ROLE OF THE POLYCOMB GROUP PROTEINS IN THE ADULT INTESTINAL STEM CELLS HOMEOSTASIS

Polycomb group proteins (PcG) are among the most important gatekeepers that ensure the correct establishment and maintenance of cellular identity in metazoans. This occurs by modifying chromatin through the activity of two Polycomb Repressive Complexes (PRC1 and PRC2) that deposit H2A ubiquitylation and H3K27 methylation respectively, in order to guarantee repression of their target genes. Although the development of PRC2 inhibitory compounds is becoming a very promising strategy for specific cancer treatment, the controversial role of PcG proteins, acting as oncogenes or tumor suppressors in a tissue/cancer specific manner, prompt us to further investigate the role PcG proteins in regulating adult tissue homeostasis. Using different genetic models, we have found that PRC1 activity is required for the integrity of the mouse intestinal epithelia. More in detail, PRC1 activity is required for the self-renewal of the intestinal stem cells (ISCs) via a cell-autonomous mechanism that is independent of Ink4a-Arf expression. Using high-throughput transcription and location analysis, we have dissected the direct transcriptional pathways regulated by PRC1 in ISC showing that PRC1 inactivation induces a loss of ISC identity as a result of a massive up-regulation of non-lineage specific transcription factors that can directly inhibit the transcriptional activity of the ß-Catenin/Tcf4 complex. Overall, we propose that PRC1 control the self-renewal of ISC by positively sustaining Wnt transcriptional activity also in the presence of oncogenic mutations that constitutively activate the Wnt pathway in intestinal tumors.