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

JCI Insight. 2024 Jan 9;9(1):e173392. doi: 10.1172/jci.insight.173392.

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.

Keywords: Epigenetics; Genetic diseases; Genetics.

MeSH terms

  • Abnormalities, Multiple
  • Animals
  • Congenital Hypothyroidism
  • Craniofacial Abnormalities
  • Disease Models, Animal
  • Fibroblasts* / metabolism
  • Hand Deformities, Congenital
  • Histone Demethylases
  • Mice
  • Osteogenesis* / physiology
  • Polycomb Repressive Complex 2

Substances

  • Polycomb Repressive Complex 2
  • Histone Demethylases

Supplementary concepts

  • Weaver syndrome