O12. Polycomb-dependent regulation for differentiation programs of stem cells and progenitors

Abstract

To clarify the molecular mechanisms linking two distinct Polycomb complexes, PRC1 and PRC2, and their biological outcomes, we examined the genome-wide distributions of PRC1 components and the PRC1-catalyzed histone modification, mono-ubiquitinated H2A (H2Aub1), in embryonic stem cells (ESCs). We also integrated data for PRC2 components and the PRC2-catalyzed modification, trimethylated H3K27 (H3K27me3). H2Aub1 localizes to silent developmental gene promoters, nearly all of which are also enriched for PRC1 and PRC2. H2Aub1 deposition and PRC1 localization are shown to depend on two parallel pathways. The first pathway is PRC2-dependent and involves recognition of H3K27me3 by Cbx2 in PRC1. The second is independent of PRC2 and instead depends on the catalytic activity of Ring1B at key PRC1 target genes. The catalytic activity of Ring1B promotes the expression of Mel18 and Bmi1, which in turn help bring PRC1 to the chromatin and concurrently enhance its catalytic activity to ubiquitinate H2A. We propose that these two mechanisms complement each other to deposit PRC1 and H2Aub1 at critical differentiation genes in ESCs and mediate stable and reversible repression in response to subsequent induction of developmental programs.