Center for Genomic Regulation (CRG) and UPF, 08003, Barcelona, Spain.
Cell Stem Cell. 2011 Sep 2;9(3):233-46. doi: 10.1016/j.stem.2011.07.013.
Human epidermal stem cells transit from a slow cycling to an actively proliferating state to contribute to homeostasis. Both stem cell states differ in their cell cycle profiles but must remain guarded from differentiation and senescence. Here we show that Cbx4, a Polycomb Repressive Complex 1 (PRC1)-associated protein, maintains human epidermal stem cells as slow-cycling and undifferentiated, while protecting them from senescence. Interestingly, abrogating the polycomb activity of Cbx4 impairs its antisenescent function without affecting stem cell differentiation, indicating that differentiation and senescence are independent processes in human epidermis. Conversely, Cbx4 inhibits stem cell activation and differentiation through its SUMO ligase activity. Global transcriptome and chromatin occupancy analyses indicate that Cbx4 regulates modulators of epidermal homeostasis and represses factors such as Ezh2, Dnmt1, and Bmi1 to prevent the active stem cell state. Our results suggest that distinct Polycomb complexes balance epidermal stem cell dormancy and activation, while continually preventing senescence and differentiation.
人类表皮干细胞从缓慢循环到活跃增殖状态，以维持内稳态。这两种干细胞状态在细胞周期特征上存在差异，但必须防止其分化和衰老。本文研究表明，多梳抑制复合物 1（PRC1）相关蛋白 Cbx4 将人类表皮干细胞维持在缓慢循环和未分化状态，同时防止其衰老。有趣的是，消除 Cbx4 的多梳活性会损害其抗衰老功能，而不影响干细胞分化，表明分化和衰老在人类表皮中是独立的过程。相反，Cbx4 通过其 SUMO 连接酶活性抑制干细胞的激活和分化。全转录组和染色质占据分析表明，Cbx4 调节表皮内稳态的调节剂，并抑制 Ezh2、Dnmt1 和 Bmi1 等因子，以防止干细胞的激活状态。我们的研究结果表明，不同的多梳复合物平衡表皮干细胞的休眠和激活，同时持续防止衰老和分化。
