Deterministic Restriction on Pluripotent State Dissolution by Cell-Cycle Pathways
Deterministic Restriction on Pluripotent State Dissolution by Cell-Cycle Pathways
复制标题
DOI：
10.1016/j.cell.2015.07.001
复制
发表时间：
2015-07-30
期刊：
影响因子：
64.5
通讯作者：
Ng, Huck-Hui
中科院分区：
文献类型：
--
作者：
Gonzales, Kevin Andrew Uy;Liang, Hongqing;Ng, Huck-Hui
在分化过程中，人类胚胎干细胞(HESCs)关闭了赋予多能性的调控网络，我们称之为多潜能状态溶解(PSD)。在使用一组包含的分化条件的高通量RNAi筛选中，我们识别了调节hESCs中PSD的中心重要和上下文相关的过程，包括组蛋白乙酰化、染色质重塑、RNA剪接和信号通路。值得注意的是，我们检测到与DNA复制和G2期进展有关的细胞周期基因的强烈和特异的丰富。遗传和化学微扰研究表明，S和G2期具有减弱PSD的作用，因为它们具有独立于G1期的多能态的内在倾向。因此，我们的数据从功能上建立了多能性控制与细胞周期机制的硬连接，在细胞周期机制中，S和G2期特定的通路确定地限制了PSD，而在G1期缺乏这样的通路可能允许分化的启动。
During differentiation, human embryonic stem cells (hESCs) shut down the regulatory network conferring pluripotency in a process we designated pluripotent state dissolution (PSD). In a high-throughput RNAi screen using an inclusive set of differentiation conditions, we identify centrally important and context-dependent processes regulating PSD in hESCs, including histone acetylation, chromatin remodeling, RNA splicing, and signaling pathways. Strikingly, we detected a strong and specific enrichment of cell-cycle genes involved in DNA replication and G2 phase progression. Genetic and chemical perturbation studies demonstrate that the S and G2 phases attenuate PSD because they possess an intrinsic propensity toward the pluripotent state that is independent of G1 phase. Our data therefore functionally establish that pluripotency control is hardwired to the cell-cycle machinery, where S and G2 phase-specific pathways deterministically restrict PSD, whereas the absence of such pathways in G1 phase potentially permits the initiation of differentiation.