Polycomb silencing mechanisms and the management of genomic programmes

Abstract

Polycomb group (PcG) proteins were initially identified as crucial epigenetic regulators of homeotic genes in Drosophila species, but have recently been found to control hundreds of genes in insects and in mammals. The majority of PcG targets are key regulators of essentially all developmental pathways. PcG silencing involves at least three kinds of multiprotein complexes: PRC1, PRC2 and the newly discovered PhoRC. The RING component of PRC1 functions as a histone H2A lysine 119 ubiquitin ligase, whereas the PRC2 component Enhancer of zeste (E(Z)) has histone methyltransferase activity, which is directed towards lysine 27 of histone H3. In Drosophila, PcG silencing is directed to its target genes by specific DNA elements called Polycomb response elements (PREs). These elements are modular in nature and consist of clusters of sites for DNA-binding proteins, many of which remain to be discovered. Dense binding of proteins to the PRE DNA is incompatible with its organization in nucleosomes. Mammalian PREs have not been identified. PREs serve as binding platforms for PcG proteins, which can then work at considerable distances through DNA looping. We propose that such looping is principally responsible for the broad domain of histone H3 trimethylated at lysine 27 that is produced by PRC2 over the silenced gene. Histone methylation might, in turn, stabilize the PRE-bound complexes, but might also provide means for the long-distance interaction between the PRE and promoter. Recent experiments indicate that PcG silencing mechanisms do not involve higher order chromatin packaging, but rather direct the interaction between PcG proteins and transcriptional machinery. The mechanism of transcriptional interference is unknown, but could take many forms, including covalent modification of promoter or elongation factors; for example, by methylation or ubiquitylation mediated by PRC2 or PRC1. The spectrum of PcG targets indicates that PcG silencing functions as a general enforcement mechanism that is necessary for the maintenance of a genomic programme of gene expression. This in turn implies the existence of mechanisms to redirect PcG silencing should the state of differentiation be reprogrammed during development or tissue regeneration.