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bioRxiv · 10.1101/2023.06.23.546270

Novel mouse model of Weaver syndrome displays overgrowth and excess osteogenesis reversible with KDM6A/6B inhibition

Gao, C. W.·Lin, W.·Riddle, R. C.·Kushwaha, P.·Boukas, L.·Bjornsson, H. T.·Hansen, K. D.·Fahrner, J. A.
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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+/+ bone marrow mesenchymal stem cells (BM-MSCs) indicated collective dysregulation of the BMP pathway and osteoblast differentiation. Inhibition of the opposing H3K27 demethylases Kdm6a/6b 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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Gao, C. W., Lin, W., Riddle, R. C., Kushwaha, P., Boukas, L., Bjornsson, H. T., Hansen, K. D., Fahrner, J. A.. 2023-06-26. Novel mouse model of Weaver syndrome displays overgrowth and excess osteogenesis reversible with KDM6A/6B inhibition. https://doi.org/10.1101/2023.06.23.546270

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