Histone modification cross-talk and protein complex diversification confer plasticity to Polycomb repression

Polycomb chromatin domains are chromosomal regions decorated with histone H2A monoubiquitination at lysine 119 (H2Aub1) and histone H3 trimethylation at lysine 27 (H3K27me3). These domains are dynamically shaped through the actions of different Polycomb group protein complexes to control gene expression during development. To assess how different Polycomb group subcomplexes contribute to these histone modification profiles in <i>Drosophila</i> embryos, we used mutants that abrogate their function. Canonical Polycomb repressive complex (PRC) 1 deposits low levels of H2Aub1 solely at Polycomb target genes, whereas variant PRC1 generates the bulk of H2Aub1 genome-wide. In late-stage embryos, PR-DUB-mediated deubiquitination effectuates a uniform low-level H2Aub1 profile across the genome. The combined activities of PRC2.1 and PRC2.2 drive the formation and maintenance of most H3K27me3 domains, but PRC2.1 is the limiting enzyme for creating such domains at HOX genes. Surprisingly, reduction in the H3K27me3 level and repression defects caused by removing PRC2.1 were largely rescued in animals also lacking PR-DUB, which showed extensive H2Aub1 accumulation at Polycomb targets that promoted compensatory H3K27me3 deposition by PRC2.2. Diversification of Polycomb protein complexes combined with feedback loop mechanisms involving histone modification cross-talk equips the system with the plasticity, adaptability, and buffering capacity needed to safeguard cell fate decisions during development.