Researchers have elucidated the pathogenic mechanism underlying the histone H3 lysine-36-to-methionine (H3K36M) mutation, which is a frequent acquired mutation in children with chondroblastoma, a type of bone cancer. The H3K36M mutation disrupted the expression of genes involved in the differentiation of mesenchymal progenitor cells (MPCs) in vitro, and led to tumour formation after injection of mutated MPCs into severe combined immunodeficiency (SCID) mice. H3K36M mutations dominantly inhibited H3K36 methyltransferases, leading to H3K36 hypomethylation and subsequent H3K27 hypermethylation. Quantification by chromatin immunoprecipitation followed by sequencing (ChIP–seq) in H3K36M-mutant cells identified an intergenic gain of H3K27 trimethylation (H3K27me3). The shift in the ratio of gene-associated H3K27me3 to intergenic H3K27me3 led to the redistribution of Polycomb-repressive complex 1 (PRC1) and aberrant gene activation.