A conditional histone H3.3 mutation in mice orthologous to a driver of paediatric diffuse instrinsic pontine glioma

Abstract

Most paediatric diffuse intrinsic pontine gliomas carry a lysine- to methionine-27 (K27M) mutation in the histone variant H3.3 encoded by the H3.3 histone A (H3F3A) gene. To establish a pre-clinical model of the disease we made a Cre/loxP conditional H3.3K27M mutation at the orthologous H3f3a locus in mice. Importantly, expression of the mutant transcript is under endogenous H3f3a regulatory control. This system is distinct from others in which H3.3M27 is ectopically expressed, thereby providing a resource for the development of pDIPG models with orthologous regulation of mutant H3.3. Mice in which expression of the mutant transcript was induced with a nestin-cre transgene developed as dwarfs in the presence of intact growth hormone signaling.