Missense mutations K27M and G34R/V in the human genes encoding histones H3.3 and H3.1 are present in the majority of pediatric gliomas. Allis and coworkers now have shown that histones extracted from diffuse intrinsic pontine gliomas containing the K27M mutation have significantly lower H3K27me3 levels and that H3K27M transgenes also cause a global decrease in H3K27me3. Although cells carrying the H3.3G34R/V mutation did not exhibit a global reduction in H3K36me3, the authors found reduced H3K36me2 and H3K36me3 levels on H3.3G34R/V-containing nucleosomes. Moreover, H3.3G34R/V-containing nucleosomes were methylated to a lower extent by recombinant SET2 in vitro. Whereas H3K27me3 peptides allosterically stimulated PRC2 methyltransferase activity on nucleosome substrates, H3K27M peptides inhibited PRC2 activity on nucleosomes. This dose-dependent inhibition was specific to K27M, as other substitutions did not affect the methylation efficiency. Synthesized photoactivatable H3K27M peptides could be cross-linked to the SET domain–containing EZH2 catalytic subunit but not to other PRC2 subunits, which suggests that K27M peptides inhibit PRC2 through interaction with the EZH2 active site. Other SET-domain methyltransferases were found to be similarly sensitive to methionine substitution at their cognate methylated lysines (H3K9 and H3K36). The authors propose that aberrant epigenetic silencing by the H3K27M gain-of-function mutation through inhibition of PRC2 activity may promote gliomagenesis, and the current work further suggests that other K-to-M histone mutations may be linked to disease. (Sciencehttp://dx.doi.org/10.1126/science.1232245,publishedonline28March2013)