A general model for binary cell fate decision gene circuits with degeneracy: indeterminacy and switch behavior in the absence of cooperativity.
A general model for binary cell fate decision gene circuits with degeneracy: indeterminacy and switch behavior in the absence of cooperativity.
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DOI：
10.1371/journal.pone.0019358
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Huang S
中科院分区：
文献类型：
--
作者：
Andrecut M;Halley JD;Winkler DA;Huang S
决定命运的两个相反转录因子相互抑制但又相互激活的基因调控电路基序已被用于多能干细胞或祖细胞的二元细胞命运决定的数学模型。这个简单的电路可以产生多稳定性，并解释了对称的“稳定的”前体状态，其中两个因子在细胞中以相等的量存在，以及当细胞致力于以两个因子的不对称表达模式为特征的细胞命运时这种不确定状态的解决。这建立了代表两个命运选项的两个可选稳定吸引子。关于分子相互作用的协作性是否有必要产生这样的多重稳定性，一直存在争论。在这里，我们采用一般的建模方法，并认为这个问题不相关。我们表明，在两个不同的模型中可以出现非线性，其中没有假设两个因素之间的显式相互作用，并且不同的化学反应动力学形式可以导致相同的(一般的)动力学系统形式。此外，我们描述了一种新型的分支，它产生简并的稳定状态，可以解释细胞命运决策之前的不确定性亚稳态，并与生物学观察一致。因此，这里提出的通用模型提供了一种新的原理，用于将调节电路与多潜能(干细胞)细胞的不确定性特征联系起来。
The gene regulatory circuit motif in which two opposing fate-determining transcription factors inhibit each other but activate themselves has been used in mathematical models of binary cell fate decisions in multipotent stem or progenitor cells. This simple circuit can generate multistability and explains the symmetric “poised” precursor state in which both factors are present in the cell at equal amounts as well as the resolution of this indeterminate state as the cell commits to either cell fate characterized by an asymmetric expression pattern of the two factors. This establishes the two alternative stable attractors that represent the two fate options. It has been debated whether cooperativity of molecular interactions is necessary to produce such multistability. Here we take a general modeling approach and argue that this question is not relevant. We show that non-linearity can arise in two distinct models in which no explicit interaction between the two factors is assumed and that distinct chemical reaction kinetic formalisms can lead to the same (generic) dynamical system form. Moreover, we describe a novel type of bifurcation that produces a degenerate steady state that can explain the metastable state of indeterminacy prior to cell fate decision-making and is consistent with biological observations. The general model presented here thus offers a novel principle for linking regulatory circuits with the state of indeterminacy characteristic of multipotent (stem) cells.
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