Sriram K, Bernot G, Képès F
Epigenomics Project, 523, Place des Terrasses de 1' Agora, Tour Evry 2, Genopole, Evry, 91000 France.
IET Syst Biol. 2007 Nov;1(6):326-41. doi: 10.1049/iet-syb:20070018.
A novel topology of regulatory networks abstracted from the budding yeast cell cycle is studied by constructing a simple nonlinear model. A ternary positive feedback loop with only positive regulations is constructed with elements that activates the subsequent element in a clockwise fashion. A ternary negative feedback loop with only negative regulations is constructed with the elements that inhibit the subsequent element in an anticlockwise fashion. Positive feedback loop exhibits bistability, whereas the negative feedback loop exhibits limit cycle oscillations. The novelty of the topology is that the corresponding elements in these two homogeneous feedback loops are linked by the binary positive feedback loops with only positive regulations. This results in the emergence of mixed feedback loops in the network that displays complex behaviour like the coexistence of multiple steady states, relaxation oscillations and chaos. Importantly, the arrangement of the feedback loops brings in the notion of checkpoint in the model. The model also exhibits domino-like behaviour, where the limit cycle oscillations take place in a stepwise fashion. As the aforementioned topology is abstracted from the budding yeast cell cycle, the events that govern the cell cycle are considered for the present study. In budding yeast, the sequential activation of the transcription factors, cyclins and their inhibitors form mixed feedback loops. The transcription factors that involve in the positive regulation in a clockwise orientation generates ternary positive feedback loop, while the cyclins and their inhibitors that involve in the negative regulation in an anticlockwise orientation generates ternary negative feedback loop. The mutual regulation between the corresponding elements in the transcription factors and the cyclins and their inhibitors generates binary positive feedback loops. The bifurcation diagram constructed for the whole system can be related to the different events of the cell cycle in terms of dynamical system theory. The checkpoint mechanism that plays an important role in different phases of the cell cycle are accounted for by silencing appropriate feedback loops in the model.
通过构建一个简单的非线性模型，研究了从芽殖酵母细胞周期中抽象出来的调控网络的一种新型拓扑结构。构建了一个仅具有正调控的三元正反馈环，其元件以顺时针方式激活后续元件。构建了一个仅具有负调控的三元负反馈环，其元件以逆时针方式抑制后续元件。正反馈环表现出双稳性，而负反馈环表现出极限环振荡。这种拓扑结构的新颖之处在于，这两个同构反馈环中的相应元件通过仅具有正调控的二元正反馈环相连。这导致网络中出现混合反馈环，表现出复杂行为，如多个稳态共存、弛豫振荡和混沌。重要的是，反馈环的排列在模型中引入了检查点的概念。该模型还表现出多米诺骨牌式行为，其中极限环振荡以逐步方式发生。由于上述拓扑结构是从芽殖酵母细胞周期中抽象出来的，本研究考虑了控制细胞周期的事件。在芽殖酵母中，转录因子、细胞周期蛋白及其抑制剂的顺序激活形成混合反馈环。以顺时针方向参与正调控的转录因子产生三元正反馈环，而以逆时针方向参与负调控的细胞周期蛋白及其抑制剂产生三元负反馈环。转录因子与细胞周期蛋白及其抑制剂中相应元件之间的相互调控产生二元正反馈环。根据动力系统理论，为整个系统构建的分岔图可以与细胞周期的不同事件相关联。在细胞周期不同阶段起重要作用的检查点机制通过在模型中沉默适当的反馈环来体现。
