Expression of histone H3.3K27M mutant proteins in human diffuse intrinsic 
pontine glioma (DIPG) results in a global reduction of tri-methylation of H3K27 
(H3K27me3), and paradoxically, H3K27me3 peaks remain at hundreds of genomic 
loci, a dichotomous change that lacks mechanistic insights. Here, we show that 
the PRC2 complex is sequestered at poised enhancers, but not at active promoters 
with high levels of H3.3K27M proteins, thereby contributing to the global 
reduction of H3K27me3. Moreover, the levels of H3.3K27M proteins are low at the 
retained H3K27me3 peaks and consequently having minimal effects on the PRC2 
activity at these loci. H3K27me3-mediated silencing at specific tumor suppressor 
genes, including Wilms Tumor 1, promotes proliferation of DIPG cells. These 
results support a model in which the PRC2 complex is redistributed to poised 
enhancers in H3.3K27M mutant cells and contributes to tumorigenesis in part by 
locally enhancing H3K27me3, and hence silencing of tumor suppressor genes.