The dynamic interactome and genomic targets of Polycomb complexes during stem cell differentiation

While the core subunits of Polycomb group (PcG) complexes are well characterized, little is known about the dynamics of these protein complexes during cellular differentiation. We used quantitative interaction proteomics and genome-wide profiling to study PcG proteins in mouse embryonic stem cells (ESCs) and neural progenitor cells (NPCs). We found the stoichiometry and genome-wide binding of PRC1 and PRC2 to be highly dynamic during neural differentiation. Intriguingly, we observed a downregulation and loss of PRC2 from H3K27me3-marked chromatin during differentiation, whereas PRC1 was retained at these sites. Additionally, we found PRC1 at enhancer and promoter regions independent of PRC2 binding and H3K27me3. Finally, overexpression of NPC-specific PRC1 interactors in ESCs led to increased Ring1b binding to and decreased expression of NPC-enriched Ring1b target genes. In summary, our integrative analyses have uncovered dynamic PcG subcomplexes and widespread co-localization with active chromatin marks during differentiation.