Home › Research groups › Mechanisms of Repression by Polycomb Proteins

Mechanisms of Repression by Polycomb Proteins

Imprimer la page

-A +A
Group leader : R. Margueron
Mechanisms of Repression by Polycomb Proteins

Keywords

Polycomb, Chromatin, Biochemistry, Methylation, Cancer

Plain english

Polycomb Group Proteins maintain gene silencing throughout development and adulthood by interfering with chromatin structure. Depending on the cell type, distinct sets of genes get targeted by these proteins. How is this cell specificity established and maintained, what happen when the machinery gets awry are the main questions that we are investigating.

 

 

Polycomb Group (PcG) proteins maintain the pattern of gene expression of different cells set early during development by regulating chromatin structure. Consequently interfering with PcG proteins expression affects various biological processes such as differentiation, proliferation or maintenance of pluripotency. In addition, PcG genes are found deregulated in various pathologies including cancer.

Chromatin structure is defined by several parameters such as combination of histone post-translational marks, nucleosome occupancy, DNA methylation or incorporation of histone variants. Chromatin structure contributes to the epigenetic regulation of gene expression, DNA replication or DNA repair. The polycomb complex PRC2 maintains gene silencing throughout development and is responsible for the di- and tri- methylation of histone H3 lysine 27 (figure 1). This post-translational mark is associated to parts of the genome that are either weakly transcribed or silent.

Considering its importance in modulating various biological processes, the PRC2 complex is tightly regulated. Hence, it has been shown that in addition to its four core components, the PRC2 complex comprises additional cofactors (Jarid2, Pcl, AEBP2) that are required for its functioning. PRC2 components are also subjected to post-translational modifications. Finally, long non-coding RNAs interact with PRC2. How all those regulatory cues (figure 2) come together to orchestrate the activity of PRC2 remains unclear.

The PRC2 component, Ezh2, was found to be upregulated in advanced stages of prostate and breast cancer (Figure 3). Furthermore, its level of expression is correlated to poor outcome. In contrast, somatic mutations interfering with the enzymatic activity of Ezh2 were reported in subtypes of lymphoma. Hence, both upregulation and inactivation of Ezh2 could have deleterious consequences. How modulating Ezh2 interferes with the tumorigenic process? Is PRC2 deregulation a leading event in this process? ...

fig 1:Schematic representation of chromatin structurefig 1:Schematic representation of chromatin structure

Fig2. Schematic representation of pathways regulating PRC2.Fig2. Schematic representation of pathways regulating PRC2.

Fig 3:Ezh2 and PCNA expression in a mouse model of prostate cancer based on the overexpression c-myc (HM)Fig 3:Ezh2 and PCNA expression in a mouse model of prostate cancer based on the overexpression c-myc (HM)

Key publications

  • Year of publication : 2011

  • Raphaël Margueron, Danny Reinberg (2011 Jan 20) The Polycomb complex PRC2 and its mark in life.

    Nature, 469(7330): 343-9
    Polycomb group proteins maintain the gene-expression pattern of different cells that is set during early development by regulating chromatin structure. In mammals, two main Polycomb group complexes exist - Polycomb repressive complex 1 (PRC1) and 2 (PRC2). PRC1 compacts chromatin and catalyses the monoubiquitylation of histone H2A. PRC2 also contributes to chromatin compaction, and catalyses the methylation of histone H3 at lysine 27. PRC2 is involved in various biological processes, including differentiation, maintaining cell identity and proliferation, and stem-cell plasticity. Recent studies of PRC2 have expanded our perspectives on its function and regulation, and uncovered a role for non-coding RNA in the recruitment of PRC2 to target genes.
    Read more

  • Year of publication : 2009

  • Raphael Margueron, Neil Justin, Katsuhito Ohno, Miriam Sharpe, Jinsook Son, William Drury, Philipp Voigt, Stephen Martin, William Taylor, Valeria De Marco, Vincenzo Pirrotta, Danny Reinberg, Steven Gamblin (2009 Oct 8) Role of the polycomb protein EED in the propagation of repressive histone marks.

    Nature, 461(7265): 762-7
    Polycomb group proteins have an essential role in the epigenetic maintenance of repressive chromatin states. The gene-silencing activity of the Polycomb repressive complex 2 (PRC2) depends on its ability to trimethylate lysine 27 of histone H3 (H3K27) by the catalytic SET domain of the EZH2 subunit, and at least two other subunits of the complex: SUZ12 and EED. Here we show that the carboxy-terminal domain of EED specifically binds to histone tails carrying trimethyl-lysine residues associated with repressive chromatin marks, and that this leads to the allosteric activation of the methyltransferase activity of PRC2. Mutations in EED that prevent it from recognizing repressive trimethyl-lysine marks abolish the activation of PRC2 in vitro and, in Drosophila, reduce global methylation and disrupt development. These findings suggest a model for the propagation of the H3K27me3 mark that accounts for the maintenance of repressive chromatin domains and for the transmission of a histone modification from mother to daughter cells.
    Read more

  • Year of publication : 2008

  • Raphael Margueron, Guohong Li, Kavitha Sarma, Alexandre Blais, Jiri Zavadil, Christopher Woodcock, Brian Dynlacht, Danny Reinberg (2008 Nov 21) Ezh1 and Ezh2 maintain repressive chromatin through different mechanisms.

    Molecular cell, 32(4): 503-18
    Polycomb group proteins are critical to maintaining gene repression established during Drosophila development. Part of this group forms the PRC2 complex containing Ez that catalyzes di- and trimethylation of histone H3 lysine 27 (H3K37me2/3), marks repressive to transcription. We report that the mammalian homologs Ezh1 and Ezh2 form similar PRC2 complexes but exhibit contrasting repressive roles. While PRC2-Ezh2 catalyzes H3K27me2/3 and its knockdown affects global H3K27me2/3 levels, PRC2-Ezh1 performs this function weakly. In accordance, Ezh1 knockdown was ineffectual on global H3K27me2/3 levels. Instead, PRC2-Ezh1 directly and robustly represses transcription from chromatinized templates and compacts chromatin in the absence of the methyltransferase cofactor SAM, as evidenced by electron microscopy. Ezh1 targets a subset of Ezh2 genes, yet Ezh1 is more abundant in nonproliferative adult organs while Ezh2 expression is tightly associated with proliferation, as evidenced when analyzing aging mouse kidney. These results might reflect subfunctionalization of a PcG protein during evolution.
    Read more