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

Abstract

ABSTRACTMost 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/loxPconditional H3.3K27M mutation at the orthologousH3f3alocus in mice. Importantly, expression of the mutant transcript is under endogenousH3f3aregulatory 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-cretransgene developed as dwarfs in the presence of intact growth hormone signaling.