:eu-repo/semantics/openAccess |
dc.subject |
Lífefna- og sameindalíffræði |
dc.subject |
General Medicine |
dc.title |
A mouse model of Weaver syndrome displays overgrowth and excess osteogenesis reversible with KDM6A/6B inhibition |
dc.type |
/dk/atira/pure/researchoutput/researchoutputtypes/contributiontojournal/article |
dc.description.version |
Peer reviewed |
dc.identifier.doi |
10.1172/jci.insight.173392 |
dc.relation.url |
http://www.scopus.com/inward/record.url?scp=85182016880&partnerID=8YFLogxK |
dc.contributor.department |
Faculty of Medicine |
dc.contributor.department |
Other departments |