Schematics depicting mechanisms which mediate global loss of H3K27me3 in H3K27M pediatric high-grade glioma (pHGG) and PFA. (a) In normal cells, PRC2 is recruited to CpG islands and catalyzes H3K27 trimethylation and spreading of H3K27me3; (b) in H3K27M mutant pHGG, PRC2 is recruited at hypermethylated CpG islands, but H3K27M prevents spreading of H3K27Me3; (c) in PFA with EZHIP overexpression, PRC2 is recruited to hypermethylated CpG islands, but EZHIP competitively binds to and inhibits EZH2-mediated trimethylation of H3K27 and spreading. Both mechanisms in (b,c) determine loss of PRC2-mediated gene repression and transcription of normally silenced genes (Reprinted with permission from Siddhant U. Jain, (2020), Elsevier and Copyright Clearance Center, Licence Number 5200711451432, 2 December 2021).