Systems-level dynamic analyses of fate change in murine embryonic stem cells.
Systems-level dynamic analyses of fate change in murine embryonic stem cells.
复制标题
作者：
胚胎干细胞（ESC）命运的分子调控涉及表观遗传、转录和翻译机制之间的协调相互作用。目前尚不清楚这些不同的分子调控机制如何相互作用来调节干细胞命运的变化。在这里，我们提出了一个动态的系统水平的研究细胞命运的变化在小鼠ESCs定义良好的扰动后。在下调Nanog（一种关键的多能性调节因子）后的5天内，研究人员测量了组蛋白乙酰化、染色质结合RNA聚合酶II、信使RNA （mRNA）和核蛋白水平的全球变化。我们的数据展示了单个遗传扰动如何导致几个分子调控层的渐进式广泛变化，并提供了表观基因组、转录组和蛋白质组信息流的动态视图。我们观察到，很大一部分核蛋白水平的变化并不伴随着相应mrna表达的一致变化，这表明在ESC命运的翻译和翻译后调控中起重要作用。跨不同分子层的基因本体论分析表明，尽管染色质重构对改变细胞命运很重要，但它之前是转录因子介导的调控事件。基因表达变化的时间顺序显示了调控网络重构的顺序，为进一步了解基因调控网络提供了依据。我们的研究扩展了传统的系统生物学方法，包括许多分子物种、调控层和时间序列，并强调了决定干细胞命运的蛋白质表达变化的多层调控机制的复杂性。
Molecular regulation of embryonic stem cell (ESC) fate involves a coordinated interaction between epigenetic, transcriptional and translational mechanisms. It is unclear how these different molecular regulatory mechanisms interact to regulate changes in stem cell fate. Here we present a dynamic systems-level study of cell fate change in murine ESCs following a well-defined perturbation. Global changes in histone acetylation, chromatin-bound RNA polymerase II, messenger RNA (mRNA), and nuclear protein levels were measured over 5 days after downregulation of Nanog, a key pluripotency regulator. Our data demonstrate how a single genetic perturbation leads to progressive widespread changes in several molecular regulatory layers, and provide a dynamic view of information flow in the epigenome, transcriptome and proteome. We observe that a large proportion of changes in nuclear protein levels are not accompanied by concordant changes in the expression of corresponding mRNAs, indicating important roles for translational and post-translational regulation of ESC fate. Gene-ontology analysis across different molecular layers indicates that although chromatin reconfiguration is important for altering cell fate, it is preceded by transcription-factor-mediated regulatory events. The temporal order of gene expression alterations shows the order of the regulatory network reconfiguration and offers further insight into the gene regulatory network. Our studies extend the conventional systems biology approach to include many molecular species, regulatory layers and temporal series, and underscore the complexity of the multilayer regulatory mechanisms responsible for changes in protein expression that determine stem cell fate.
登录
查看更多内容
影响因子：
4.3
作者：
Airoldi EM
通讯作者：
Airoldi EM
影响因子：
4.4
作者：
Liu CL;Schreiber SL;Bernstein BE
通讯作者：
Bernstein BE
影响因子：
64.5
作者：
Mitsui, K;Tokuzawa, Y;Yamanaka, S
通讯作者：
Yamanaka, S
影响因子：
5.8
作者：
Eichler, GS;Huang, S;Ingber, DE
通讯作者：
Ingber, DE
影响因子：
64.5
作者：
Kim, Jonghwan;Chu, Jianlin;Orkin, Stuart H.
通讯作者：
Orkin, Stuart H.