State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, China.
Biophys J. 2010 Jul 7;99(1):29-39. doi: 10.1016/j.bpj.2010.03.058.
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.
从多能干细胞或祖细胞状态分化为成熟细胞是一个本质上不可逆的过程。基因表达模式的相关变化表现出时间方向性。这种在多个稳定基因表达模式（吸引子）中基因表达集体变化的“时间箭头”，不能用受调控的激活来解释，也不能用基础基因电路的双向分子过程的单个基因的抑制来解释，因为这些只考虑了吸引子的局部稳定性的标准动力学模型。为了捕捉这个非平衡系统的全局动力学，并深入了解状态转变的时间不对称性，我们计算了一个规范基因电路的随机动力学的准势能景观，该电路控制着分支细胞命运的决定。势景观揭示了全局动力学，并允许计算由电路结构施加的细胞表型之间的势垒。势垒高度的通用不对称性表明，从未分化的多能状态向分化状态的转变本质上是单向的。该模型与观察结果一致，并预测了将细胞重新编程回未分化状态的极端条件。
