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

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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. Ezh2 R684C/R684C mouse embryonic fibroblasts (MEFs) showed global depletion of H3K27me3. Ezh2 R684C/+ mice had abnormal bone parameters, indicative of skeletal overgrowth, and Ezh2 R684C/+ osteoblasts showed increased osteogenic activity. RNA-Seq comparing osteoblasts differentiated from Ezh2 R684C/+ , 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 Ezh2 R684C/+ 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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Funding Information
  • National Institutes of Health (NIH)/National Institute for Child Health and Human Development (K08HD086250)
  • Hartwell Foundation (Individual Biomedical Research Award)
  • School of Medicine, Johns Hopkins University (Clinician-Scientist Award)
  • William and Ella Owens Medical Research Foundation (Research Grant)
  • Biomedical Laboratory Research and Development Service of the Veterans Affairs Office of Research and Development (Merit Review Grant BX003724)
  • Louma G. Foundation (Research grant)
  • National Institutes of Health (NIH)/National Institute of General Medical Sciences (T32GM136577)
  • Johns Hopkins University (Bloomberg Distinguished Professorship to Carol W Greider)

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