EPIGENETIC MECHANISMS OF POLYCOMB REPRESSIVE COMPLEX 1 IN INTESTINAL LINEAGE COMMITMENT

Polycomb group proteins are key transcriptional repressive complexes involved in cell fate decisions during development and cell identity maintenance during homeostasis (1). Polycomb group proteins primarily assemble into two different complexes: Polycomb repressive complex 2 (PRC2) with the catalytic subunit EZH1/2 which can mono, di, and tri- methylase the histone H3 at lysine 27 (H3K27); and Polycomb Repressive Complex 1 (PRC1) with the catalytic subunits RING1A/B, which catalyze the monoubiquitylation of histone H2A at lysine 119 (H2AK119) (1,2). In PRC1, the RING1A/B subunits form a core heterodimer with one of the 6 mutually exclusive PCGF (1-6) proteins, thus creating six subcomplexes (PRC1.1 – PRC1.6). Simply put, PRC1 subcomplexes can be divided into canonical PRC1 (PRC1.2 and PRC1.4) and variant PRC1 (PRC1.1, PRC1.3, PRC1.5 and PRC1.6) (1,2). Polycomb Repressive Complexes are essential for the transcriptional repression of developmental genes, such as germ-line related genes in embryonic stem cells (ESCs) (3). During intestinal homeostasis, chromatin modifiers play important roles in maintaining transcriptional signatures of specific cell types. Our group has already demonstrated that RING1A/B are necessary to maintain normal tissue homeostasis by preservation of the WNT/B-catenin activity (4). However, the contribution of PCGFs in adult intestinal homeostasis is unclear. To address this, we evaluated the role of six different PRC1 subcomplexes in transcriptional repression maintenance in intestinal cells by using several inducible PCGFs knockout mouse models. Our data suggest that the lack of single PCGF proteins does not alter intestinal homeostasis due to the compensatory effects of PRC1 subcomplexes in chromatin binding and in transcriptional repression maintenance. In fact, we observed that PRC1.1, PRC1.2 and PRC1.4 share binding sites on chromatin in intestinal cells. The simultaneous depletion of PCGF1, PCGF2, PCGF4 affects not only RING1b binding, but also its activity and H2AK119ub deposition. This leads to a transcriptional de-repression in adult intestinal cells, and so to a disrupted intestinal homeostasis. Interestingly, we observed that the Tuft cell number increases remarkably following PCGF6-deletion. Tuft or Brush cells are a very rare cell population with chemosensory activity in the intestinal epithelium (5). However, the Tuft cell differentiation program is under investigation.