Tumour Suppression Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Cell Cycle. 2011 May 1;10(9):1488-98. doi: 10.4161/cc.10.9.15658.
Nanog levels in pluripotent stem cells are heterogeneous and this is thought to reflect two different and interchangeable cell states, respectively poised to self-renew (Nanog-high subpopulation) or to differentiate (Nanog-low subpopulation). However, little is known about the mechanisms responsible for this pattern of Nanog expression. Here, we have examined the impact of the histone methyltransferase Ezh2 on pluripotent stem cells and on Nanog expression. Interestingly, induced pluripotent stem (iPS) cells lacking Ezh2 presented higher levels of Nanog due to a relative expansion of the Nanog-high subpopulation, and this was associated to severe defects in differentiation. Moreover, we found that the Nanog promoter in embryonic stem (ES) cells and iPS cells coexists in two alternative univalent chromatin configurations, either H3K4me3 or H3K27me3, the latter being dependent on the presence of functional Ezh2. Finally, the levels of expression of Ezh2, as well as the amount of H3K27me3 present at the Nanog promoter, were higher in the Nanog-low subpopulation of ES/iPS cells. Together, these data indicate that Ezh2 directly regulates the epigenetic status of the Nanog promoter affecting the balance of Nanog expression in pluripotent stem cells and, therefore, the equilibrium between self-renewal and differentiation.
多能干细胞中的 Nanog 水平存在异质性，这被认为分别反映了两种不同且可互换的细胞状态，分别处于自我更新（Nanog-high 亚群）或分化（Nanog-low 亚群）的状态。然而，对于导致这种 Nanog 表达模式的机制知之甚少。在这里，我们研究了组蛋白甲基转移酶 Ezh2 对多能干细胞和 Nanog 表达的影响。有趣的是，由于 Nanog-high 亚群的相对扩张，缺乏 Ezh2 的诱导多能干细胞 (iPS) 呈现出更高水平的 Nanog，这与分化的严重缺陷有关。此外，我们发现胚胎干细胞 (ES) 细胞和 iPS 细胞中的 Nanog 启动子存在两种替代的单价染色质构型，要么是 H3K4me3，要么是 H3K27me3，后者依赖于功能齐全的 Ezh2 的存在。最后，Ezh2 的表达水平以及 Nanog 启动子上存在的 H3K27me3 量在 ES/iPS 细胞的 Nanog-low 亚群中更高。综上所述，这些数据表明 Ezh2 直接调节 Nanog 启动子的表观遗传状态，影响多能干细胞中 Nanog 表达的平衡，从而影响自我更新和分化之间的平衡。
