The Potential Landscape of Genetic Circuits Imposes the Arrow of Time in Stem Cell Differentiation
The Potential Landscape of Genetic Circuits Imposes the Arrow of Time in Stem Cell Differentiation
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遗传电路的潜在景观决定了干细胞分化的时间之箭
DOI：
10.1016/j.bpj.2010.03.058
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发表时间：
2010-07-07
影响因子：
3.4
通讯作者：
Huang, Sui
中科院分区：
文献类型：
--
作者：
Wang, Jin;Xu, Li;Huang, Sui
从多能干细胞或祖细胞状态分化为成熟细胞基本上是不可逆的过程。基因表达模式的相关变化表现出时间方向性。跨多个稳定基因表达模式（吸引子）的基因表达集体变化中的这种“时间箭头”不能用双向分子过程的单个基因的调节激活和抑制来解释，也不能用仅解释吸引子局部稳定性的基础基因回路的标准动态模型来解释。为了捕捉这种非平衡系统的全局动态并深入了解状态转换的时间不对称性，我们计算了控制分支细胞命运承诺的规范基因回路的随机动态的准势图。电位景观揭示了全局动态，并允许计算电路架构所施加的细胞表型之间的电位势垒。势垒高度的一般不对称性表明从未提交的多能状态到分化状态的转变本质上是单向的。该模型与观察结果一致，并预测了将细胞重编程回未分化状态的极端条件。
Differentiation from a multipotent stem or progenitor state to a mature cell is an essentially irreversible process. The associated changes in gene expression patterns exhibit time-directionality. This "arrow of time" in the collective change of gene expression across multiple stable gene expression patterns (attractors) is not explained by the regulated activation, the suppression of individual genes which are bidirectional molecular processes, or by the standard dynamical models of the underlying gene circuit which only account for local stability of attractors. To capture the global dynamics of this nonequilibrium system and gain insight in the time-asymmetry of state transitions, we computed the quasipotential landscape of the stochastic dynamics of a canonical gene circuit that governs branching cell fate commitment. The potential landscape reveals the global dynamics and permits the calculation of potential barriers between cell phenotypes imposed by the circuit architecture. The generic asymmetry of barrier heights indicates that the transition from the uncommitted multipotent state to differentiated states is inherently unidirectional. The model agrees with observations and predicts the extreme conditions for reprogramming cells back to the undifferentiated state.