Local inhibition of PRC2 activity by histone H3.3K27M drives replication defects through misregulation of the JNK pathway [ChIP-seq]

Substitution of lysine 27 with methionine in histone H3.3 is a recently discovered driver mutation of pediatric high-grade gliomas. Tumor cells carrying the mutation show a dramatic decrease in H3K27me3 levels due to physical inhibition of PRC2 methyltransferase activity. Here we use a C. elegans model to quantify the antagonistic effects of the H3.3K27M oncohistone on H3K27 trimethylation genome wide. We demonstrate that PRC2 is locally both simulated by H3K27me3 and inhibited by the oncohistone in a concentration-dependent manner. Overall design: Examination of relevant histone modifications and K27M incorporation in gonads of several C. elegans strains by ChIP-seq.