The polycomb repressive complex 2 (PRC2) is a histone methyltransferase that maintains the repressed state of developmentally expressed genes in all multicellular eukaryotes. PRC2 marks genes for repression by the tri-methylation of lysine 27 of histone H3 (H3K27me3). The repressive H3K27me3 histone mark is required for (i) the maintenance of genes in a repressed state, (ii) the maintenance of cell identity and (iii) the facilitation of normal cell differentiation. PRC2 is a multi-subunit complex, comprised of four core subunits and at least one or two accessory subunits. A variety of mutually exclusive accessory subunits define two subtypes of holo-PRC2: PRC2.1 and PRC2.2. PALI1 is a PRC2.1-specific accessory subunit that enhances its methyltransferase activity and is essential for mouse development, but the mechanism for this is unknown.
We show that PRC2 methylates a conserved lysine in human PALI1 in vitro. This methylated lysine in PALI1 then triggers an allosteric activation of PRC2. To assess the biological relevance of lysine-methylation in PALI1, we mapped the PRC2 methylome from affinity purification mass spectrometry (AP-MS) data generated from human and mouse cell lines. We found that the same methylation event that was observed in vitro also occurs in cells, and is conserved between human and mouse. Overexpression of PALI1 in chronic myelogenous leukemia cells leads to cell differentiation and reduced proliferation. This PALI1-driven phenotype is reduced upon the expression of a methylation-defective PALI1 mutant, supporting a function of PALI1-mediated allosteric activation of PRC2 in vivo. Our results provide a molecular mechanism to explain how PALI1 regulates PRC2 and the first evidence for allosteric activation of PRC2 by a PRC2.1-sepcific accessory subunit.