PcG proteins form the Polycomb repressive complexes 1 and 2 (PRC1/PRC2) as well as the Polycomb repressive deubiquitinase complex (PR-DUB). Genomic binding sites of PRC1 and PRC2 overlap, and both complexes are primarily enriched at CpG-rich promoters of non-transcribed genes, where they contribute to the correct spatiotemporal expression pattern of developmentally regulated genes. Loss of PRC function during development leads to embryonic lethality, and PcG proteins are often found mutated or deregulated in human diseases, including cancer.

Transcriptional regulation by Polycomb repressive complexes. PRCs are recruited to CpG islands (CGIs) of non-transcribed genes, contributing to their maintained repression. PRC2 catalyzes H3K27 methylation, which is recognized by EED of PRC2 and CBX of PRC1. PRC1 catalyzes H2AK119 ubiquitination, which can be bound by JARID2/AEBP2-containing PRC2.2 complexes. H2AK119ub1 can be removed by PR-DUB.

PRC1 complex

PRC1 complexes contain an E3 ubiquitin ligase (RING1A or RING1B) with activity towards H2AK119, closely associated with a PCGF component (PCGF1-6), which is required for the catalytic activity of the complex to form H2AK119ub1.

PRC2 complex

The core PRC2 complex consists of a histone methyltransferase subunit (EZH1 or EZH2), which depends on association with SUZ12 and EED for in vitro activity and the additional association with the histone-binding proteins RBBP4 or RBBP7 for in vivo activity. PRC2 catalyzes mono-, di- and trimethylation of H3K27.

For more information on the structure and function of PRC1, PRC2, and PR-DUB complexes, please refer to the full guide.

PR-DUB complex

The PR-DUB complex catalyzes the deubiquitination of PRC1-deposited H2AK119ub1. It consists of a deubiquitinase subunit (BAP1) and an ASXL homolog (ASXL1-3), which is required for the catalytic activity of the complex. The core complex is further associated with accessory proteins, including the FOXK1/2 transcription factors and chromatin-modifying proteins that contribute to recruitment and chromatin modulation. Given that PR-DUB counteracts PRC1 function through the deubiquitination of H2AK119ub1, its classification as a PRC may seem counterintuitive. However, mutants of the Drosophila homologs of BAP1 and ASXL1-3 yield Polycomb-like phenotypes of homeotic transformation¹.

References

1. Schuettengruber, B., Bourbon, H. M., Di Croce, L., et al. Genome regulation by polycomb and trithorax: 70 years and counting Cell 171 ,34-57 (2017)