SKP1A-mediated degradation of PRC2 triggers activation of Polycomb-silenced genes

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.

多梳蛋白家族（Polycomb group, PcG）是进化保守的发育基因抑制因子。矛盾的是，同一PcG蛋白还可通过尚未完全阐明的机制参与基因激活。本研究发现，S期激酶相关蛋白1A（SKP1A, S-phase kinase-associated protein 1A）——作为SCF（SKP1A/CULLIN1/F-box）泛素连接酶的必需因子，同时也是多梳抑制复合体1（PCGF1-PRC1）中PCGF1（多梳家族环指蛋白1, Polycomb group RING finger protein 1）组分的亚基——介导了PcG依赖的基因调控与泛素依赖的蛋白酶体降解之间的联系。通过分化中的小鼠胚胎干细胞实验，我们发现SKP1A可通过蛋白酶体降解途径，清除结合于PcG靶基因启动子区域的多梳抑制复合体2（PRC2, Polycomb repressive complex 2）核心组分EED（胚胎外胚层发育蛋白, Embryonic Ectoderm Development），从而赋予这些基因后续激活的敏感性。此外，我们证实SKP1A可在发育中小鼠胚胎的中脑内，从Meis2基因的启动子区域清除EED，进而启动Meis2基因的表达。综上，本研究揭示了SKP1A此前未被报道的功能：通过介导PRC2的蛋白酶体降解来激活PcG靶基因。这表明含有SKP1A的PCGF1-PRC1可使PcG介导的基因沉默具备可逆性，从而实现靶基因的稳健时空调控。