Histone H3 lysine(27)-to-methionine (H3K27M) gain-of-function mutations occur in 
highly aggressive pediatric gliomas. We established a Drosophila animal model 
for the pathogenic histone H3K27M mutation and show that its overexpression 
resembles polycomb repressive complex 2 (PRC2) loss-of-function phenotypes, 
causing derepression of PRC2 target genes and developmental perturbations. 
Similarly, an H3K9M mutant depletes H3K9 methylation levels and suppresses 
position-effect variegation in various Drosophila tissues. The histone H3K9 
demethylase KDM3B/JHDM2 associates with H3K9M-containing nucleosomes, and its 
misregulation in Drosophila results in changes of H3K9 methylation levels and 
heterochromatic silencing defects. We have established histone 
lysine-to-methionine mutants as robust in vivo tools for inhibiting methylation 
pathways that also function as biochemical reagents for capturing site-specific 
histone-modifying enzymes, thus providing molecular insight into chromatin 
signaling pathways.