ArticleJCI insight2024
A mouse model of Weaver syndrome displays overgrowth and excess osteogenesis reversible with KDM6A/6B inhibition.
Article in JCI insight, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 16 citations in OpenAlex.
- From chromatin dynamics to brain disease: Polycomb-Trithorax mechanisms in neurodevelopment.Trends in neurosciences · 2026Review
- Histone arginine demethylase JMJD7 promotes bone formation through regulating α-Ketoglutarate metabolism.Cell death and differentiation · 2026Article
- Convergent DNA methylation abnormalities at enhancers and bivalent promoters in human growth disorders.Epigenetics & chromatin · 2025Article
- Article
- Dominant-negative effects of Weaver syndrome-associated EZH2 variants.Genes & development · 2025Article
- Review
- Article
- KDM6A downregulation promotes tumor-prone cytokines expression in cancer-associated fibroblasts by activating enhancers.Cell death & disease · 2025Article
- Elevated levels of neutrophils with a pro-inflammatory profile in Turner syndrome across karyotypes.NPJ genomic medicine · 2025Article
- Chromatin modifiers in neurodevelopment.Frontiers in molecular neuroscience · 2025Review
- Growth deficiency in a mouse model of Kabuki syndrome 2 bears mechanistic similarities to Kabuki syndrome 1.PLoS genetics · 2024Article
- Tricarboxylic Acid Cycle Regulation of Metabolic Program, Redox System, and Epigenetic Remodeling for Bone Health and Disease.Antioxidants (Basel, Switzerland) · 2024Review
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Authors and funding
8 authors at 3 institutions in 2 countries.
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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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.