Biochemical mechanisms of gene regulation by polycomb group protein complexes
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).
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