This paper is one of several recent publications to examine the mechanisms through which mutations of genes that encode histone 3 (H3) variants contribute to glioma development in young children, including in those with diffuse intrinsic pontine glioma (DIPG). A mutation in H3F3A that results in a lysine 27 to methionine mutation (K27M) in H3.3, which is found in DIPG, results in reduced levels of trimethylated and dimethylated H3K27 (H3K27me3 and H3K27me2, respectively). However, using two DIPG cell lines that have the H3.3K27M mutation, these authors also found that, at specific cancer-associated loci throughout the genome, H3K27me3 levels and levels of bound EZH2 (the catalytic subunit of polycomb repressive complex 2) were increased, leading to decreased gene expression levels from these loci. These data add more weight to the evidence that epigenetic changes underlie the development of DIPG.