SKP1A-mediated degradation of PRC2 triggers activation of Polycomb-silenced genes : CUT&Tag 1

Polycomb group (PcG) proteins are evolutionarily conserved repressors of developmental genes. Paradoxically, the same PcG proteins also play roles in gene activation via mechanisms that are not yet fully understood. Here, we found that S-phase kinase-associated protein 1A (SKP1A), an essential factor of SCF (SKP1A/CULLIN1/F-box) ubiquitin ligases and a subunit of the PCGF1 (Polycomb group RING finger protein 1) component of Polycomb repressive complex 1 (PCGF1-PRC1), mediates the link between PcG-dependent gene regulation and ubiquitin-dependent proteasomal degradation. By using differentiating mouse embryonic stem cells, we found that SKP1A removes EED, a core component of Polycomb repressive complex 2 (PRC2) that is bound to PcG target gene promoters, via proteasomal degradation, and it thereby sensitises these genes for subsequent activation. Furthermore, we show that SKP1A removes EED from the Meis2 promoter in the midbrain of developing mouse embryos, leading to Meis2 gene expression. In summary, we reveal here a previously unknown role of SKP1A in activating PcG-target genes via the proteasomal degradation of PRC2. This implies that SKP1A-containing PCGF1-PRC1 may confer reversibility on PcG-mediated gene silencing for robust spatiotemporal regulation of target genes.