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建模揭示了决定血液干细胞命运的网络模块中的双稳定性和低通滤波。

Modeling reveals bistability and low-pass filtering in the network module determining blood stem cell fate.

机构信息

Department of Bioengineering, Rice University, Houston, Texas, USA.

出版信息

PLoS Comput Biol. 2010 May 6;6(5):e1000771. doi: 10.1371/journal.pcbi.1000771.

Abstract

Combinatorial regulation of gene expression is ubiquitous in eukaryotes with multiple inputs converging on regulatory control elements. The dynamic properties of these elements determine the functionality of genetic networks regulating differentiation and development. Here we propose a method to quantitatively characterize the regulatory output of distant enhancers with a biophysical approach that recursively determines free energies of protein-protein and protein-DNA interactions from experimental analysis of transcriptional reporter libraries. We apply this method to model the Scl-Gata2-Fli1 triad-a network module important for cell fate specification of hematopoietic stem cells. We show that this triad module is inherently bistable with irreversible transitions in response to physiologically relevant signals such as Notch, Bmp4 and Gata1 and we use the model to predict the sensitivity of the network to mutations. We also show that the triad acts as a low-pass filter by switching between steady states only in response to signals that persist for longer than a minimum duration threshold. We have found that the auto-regulation loops connecting the slow-degrading Scl to Gata2 and Fli1 are crucial for this low-pass filtering property. Taken together our analysis not only reveals new insights into hematopoietic stem cell regulatory network functionality but also provides a novel and widely applicable strategy to incorporate experimental measurements into dynamical network models.

摘要

组合调控基因表达在真核生物中普遍存在,多个输入汇聚到调控控制元件上。这些元件的动态特性决定了调节分化和发育的遗传网络的功能。在这里,我们提出了一种定量描述远距离增强子调控输出的方法,该方法采用一种生物物理方法,从转录报告基因文库的实验分析中递归确定蛋白质-蛋白质和蛋白质-DNA 相互作用的自由能。我们应用这种方法来模拟 Scl-Gata2-Fli1 三聚体-一个对造血干细胞细胞命运特化很重要的网络模块。我们表明,这个三聚体模块本质上是双稳态的,对生理相关信号(如 Notch、Bmp4 和 Gata1)的响应具有不可逆的转变,我们使用该模型来预测网络对突变的敏感性。我们还表明,该三聚体仅在响应持续时间超过最小持续时间阈值的信号时,通过在稳定状态之间切换来充当低通滤波器。我们发现,将缓慢降解的 Scl 连接到 Gata2 和 Fli1 的自动调节环对于这种低通滤波特性至关重要。总之,我们的分析不仅揭示了造血干细胞调控网络功能的新见解,还为将实验测量纳入动态网络模型提供了一种新颖且广泛适用的策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d843/2865510/2a905fff7b27/pcbi.1000771.g001.jpg

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