Programming of gene expression by Polycomb group proteins

doi:10.1016/j.tcb.2008.02.005

Trends in Cell Biology

Volume 18, Issue 5, May 2008, Pages 236-243

https://doi.org/10.1016/j.tcb.2008.02.005 Get rights and content

Polycomb group (PcG) complexes maintain epigenetically repressed states that need to be reprogrammed when cells become committed to differentiation. In contrast to the previously held belief that PcG complexes regulate only a few selected genes, recent efforts have revealed hundreds of potential PcG targets in mammals, insects and plants. These results have changed our perception about PcG recruitment and function on chromatin. Both in animals and plants, evolutionarily conserved PcG complexes mark the chromatin of their target genes by methylation at histone H3 lysine 27. Surprisingly, however, both the proteins recognizing this mark and the mechanisms causing gene repression differ between both kingdoms. This suggests that different developmental strategies used in plant and animal development entailed the evolution of different repressive maintenance mechanisms.

Introduction

Polycomb group (PcG) proteins were first discovered in the fruit fly Drosophila melanogaster. In Drosophila as well as in other organisms, the family of PcG proteins are required for the control of body segmentation by preventing inappropriate expression of homeotic (Hox) genes. Later work demonstrated that PcG proteins are master regulators of so-called genomic programs – owing to their ability to maintain genes in an active or repressed state, dependent on the differentiation status over many cell divisions [1]. It appears that, in any particular cell type, PcG proteins repress all alternative genetic programs that are not needed. Consequently, PcG proteins are required to maintain stem cell identity, and they do this by suppressing key regulators of differentiation pathways 2, 3, 4. In this review, we discuss recent progress in our understanding of PcG function by highlighting similarities and differences of PcG action in Drosophila, mammals and plants. Several aspects of PcG proteins will not be discussed in our review, because they have recently been covered by other reviews. These aspects include the role of PcG proteins in mammalian X chromosome inactivation [5] and in genomic imprinting 6, 7.

Section snippets

PcG complexes

PcG proteins assemble as high molecular weight complexes. They were initially purified from Drosophila, but homologous complexes were later isolated in other organisms (Table 1). Drosophila has three different PcG complexes – Polycomb repressive complex 1 (PRC1), Polycomb repressive complex 2 (PRC2) and Pleiohomeotic repressive complex (PhoRC). PRC2 is thought to be involved in the initiation of gene silencing, whereas PRC1 is implicated in the stable maintenance of gene repression [8]. The

Biological functions of PcG proteins

Although it was long suspected that PcG proteins regulate not only Hox genes but many more targets, only the recently applied combination of chromatin immunoprecipitation (ChIP) with microarray analysis (ChIP-on-Chip) revealed that PcG proteins are involved in all the main developmental pathways in flies and mammals [1]. They are likely to repress alternative genetic programs that are not needed in any particular cell type, and they are required to maintain stem cell identity by suppressing key

Recruitment of PcG proteins to their targets

To date, the question of how PcG proteins are targeted to chromatin is still unanswered, because neither PRC1 nor PRC2 core complexes contain sequence-specific DNA binding factors. The Drosophila Pho protein is the only PcG protein with DNA binding specificity and is able to recruit PRC2 in addition to PRC1 to target loci 24, 25. However, biochemically purified Pho complexes did not contain PRC1 or PRC2 subunits, and Pho wasn’t identified as a subunit of purified PRC1 or PRC2 15, 26, suggesting

Mechanisms of H3K27me3 deposition

The biochemical composition of PRC2 complexes is conserved between Drosophila and mammals, but the mechanisms of H3K27me3 deposition differ. In Drosophila, PRC2 components were found only at restricted chromosomal regions, whereas H3K27me3 covers large domains 31, 32. By contrast, mammalian PRC2 components were found throughout the entire regions covered by H3K27me3 3, 4. In plants, H3K27me3 regions span significant proportions of their target genes, with a significant bias towards the promoter

Silencing mechanisms of PcG proteins

Although our understanding of PcG function has greatly increased during recent years, the principal mechanism of how PcG proteins achieve transcriptional repression is still unknown. The Drosophila PRC1 core complex was shown to cause compaction of nucleosomes in vitro [35], but it is not clear whether these findings reflect the in vivo situation, because there is no strong evidence for chromatin compaction by PcG proteins in vivo. Also, the connection between PRC1-mediated mono-ubiquitination

