A Functional genomics approach to identify new therapeutic targets in DIPG

Diffuse intrinsic pontine glioma (DIPG) is an aggressive paediatric brain tumour that is incurable. H3K27 methylation is catalysed by PRC2 via EZH1/EZH2. We show that EZH1 partially compensates for EZH2 loss in DIPG cells. Dual targeting of EZH1/EZH2 inhibits proliferation of DIPG cells and reduces H3K27me3 more effectively than selective targeting of EZH2. H3K27M mutations affected H3K27me3 distribution and DIPG cell proliferation directly. Furthermore, EZH1/EZH2 and H3K27M alter gene expression. The work presented here has identified several potential combinations that act by altering abnormal trimethylation levels. Taken together, we revealed a therapeutic vulnerability that can be targeted using combination therapies.