Biochemical mechanisms of gene regulation by polycomb group protein complexes

https://doi.org/10.1016/j.gde.2009.03.001Get rights and content

Polycomb group (PcG) proteins are transcriptional repressors that control expression of developmental regulator genes in animals and plants. Recent advances in our understanding of the PcG system include biochemical purifications that revealed a substantial variety in PcG complex composition. These different complexes contain distinct chromatin-modifying activities and engage in cross-talk with other chromatin modifications. Complementing these biochemical analyses, structural studies have begun to provide insight into how PcG proteins interact with each other and with chromatin. Finally, genome-wide binding profiling and the ensuing functional analysis of target gene regulation revealed that the PcG system is not only used for the permanent silencing of developmental regulator genes. Rather, PcG mediated repression also constitutes a mechanism for dynamic control of gene transcription.

Introduction

The conserved Polycomb group (PcG) proteins perform crucial regulatory functions in development, stem cell biology, and cancer. Genetic studies in Drosophila originally identified the PcG as a set of genes that are required for the long-term repression of HOX genes during development [1]. Plant PcG proteins act as regulators in a variety of processes, including the long-term repression of the Flowering Locus C (FLC) gene following vernalization [2]. Epigenetic processes have been defined as mechanisms of regulation that provide a heritable state of gene activity that neither involves alterations in DNA sequence nor the continuous presence of the initiating signal [3]. Because PcG proteins maintain HOX gene silencing at developmental stages when the initiating repressors are no longer present, and FLC silencing long after cold-induced repression was established PcG proteins are often referred to as ‘epigenetic’ regulators. However, this classification can be confusing when it takes on a mechanistic meaning and is interpreted to imply a static association of proteins with chromatin or irreversibility of a gene activity state. Recent studies provide evidence that the PcG system is not only used to permanently shut down target genes but that it also confers dynamic control of gene transcription.

PcG function is closely associated with the modulation of chromatin structure and covalent post-translational modifications of histones. Repression by PcG proteins is counteracted by trithorax group (trxG) regulators that also act through the modification of chromatin. Recent reviews discuss the enzymes and mechanisms responsible for adding or removing histone modifications and how they promote binding of specific proteins [4, 5, 6, 7]. The general functions of PcG and trxG proteins have been well covered in a number of comprehensive reviews [1, 8, 9]. Here, we will therefore limit our discussion mainly on new insights into the biochemical mechanisms underpinning gene control by PcG protein complexes. Because of space restrictions, the main focus will be on Drososphila where the core PcG system is most compact and best studied. The discussion will be extended in cases where work in mammalian cells has provided additional mechanistic insight.

Section snippets

PhoRC and genome-wide PcG complex targeting

In Drosophila, PcG protein complexes assemble at specific cis-regulatory DNA sequences called Polycomb response elements (PREs) (reviewed in [9]). Previous studies at HOX gene PREs showed that Pho and Pho-like, the only two PcG proteins containing sequence-specific DNA-binding activity, are required for anchoring the PcG protein complexes PRC1 and PRC2 at PRE DNA [9, 10, 11, 12, 13]. Pho is not a component of either PRC1 or PRC2 but exists in a distinct complex called PhoRC, comprising Pho and

Structural studies of PcG proteins

Recent structural studies have started to provide insight into how PcG proteins interact with each other and with chromatin. Several of these studies also provided important biophysical data on these interactions. Because of space restrictions, we have to limit the discussion of these findings to a table listing the PcG protein structures that have been solved to date (Table 1). Despite the shortness of this section, it is clear that the information provided by these, and hopefully, more

Gene regulation beyond permanent repression

Genome-wide binding profiling of PcG proteins in mouse, human and Drosophila cell lines [16, 67, 68, 69, 70, 71] and in developing Drosophila [14••, 15••, 72] identified a large set of potential target genes. Several studies have begun to explore whether and how expression of these genes is regulated by the PcG system [15••, 67, 72]. Many developmental regulators identified as PRC1 and PRC2 targets were found to be upregulated in ES cells lacking the PRC2 component EED [67]. Reassuringly, in

Concluding remarks and perspectives

Over the past few years, our understanding of the PcG system has expanded considerably. With respect to the mechanism of transcriptional control by PcG protein complexes, it has become clear that these complexes act in a combinatorial and interdependent fashion to generate a PcG-repressed chromatin state at target genes. This is partly achieved by the different enzymatic activities of PcG protein complexes that generate a distinct histone modification pattern at target chromatin. In addition,

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

This is not a comprehensive review and we apologize to those authors whose works we did not discuss. JM is supported by EMBL and by grants from the Deutsche Forschungsgemeinschaft, CPV is supported by grants from the Dutch Cancer Society KWF (EMCR2006-3583) and the Dutch government (BSIK 03038, SCDD).

