PREMORRIT · The Polycomb Repression Complex 2 (PRC2): Mechanisms of recruitment and role in tumorigenesis

A key to development is the maintenance of various cell identities. Despite identical genome sequence, in a defined organism, cells from different origins will have distinct pattern of gene expression. The chromatin structure plays a pivotal role in the regulation of gene expression and contributes to this so-called ""epigenetic information"". Different parameters defined the chromatin structure among which DNA methylation, histone variant incorporation and histone post-translational modifications (PTMs).Polycomb Group proteins (PcG) were identified in Drosophila by mutations that result in segmental transformation and are known to be required for proper development in mammals. It was shown that PcG proteins maintain the repressed state of genes throughout development partly by regulating the chromatin structure. The PcG multi-proteins complex, PRC2, is responsible for the methylation of the lysine 27 on the histone H3. This PTM is supposed to contribute to the recruitment of other PcG proteins that altogether maintain gene repression. How is the PRC2 complex targeted to genes in a cell specific manner? What are the factors required? What is the contribution of non-coding RNA? We will try to answer these questions in the first aim of this proposal.The tumorigenic progression of cells is associated to major rearrangements of chromatin. Not surprisingly, several PcG proteins were found deregulated in cancer. Hence, the PRC2 component Ezh2 is upregulated in many kinds of cancers including prostate and breast cancers. Following the first studies analyzing the function of Ezh2 mostly in cancer cells, it was proposed that Ezh2 could be classified as an oncogene. However recent publications as well as our unpublished results indicate that the function of Ezh2 in tumorigenesis might be more versatile. Using in vivo approaches and focusing on prostate cancer, we will investigate this question.""