Gene networks of fully connected triads with complete auto-activation enable multistability and stepwise stochastic transitions.
Gene networks of fully connected triads with complete auto-activation enable multistability and stepwise stochastic transitions.
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DOI：
10.1371/journal.pone.0102873
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Wang X
中科院分区：
文献类型：
--
作者：
Faucon PC;Pardee K;Kumar RM;Li H;Loh YH;Wang X
全连接三联体（fct），如Oct4-Sox2-Nanog三联体，被认为是嵌入在指定和维持细胞状态的调控网络中的反复出现的转录基序。为了探索FCT拓扑结构与细胞命运决定之间可能的联系，我们使用计算网络筛选来搜索所有可能的FCT拓扑结构的多稳定性，这是一种动态特性，允许从相同的转录网络中出现替代调节状态。搜索得到了具有不同多稳定性潜力的fct的层次结构，包括能够达到八种不同稳定状态的几种拓扑结构。我们的分析表明，完全自激活是多稳定性的有效指标，并且，当基因表达噪声纳入模型时，网络能够自发地传输多个状态。研究发现，不同程度的随机性会诱导或破坏随机状态转换，有些转换需要在一个或多个中间状态停留。利用这个框架，我们通过包含本构过表达项来模拟一个简化的诱导多能性模型。相应的FCT显示了从终端态到多能态的随机状态转变，这种转变的时间分布与已发表的实验数据相匹配。这项工作建立了一个潜在的理论框架，通过连接保守的调控模块与网络动力学来理解细胞命运的决定。我们的研究结果也可以用于实验，使用已建立的发育转录因子作为种子，通过使用自动激活作为密码来定位细胞谱系规范网络。
Fully-connected triads (FCTs), such as the Oct4-Sox2-Nanog triad, have been implicated as recurring transcriptional motifs embedded within the regulatory networks that specify and maintain cellular states. To explore the possible connections between FCT topologies and cell fate determinations, we employed computational network screening to search all possible FCT topologies for multistability, a dynamic property that allows the rise of alternate regulatory states from the same transcriptional network. The search yielded a hierarchy of FCTs with various potentials for multistability, including several topologies capable of reaching eight distinct stable states. Our analyses suggested that complete auto-activation is an effective indicator for multistability, and, when gene expression noise was incorporated into the model, the networks were able to transit multiple states spontaneously. Different levels of stochasticity were found to either induce or disrupt random state transitioning with some transitions requiring layovers at one or more intermediate states. Using this framework we simulated a simplified model of induced pluripotency by including constitutive overexpression terms. The corresponding FCT showed random state transitioning from a terminal state to the pluripotent state, with the temporal distribution of this transition matching published experimental data. This work establishes a potential theoretical framework for understanding cell fate determinations by connecting conserved regulatory modules with network dynamics. Our results could also be employed experimentally, using established developmental transcription factors as seeds, to locate cell lineage specification networks by using auto-activation as a cipher.
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