Diversification of PRC1 function

Although the PRC1 subunit Pc contains a chromodomain that binds specifically to H3K27me3 50, 51, ChIP experiments revealed no close overlap between Pc localization and H3K27me3. The H3K27me3 distribution is significantly more extended than the localization of Pc, which is mainly restricted to PREs 31, 52. This suggests that PRC1 recruitment occurs by a still undefined mechanism. Quite unexpectedly, it was recently shown that the Arabidopsis chromodomain protein LIKE HETERCHROMATIN PROTEIN1

The role of trithorax group proteins in preventing PcG-mediated repression

Genetic analysis of trx mutants suggested that trxG proteins work antagonistically to PcG proteins, a hypothesis that was subsequently supported by the finding that PcG target genes are positively regulated by trxG proteins [11]. Similar observations were recently also made in plants. Mutants of the PcG gene CLF ectopically express the floral organ identity gene AG, form curled leaves and flower early [61]. By contrast, mutants of the Trx homolog ATX1 (ARABIDOPSIS TRITHORAX1) have reduced AG

Conclusions

Technologies to profile PcG proteins and histone modifications have dramatically changed our view on the action of PcG proteins during development. To obtain a comprehensive picture about the dynamics of PcG recruitment during development, chromatin and expression profiles of different developmental stages and organs need to be established and compared as a next step. Although profiling is of crucial importance, it will not on its own enable us to solve one of the most fundamental questions

Acknowledgements

We thank L. Hennig for helpful comments on the manuscript. This research was supported by the Swiss National Science Foundation (PP00A-106684/1) and ETH (TH-12 06–1) to C.K., who is also supported by a European Molecular Biology Organization (EMBO) Young Investigator Award.

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Citation Excerpt :
The DNA glycosylase (or demethylase) enzymes remove 5-methylcytosine from its targets through a base excision repair mechanism and replace it with an unmethylated cytosine (Gehring et al., 2006; Morales-Ruiz et al., 2006). In Arabidopsis, AtDME was originally characterized as an epigenetic regulator required for maternal allelelic expression of the MEDEA (MEA) gene, encoding a repressive H3K27 methyltransferase, in the central cell of the embryo and endosperm (Choi et al., 2002; Kohler & Villar, 2008). Proper embryo and endosperm development depends on the expression of the maternal allele and silencing of the paternal allele (imprinting) of certain components of the Polycomb group Repressive complex2 (PRC2).
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Trends in Cell Biology

ReviewProgramming of gene expression by Polycomb group proteins

Introduction

Section snippets

PcG complexes

Biological functions of PcG proteins

Recruitment of PcG proteins to their targets

Mechanisms of H3K27me3 deposition

Silencing mechanisms of PcG proteins

Diversification of PRC1 function

The role of trithorax group proteins in preventing PcG-mediated repression

Conclusions

Acknowledgements

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Curr. Opin. Cell Biol.

Opin. Genet. Dev.

Curr. Opin. Cell Biol.

Trends Cell Biol.

Polycomb silencing mechanisms and the management of genomic programmes

Nat. Rev. Genet.

Polycomb complexes repress developmental regulators in murine embryonic stem cells

Nature

Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions

Genes Dev.

Dosage compensation in mammals: fine-tuning the expression of the X chromosome

Genes Dev.

Epigenetic mechanisms governing seed development in plants

EMBO Rep.

A Drosophila Polycomb group complex includes Zeste and dTAFII proteins

Nature

General transcription factors bind promoters repressed by Polycomb group proteins

Nature

The core of the Polycomb repressive complex is compositionally and functionally conserved in flies and humans

Mol. Cell. Biol.

Pcl-PRC2 is needed to generate high levels of H3-K27 trimethylation at Polycomb target genes

EMBO J.

A Polycomb group protein complex with sequence-specific DNA-binding and selective methyl-lysine-binding activities

Genes Dev.

Transcription factor YY1 functions as a PcG protein in vivo

EMBO J.

The Polycomb-group gene EZH2 is required for early mouse development

Mol. Cell. Biol.

Interaction of Polycomb-group proteins controlling flowering in Arabidopsis

Development

Whole-genome analysis of histone h3 lysine 27 trimethylation in Arabidopsis

PLoS Biol.

Review
Programming of gene expression by Polycomb group proteins