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 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.
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).