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  • Review Article
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Polycomb silencing mechanisms and the management of genomic programmes

Key Points

  • 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.

Abstract

Polycomb group complexes, which are known to regulate homeotic genes, have now been found to control hundreds of other genes in mammals and insects. First believed to progressively assemble and package chromatin, they are now thought to be localized, but induce a methylation mark on histone H3 over a broad chromatin domain. Recent progress has changed our view of how these complexes are recruited, and how they affect chromatin and repress gene activity. Polycomb complexes function as global enforcers of epigenetically repressed states, balanced by an antagonistic state that is mediated by Trithorax. These epigenetic states must be reprogrammed when cells become committed to differentiation.

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Figure 1: How Polycomb group complexes regulate a homeotic gene.
Figure 2: Drosophila Polycomb group complexes.
Figure 3: Phylogenetic comparison of the bxd PRE of the Ubx gene from several Drosophila species.
Figure 4: PcG proteins at a typical genomic site.
Figure 5: Methylation of histone H3 by the PRE complexes.

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Correspondence to Vincenzo Pirrotta.

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Glossary

Segmentation gene

One of a group of genes that specify the segmental pattern within the anterior–posterior body axis of Drosophila melanogaster and other arthropods.

Gastrulation

A morphogenetic process in early embryogenesis, during which the endoderm, mesoderm and ectoderm germ layers are formed.

Position-effect variegation

A phenomenon that was discovered in Drosophila melanogaster, which occurs when genes that are placed close to large heterochromatic regions are repressed. Typically, silencing occurs stochastically in some cells and their clonal descendants.

Parasegment

Regions of the Drosophila melanogaster embryo that contain the posterior part of a hemisegment and the anterior part of its neighbour. They are patterned by segmentation genes. Mesodermal thickenings and ectodermal grooves demarcate parasegment borders.

Haltere

A balancing organ that is located on the third thoracic segment in Diptera and is an evolutionary modification of a wing.

Transvection

A phenomenon whereby homologous chromosomes are synapsed in somatic cells, and as a result some enhancers and/or silencers can function in trans.

Polytene chromosomes

Chromosomes in many larval tissues that have replicated repeatedly without cell division and without separating the daughter DNA molecules, which remain aligned with one another.

Vernalization

The mechanism that makes normal flowering dependent on the exposure of the plant to cold.

Chromatin immunoprecipitation

A technique that isolates sequences from soluble DNA chromatin extracts (complexes of DNA and protein) by using antibodies that recognize specific chromosomal proteins.

Tiling arrays

Microarrays containing evenly spaced genomic sequences representing the non-repetitive parts of the genome, often at high resolution.

Scanning force microscopy

A microscopy technique that works by detecting the vertical position of a probe, which is in physical contact with the sample, while horizontally moving the probe relative to the sample.

Chromatin insulators

Cis-acting DNA sequences that function as barriers to the effects of distal enhancers and silencers.

Epigenetic state

Chromatin state that can be inherited by progeny cells and dictates the functional competence of a gene.

Imaginal discs

An epithelial sheet that gives rise to external adult structures during insect metamorphosis, including the wings, eyes and antennae.

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Schwartz, Y., Pirrotta, V. Polycomb silencing mechanisms and the management of genomic programmes. Nat Rev Genet 8, 9–22 (2007). https://doi.org/10.1038/nrg1981

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