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Mechanisms of Polycomb gene silencing: knowns and unknowns

Nature Reviews Molecular Cell Biology volume 10, pages 697–708 (2009)Cite this article

Key Points

  • Polycomb group (PcG) proteins constitute a conserved gene silencing system with widespread roles in multicellular development, stem cell biology and cancer.

  • Gene silencing is carried out by Polycomb repressive complex 1 (PRC1) and PRC2, which each consist of families of related complexes.

  • An enzyme function associated with the PRC1 family is histone H2A ubiquitylation on K119, and a function of the PRC2 family is histone H3 methylation on K27. Specific PRC1 and PRC2 variants are also implicated in polynucleosome compaction.

  • Targeting of PcG complexes is mediated by trans-acting recruiters and cis-acting Polycomb response elements. In Drosophila melanogaster, several DNA-binding proteins, including the zinc finger protein Pleiohomeotic, serve as recruiters. PcG targeting is not well understood in mammals, in which recruiters and response elements are less well defined.

  • Recent evidence implicates long non-coding RNAs in PcG recruitment to mammalian Hox loci, the inactive X-chromosome and paternally imprinted genes.

  • Trimethylated H3K27 contributes to PRC1 interaction with local nucleosomes, but there are probably other molecular determinants of PRC1 association with chromatin.

  • Multiple versions of PRC1 family complexes, with related but non-identical subunit compositions, exist in both D. melanogaster and mammalian cells. Histone H2A ubiquitylation might be mediated by a subset of these PRC1 family complexes, and additional family members might supply other chromatin-modifying functions.

  • Transcriptional elongation is emerging as an attractive candidate for a step that is affected in PcG silencing. Both histone H2A ubiquitylation and polynucleosome compaction could contribute to barriers that impede RNA polymerase II movement. This possibility correlates with recent genome-wide studies that reveal paused RNA polymerase on ∼30% of mammalian genes.

Abstract

Polycomb proteins form chromatin-modifying complexes that implement transcriptional silencing in higher eukaryotes. Hundreds of genes are silenced by Polycomb proteins, including dozens of genes that encode crucial developmental regulators in organisms ranging from plants to humans. Two main families of complexes, called Polycomb repressive complex 1 (PRC1) and PRC2, are targeted to repressed regions. Recent studies have advanced our understanding of these complexes, including their potential mechanisms of gene silencing, the roles of chromatin modifications, their means of delivery to target genes and the functional distinctions among variant complexes. Emerging concepts include the existence of a Polycomb barrier to transcription elongation and the involvement of non-coding RNAs in the targeting of Polycomb complexes. These findings have an impact on the epigenetic programming of gene expression in many biological systems.

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Figure 1: Recruitment of PcG complexes to target genes.
Figure 2: PRC2 composition in flies and humans.
Figure 3: Potential roles for H3K27me3 in PcG function.
Figure 4: PRC1 family complexes.
Figure 5: Transcription elongation by the PRC1 family.

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Authors and Affiliations

  1. Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, 55455, USA

    Jeffrey A. Simon

  2. Department of Molecular Biology, Massachusetts General Hospital and Department of Genetics, Harvard Medical School, Boston, 02114, Massachusetts, USA

    Robert E. Kingston

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Glossary

Chromatin immunoprecipitation

(ChIP). A technique by which direct or indirect protein–DNA interactions in chromatin can be studied using antibodies against specific chromosomal proteins.

X-chromosome inactivation

The process in female mammals by which gene expression from one of the pair of X chromosomes is silenced so that the overall level of X chromosome expression matches that from the single X chromosome that is present in males. It involves non-coding regulatory RNA and a range of epigenetic mechanisms operating on the inactivated chromosome, including changes in DNA methylation and histone modifications.

Imprinting

A genetic mechanism by which genes are selectively expressed from the maternal or paternal chromosomes.

RNA interference

(RNAi). The process by which double-stranded RNA specifically silences the expression of genes by causing degradation of their cognate mRNAs.

SET domain

(Su(var)3-9, Enhancer of Zeste, Trithorax). A sequence motif found in many chromatin-associated proteins, including members of both the PcG and TrxG families. The SET domain forms an active site that catalyses histone methylation on Lys residues.

Chromodomain

A sequence motif found in many chromatin-associated proteins, including Polycomb. It forms a binding pocket for histones methylated on Lys residues.

Paralogue

A sequence, or gene, that has originated from a common ancestral sequence, or gene, by a duplication event.

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Simon, J., Kingston, R. Mechanisms of Polycomb gene silencing: knowns and unknowns. Nat Rev Mol Cell Biol 10, 697–708 (2009). https://doi.org/10.1038/nrm2763

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