PcG complexes and aberrant polycomb functions in hematological malignancies. (A) Composition of canonical and noncanonical PcG complexes. (B) Oncogenic functions of activating EZH2 mutants. EZH2Y641 mutants (Y641E, Y641F, Y641N, Y641S, Y641C, and Y641H) increase the global abundance of H3K27me3 and reinforce the repression of EZH2 target genes (left). They also cause the widespread redistribution of H3K27me3, inducing the aberrant activation of EZH2 target genes (right). ChIP, Chromatin ImmunoPrecipitation; WT, wild type. (C) Tumor suppressive function of PRC2. An EZH2 insufficiency induces the activation of PRC2 target genes via a methylation-to-acetylation switch at H3K27 at promoters, thereby conferring a growth advantage to malignant clones (left). Key tumor suppressor and developmental regulator genes are largely maintained in a transcriptionally repressed state in EZH2-insufficient hematopoietic stem and progenitor cells (HSPCs) via the locus-specific repositioning of EZH1 to the EZH2 target loci (middle) and an epigenetic switch from H3K27me3 to DNA methylation at EZH2 target genes (right).