Variant PRC1 complex-dependent H2A ubiquitylation drives PRC2 recruitment and polycomb domain formation.
Bottom Line: Chromatin modifying activities inherent to polycomb repressive complexes PRC1 and PRC2 play an essential role in gene regulation, cellular differentiation, and development.Here, using a de novo targeting assay in mouse embryonic stem cells we unexpectedly discover that PRC1-dependent H2AK119ub1 leads to recruitment of PRC2 and H3K27me3 to effectively initiate a polycomb domain.This activity is restricted to variant PRC1 complexes, and genetic ablation experiments reveal that targeting of the variant PCGF1/PRC1 complex by KDM2B to CpG islands is required for normal polycomb domain formation and mouse development.
Affiliation: Laboratory of Chromatin Biology and Transcription, Department of Biochemistry, University of Oxford, Oxford, OX1 3QU, UK.Show MeSH
Mentions: Molecular and functional characterization of the polycomb repressive complexes has revealed that they do not function independently (Bracken et al., 2006; Ku et al., 2008; Papp and Müller, 2006; Schwartz et al., 2006). Instead, H3K27me3 placed by PRC2 is recognized by PRC1 complexes that contain chromobox (CBX) proteins (Cao et al., 2002; Min et al., 2003; Wang et al., 2004b). Based on these initial observations, the prevailing view over the past decade has been that PRC1 is recruited in a hierarchical manner to sites with pre-existing PRC2 activity and H3K27me3. However, it has recently emerged that CBX proteins are in direct competition with two additional factors, RYBP/YAF2, for a mutually exclusive binding site on RING1A/B (Wang et al., 2010). Significantly, H3K27me3-binding CBX proteins are limited to canonical PRC1 complexes containing either PCGF2 (MEL18) or PCGF4 (BMI1) and the Polyhomeotic proteins (PHC1/2/3) (Gao et al., 2012; Levine et al., 2002), while all PCGF proteins interact with RYBP/YAF2 to form variant PRC1 complexes lacking CBX proteins (Farcas et al., 2012; Gao et al., 2012; Gearhart et al., 2006; Lagarou et al., 2008; Sánchez et al., 2007; Tavares et al., 2012) (Figure 1A). The identification of variant PRC1 complexes and the observation that RING1B can occupy many of its target sites in the absence of H3K27me3 suggests that the hierarchical recruitment mechanism cannot explain all PRC1 complex targeting (Schoeftner et al., 2006; Tavares et al., 2012). Therefore, the central principles that underpin recognition of polycomb target sites in vivo and the molecular chain of events that leads to the formation of polycomb domains integrating both PRC1 and PRC2 activity remain unclear.
Affiliation: Laboratory of Chromatin Biology and Transcription, Department of Biochemistry, University of Oxford, Oxford, OX1 3QU, UK.