(A) Domain organisation of the PRC2 core subunits (top left) and accessory subunits of the PRC2.1 and PRC2.2 complexes, as indicated. (B) Structural basis for the allosteric regulation of PRC2. Middle panel: Cryo-EM structure of PRC2.2 (PDB: 6C23 [46]). Subunits colours used as in panel (A). Top left panel: when EZH2 is bound to EED and SUZ12, the SET-I and post-SET motifs undergo a conformational change (indicated in black arrows). In grey: the structure of the SET domain from EZH2 in isolation (PDB: 4MI5 [36]); in cyan: the SET domain from the structure of EZH2 in a complex with EED and SUZ12 (PDB: 5HYN [40]), including the SAH (in CPK colouring) and an H3K27M peptide (labelled H3, in magenta) in the substrate channel. Top right panel: stimulation of PRC2 by methylated lysine peptides through interactions between the di/tri-methyl-lysine effector, the SRM and the SET-I regions (PDB: 6C23 [46]). The allosteric effector (JARID2-K116me3) is in yellow and the H3K27M peptide in the substrate channel is in magenta. Bottom left: multiple sequence alignment of different allosteric effectors of PRC2. The substrate lysine is highlighted in yellow. The conserved lysine or arginine at the −1 position and the phenylalanine in the +1 position are in grey, with the latter conserved between JARID2, PALI1 and PALI2, but not the canonical substrate H3. Bottom right: The RNA-binding sites on the regulatory center of PRC2 are highlighted in red, orange or blue if detected in three, two or one independent RBDmap experiments [55], respectively.