References (81)

  • Y. Mito et al.

    Histone replacement marks the boundaries of cis-regulatory domains

    Science

    (2007)
  • G. Ficz et al.

    Polycomb group protein complexes exchange rapidly in living Drosophila

    Development

    (2005)
  • J.W. Tamkun et al.

    brahma: a regulator of Drosophila homeotic genes structurally related to the yeast transcriptional activator SNF2/SWI2

    Cell

    (1992)
  • R. Cao et al.

    Role of hPHF1 in H3K27 methylation and Hox gene silencing

    Mol Cell Biol

    (2008)
  • K. Sarma et al.

    Ezh2 requires PHF1 to efficiently catalyze H3 lysine 27 trimethylation in vivo

    Mol Cell Biol

    (2008)
  • A. Ebert et al.

    Su(var) genes regulate the balance between euchromatin and heterochromatin in Drosophila

    Genes Dev

    (2004)
  • M. Nekrasov et al.

    Nucleosome binding and histone methyltransferase activity of Drosophila PRC2

    EMBO Rep

    (2005)
  • L. Wang et al.

    Alternative ESC and ESC-like subunits of a polycomb group histone methyltransferase complex are differentially deployed during Drosophila development

    Mol Cell Biol

    (2006)
  • B. Tolhuis et al.

    Genome-wide profiling of PRC1 and PRC2 Polycomb chromatin binding in Drosophila melanogaster

    Nat Genet

    (2006)
  • W. Fischle et al.

    Molecular basis for the discrimination of repressive methyl-lysine marks in histone H3 by Polycomb and HP1 chromodomains

    Genes Dev

    (2003)
  • Z. Li et al.

    Structure of a Bmi-1-Ring1B polycomb group ubiquitin ligase complex

    J Biol Chem

    (2006)
  • Y.B. Schwartz et al.

    Polycomb silencing mechanisms and the management of genomic programmes

    Nat Rev Genet

    (2007)
  • S.L. Berger

    The complex language of chromatin regulation during transcription

    Nature

    (2007)
  • S.R. Bhaumik et al.

    Covalent modifications of histones during development and disease pathogenesis

    Nat Struct Mol Biol

    (2007)
  • A.J. Ruthenburg et al.

    Multivalent engagement of chromatin modifications by linked binding modules

    Nat Rev Mol Cell Biol

    (2007)
  • A. Mohd-Sarip et al.

    Synergistic recognition of an epigenetic DNA element by Pleiohomeotic and a Polycomb core complex

    Genes Dev

    (2005)
  • T. Klymenko et al.

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

    Genes Dev

    (2006)
  • C. Kwong et al.

    Stability and dynamics of polycomb target sites in Drosophila development

    PLoS Genet

    (2008)
  • K. Oktaba et al.

    Dynamic regulation by polycomb group protein complexes controls pattern formation and the cell cycle in Drosophila

    Dev Cell

    (2008)
  • C. Beisel et al.

    Comparing active and repressed expression states of genes controlled by the Polycomb/Trithorax group proteins

    Proc Natl Acad Sci U S A

    (2007)
  • Z. Shao et al.

    Stabilization of chromatin structure by PRC1, a Polycomb complex

    Cell

    (1999)
  • S.S. Levine et al.

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

    Mol Cell Biol

    (2002)
  • G. Buchwald et al.

    Structure and E3-ligase activity of the Ring-Ring complex of polycomb proteins Bmi1 and Ring1b

    EMBO J

    (2006)
  • A. Lagarou et al.

    dKDM2 couples histone H2A ubiquitylation to histone H3 demethylation during Polycomb group silencing

    Genes Dev

    (2008)
  • O. Bell et al.

    Localized H3K36 methylation states define histone H4K16 acetylation during transcriptional elongation in Drosophila

    EMBO J

    (2007)
  • Y. Tanaka et al.

    Trithorax-group protein ASH1 methylates histone H3 lysine 36

    Gene

    (2007)
  • T. Klymenko et al.

    The histone methyltransferases Trithorax and Ash-1 prevent transcriptional silencing by Polycomb group proteins

    EMBO Rep

    (2004)
  • B. Papp et al.

    Histone tri-methylation and the maintenance of transcriptional ON and OFF states by trxG and PcG proteins

    Genes Dev

    (2006)
  • J.K. Stock et al.

    Ring1-mediated ubiquitination of H2A restrains poised RNA polymerase II at bivalent genes in mouse ES cells

    Nat Cell Biol

    (2007)
  • G.I. Dellino et al.

    Polycomb silencing blocks transcription initiation

    Mol Cell

    (2004)
  • Cited by (0)

    View full text