Maintenance of Transcriptional Repression by Polycomb Proteins

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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 2017

Manuela Portoso, Roberta Ragazzini, Živa Brenčič, Arianna Moiani, Audrey Michaud, Ivaylo Vassilev, Michel Wassef, Nicolas Servant, Bruno Sargueil, Raphaël Margueron (2017 Feb 8)

PRC2 is dispensable for HOTAIR-mediated transcriptional repression.

The EMBO journal : DOI : e201695335

Year of publication 2016

Marie Schoumacher, Stéphanie Le Corre, Alexandre Houy, Eskeatnaf Mulugeta, Marc-Henri Stern, Sergio Roman-Roman, Raphaël Margueron (2016 Jun 9)

Uveal melanoma cells are resistant to EZH2 inhibition regardless of BAP1 status.

Nature medicine : 577-8 : DOI : 10.1038/nm.4098

Year of publication 2015

Wassef M1, Rodilla V1, Teissandier A2, Zeitouni B2, Gruel N3, Sadacca B3, Irondelle M3, Charruel M1, Ducos B4, Michaud A1, Caron M1, Marangoni E3, Chavrier P3, Le Tourneau C5, Kamal M6, Pasmant E7, Vidaud M7, Servant N2, Reyal F3, Meseure D8, Vincent-Salomon A3, Fre S1, Margueron R1. (2015 Dec 4)

Impaired PRC2 activity promotes transcriptional instability and favors breast tumorigenesis.

Genes & DevelopmentImpaired PRC2 activity promotes transcriptional instability and favors breast tumorigenesis. : DOI : 10.1101/gad.269522.115
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
All publications