Functional Landscape of PCGF Proteins Reveals Both RING1A/B Dependent and Independent Specific Activities

Polycomb repressive complexes 1 and 2 (PRC1 and PCR2) control cell identity by establishing facultative heterochromatin repressive domains at common sets of target genes. PRC1, which deposits H2Aub1 through the E3 ligases RING1A/B, forms six biochemically distinct subcomplexes containing one type of PCGF protein (PCGF1–6); it is unclear whether these subcomplexes also have specific activities. Here we show that PCGF1 and PCGF2 largely compensate for each other, but that the other PCGF proteins have high levels of specificity for distinct target genes, with little functional crosstalk. PCGF2 associates with transcription repression, while PCGF3 and PCGF6 associate with actively transcribed genes. Notably, PCGF3 and PCGF6 complexes can assembly and be recruited to several active sites independently of RING1A/B activity (therefore, of PRC1). For chromatin recruitment, the PCGF6 complex requires the combinatorial activities of its MGA-MAX and E2F6-DP1 subunits, while PCGF3 requires an interaction with the USF1 DNA binding transcription factor. Overall design: RNA-seq and ChIP-seq with different genotypes of E14 cells