Polycomb Group (PcG) proteins are pivotal for the specification and maintenance of cell identity by preventing inappropriate gene activation. They function mostly through the regulation of chromatin structure and, in particular, the post-translational modification of histones. Although the enzymatic activities of the main PcG complexes has been described, lots remain to be discovered in terms of how these chromatin modifying activities are regulated. Genome wide analysis uncovered genes that are targeted by PcG proteins in various model cell lines, however it still very unclear how PcG proteins are targeted to a specific set of genes depending on the cell type. Finally, PcG proteins are frequently fund deregulated in diseases among which cancer but whether the alteration of their expression is a causative event to pathologies requires further investigation.This proposal is focused on the Polycomb Repressive Complex 2 (PRC2) whose function is pivotal to the polycomb machinery. In the first two aims of this proposal, we will investigate mechanistically how transcription factors, non-coding RNAs and chromatin structure might independently or in conjunction establish the conditions conducive to gene targeting by PRC2 and regulate its activity. In the third and fourth aims of this proposal, we will investigate what is the function of PRC2 during tumorigenesis and cell reprogramming and how its function is regulated during these processes.