Dissecting mechanisms of mouse embryonic stem cells heterogeneity through a model-based analysis of transcription factor dynamics
Dissecting mechanisms of mouse embryonic stem cells heterogeneity through a model-based analysis of transcription factor dynamics
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DOI：
10.1098/rsif.2016.0167
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发表时间：
2016-04-01
影响因子：
3.9
通讯作者：
Roeder, Ingo
中科院分区：
文献类型：
--
作者：
Herberg, Maria;Glauche, Ingmar;Roeder, Ingo
多能小鼠胚胎干细胞（mESC）显示参与多能性调节的转录因子（TF）的异质表达水平，其中包括Nanog和Rex1。这两种TF的表达可以在高活性和低活性状态之间动态变化，与细胞的自我更新能力相关。基因表达的随机波动和持续振荡可能是解释这种行为的机制，但缺乏合适的数据阻碍了它们的明确区分。在这里，我们提出了一个系统生物学的方法，其中新的TF异质性的实验数据是由一个基于代理的mESC自我更新模型的补充。由于该模型考虑了细胞内相互作用、细胞分裂和遗传结构，因此可以评估所提出的机制与细胞分选后的群体增长和TF动力学数据的一致性。我们基于模型的分析表明，一个噪声驱动的网络模型满足最低要求，以一致地解释Nanog和Rex1在异质性和分选的mESC群体中的表达动态。此外，我们研究了TF相关的增殖能力对状态转换频率的影响，并证明细胞谱系可以提供对mESCs遗传结构的见解。
Pluripotent mouse embryonic stem cells (mESCs) show heterogeneous expression levels of transcription factors (TFs) involved in pluripotency regulation, among them Nanog and Rex1. The expression of both TFs can change dynamically between states of high and low activity, correlating with the cells' capacity for self-renewal. Stochastic fluctuations as well as sustained oscillations in gene expression are possible mechanisms to explain this behaviour, but the lack of suitable data hampered their clear distinction. Here, we present a systems biology approach in which novel experimental data on TF heterogeneity is complemented by an agent-based model of mESC self-renewal. Because the model accounts for intracellular interactions, cell divisions and heredity structures, it allows for evaluating the consistency of the proposed mechanisms with data on population growth and on TF dynamics after cell sorting. Our model-based analysis revealed that a bistable, noise-driven network model fulfils the minimal requirements to consistently explain Nanog and Rex1 expression dynamics in heterogeneous and sorted mESC populations. Moreover, we studied the impact of TF-related proliferation capacities on the frequency of state transitions and demonstrate that cellular genealogies can provide insights into the heredity structures of mESCs.