PRC2 Mediated H3K27 Methylations in Cellular Identity and Cancer

The Polycomb Repressive Complex 2 (PRC2) is a multiprotein chromatin modifying complex that is essential for vertebrate development and differentiation. It is composed of a trimeric core of SUZ12, EED and EZH1/2 and is responsible for catalysing both di-methylation and tri-methylation of Histone H3 at lysine 27 (H3K27me2/3). Both H3K27 methylations contribute to the role of PRC2 in maintaining cellular identity. In all cell types, the H3K27me3 modification is associated with repression of genes encoding regulators of alternative lineages. The less well-characterised H3K27me2 modification is ubiquitous throughout the genome and is thought to act like a protective blanket to maintain the repression of non-H3K27me3 associated genes and cell-type-specific enhancers of alternative lineages. Recent cancer genome sequencing studies highlighted that several genes encoding PRC2 components as well as Histone H3 are mutated in multiple cancer types. Intriguingly, these cancers have changes in the global levels of the H3K27me2 and H3K27me3 modifications as well as genome-wide redistributions. Exciting new studies suggest that these changes confer context dependent blocks in cellular differentiation and increased vulnerability to aberrant cancer signalling pathways.