Titill: | A mouse model of Weaver syndrome displays overgrowth and excess osteogenesis reversible with KDM6A/6B inhibition |
Höfundur: |
|
Útgáfa: | 2024-01-09 |
Tungumál: | Enska |
Umfang: | 1467611 |
Deild: | Faculty of Medicine Other departments |
Birtist í: | JCI insight; 9(1) |
ISSN: | 2379-3708 |
DOI: | 10.1172/jci.insight.173392 |
Efnisorð: | Lífefna- og sameindalíffræði; General Medicine |
URI: | https://hdl.handle.net/20.500.11815/4693 |
Tilvitnun: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
|
|
Útdráttur: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.
|
|
Athugasemdir:Publisher Copyright: © 2024 American Society for Clinical Investigation. All rights reserved.
|