Maintenance of Transcriptional Repression by Polycomb Proteins

Raphaël Margueron

Raphaël Margueron Chef d'équipe Tel:

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.

Figure 1 : Représentation schématique des boucles réglementaires touchant H3K27me3 et Jarid2 - K116me3 dans la régulation de l'activité enzymatique PRC2 (de Sanulli et al 2015) .
Figure 1: Schematic representation of the regulatory loops involving H3K27me3 and Jarid2-K116me3 in the regulation of PRC2 enzymatic activity (from Sanulli et al. 2015)

 

The polycomb machinery maintains gene silencing throughout development. Consequently, interfering with its function alters various biological processes such as differentiation, cell identity or proliferation. How are the different Polycomb complexes orchestrated to maintain transcriptional repression and how are those complexes targeted to specific loci remain open questions.

The PRC2 complex is a key player of the polycomb machinery responsible for the methylation of histone H3 on lysine 27 (H3K27me3). We previously reported that the presence of H3K27me3 on the chromatin promotes the enzymatic activity of PRC2 and that this mechanism could be important for the spreading of this mark (figure 1). Our recent results reveal that Jarid2 is also a substrate of PRC2 capable of modulating PRC2 enzymatic activity (figure 1). Using various approaches based on biochemistry and genetic screen, we are further investigating what controls PRC2 and other polycomb complexes function.

Figure 2: Immunohistochemistry showing the expression of Ezh2 and PCNA in mouse prostate of animal either wild type (WT) or developing a cancer consequently to the expression of an oncogene (HM).
Figure 2: Immunohistochemistry showing the expression of Ezh2 and PCNA in mouse prostate of animal either wild type (WT) or developing a cancer consequently to the expression of an oncogene (HM).

 

Components of the polycomb machinery are often found altered in diseases among which cancer. Yet, components of the polycomb machinery were reported to act both as tumor suppressor and oncogene. What is the contribution of alterations of the polycomb machinery to cancer progression? What are the classes of genes affected by the alteration of the polycomb machinery? How is transcription affected? Does is creates a sensitivity to specific inhibitors? We are investigating these questions using genome wide analysis, mouse models and cell biology (Figure 2).

Key publications

Year of publication 2015

Serena Sanulli, Neil Justin, Aurélie Teissandier, Katia Ancelin, Manuela Portoso, Matthieu Caron, Audrey Michaud, Berangère Lombard, Simao T da Rocha, John Offer, Damarys Loew, Nicolas Servant, Michel Wassef, Fabienne Burlina, Steve J Gamblin, Edith Heard, Raphaël Margueron (2015 Mar 5)

Jarid2 Methylation via the PRC2 Complex Regulates H3K27me3 Deposition during Cell Differentiation.

Molecular cell : 769-83 : DOI : 10.1016/j.molcel.2014.12.020

Year of publication 2014

Steven Zuryn, Arnaud Ahier, Manuela Portoso, Esther Redhouse White, Marie-Charlotte Morin, Raphaël Margueron, Sophie Jarriault (2014 Aug 16)

Transdifferentiation. Sequential histone-modifying activities determine the robustness of transdifferentiation.

Science (New York, N.Y.) : 826-9 : DOI : 10.1126/science.1255885

Year of publication 2013

Simão Teixeira da Rocha, Valentina Boeva, Martin Escamilla-Del-Arenal, Katia Ancelin, Camille Granier, Neuza Reis Matias, Serena Sanulli, Jen Chow, Edda Schulz, Christel Picard, Syuzo Kaneko, Kristian Helin, Danny Reinberg, A Francis Stewart, Anton Wutz, Raphaël Margueron, Edith Heard (2013 Nov 4)

Jarid2 Is Implicated in the Initial Xist-Induced Targeting of PRC2 to the Inactive X Chromosome.

Molecular cell : 301-16 : DOI : 10.1016/j.molcel.2014.01.002

Year of publication 2012

Monica Rolando, Serena Sanulli, Christophe Rusniok, Laura Gomez-Valero, Clement Bertholet, Tobias Sahr, Raphael Margueron, Carmen Buchrieser (2012 Dec 10)

Legionella pneumophila effector RomA uniquely modifies host chromatin to repress gene expression and promote intracellular bacterial replication.

Cell host & microbe : 395-405 : DOI : 10.1016/j.chom.2013.03.004
Philipp Tropberger, Sebastian Pott, Claudia Keller, Kinga Kamieniarz-Gdula, Matthieu Caron, Florian Richter, Guohong Li, Gerhard Mittler, Edison T Liu, Marc Bühler, Raphael Margueron, Robert Schneider (2012 Apr 4)

Regulation of transcription through acetylation of H3K122 on the lateral surface of the histone octamer.

Cell : 859-72 : DOI : 10.1016/j.cell.2013.01.032
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