Edgetic perturbations to eliminate fixed-point attractors in Boolean regulatory networks
Edgetic perturbations to eliminate fixed-point attractors in Boolean regulatory networks
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DOI：
10.1063/1.5083060
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发表时间：
2019-02-01
期刊：
影响因子：
2.9
通讯作者：
Albert, Reka
中科院分区：
文献类型：
--
作者：
Campbell, Colin;Albert, Reka
复杂生物网络的动态可以在布尔框架中建模，其中每个系统组件的状态要么是丰富（ON），要么是稀缺/缺失（OFF），每个组件的动态轨迹由涉及其调节器状态的逻辑更新规则决定。在所谓的扩展图的拓扑结构中编码更新规则是可能的，对扩展图的分析揭示了网络的长期行为或吸引子。在这里，我们开发了一种算法来扰动扩展图（或等价地，逻辑更新规则）以消除稳定的主题：导致组件子集稳定到一种状态的子图。根据扩展图的拓扑，这些扰动导致相应吸引子的修改或损失。虽然文献中大多数生物调控网络的扰动涉及一个或多个节点的敲除（固定为OFF）或本构激活（固定为ON），但我们在这里考虑边缘扰动，其中节点的更新规则被修改，使其一个或多个调节器被视为ON或OFF，而不管其实际状态如何。我们将该方法应用于两个生物网络。在代表T-LGL白血病的网络中，我们确定了消除癌变吸引子的边缘扰动，只留下代表细胞死亡的健康吸引子。在一个代表干旱引起的植物气孔关闭的网络中，我们确定了改变单个吸引子的边缘扰动，使得气孔不是固定在关闭状态，而是在打开和关闭状态之间振荡。(c) 2019作者。除另有说明外，所有文章内容均遵循知识共享署名（CC BY）许可协议（http://creativecommons.org/licenses/by/4.0/）。
The dynamics of complex biological networks may be modeled in a Boolean framework, where the state of each system component is either abundant (ON) or scarce/absent (OFF), and each component's dynamic trajectory is determined by a logical update rule involving the state(s) of its regulator(s). It is possible to encode the update rules in the topology of the so-called expanded graph, analysis of which reveals the long-term behavior, or attractors, of the network. Here, we develop an algorithm to perturb the expanded graph (or, equivalently, the logical update rules) to eliminate stable motifs: subgraphs that cause a subset of components to stabilize to one state. Depending on the topology of the expanded graph, these perturbations lead to the modification or loss of the corresponding attractor. While most perturbations of biological regulatory networks in the literature involve the knockout (fixing to OFF) or constitutive activation (fixing to ON) of one or more nodes, we here consider edgetic perturbations, where a node's update rule ismodified such that one ormore of its regulators is viewed as ON or OFF regardless of its actual state. We apply the methodology to two biological networks. In a network representing T-LGL leukemia, we identify edgetic perturbations that eliminate the cancerous attractor, leaving only the healthy attractor representing cell death. In a network representing drought-induced closure of plant stomata, we identify edgetic perturbations that modify the single attractor such that stomata, instead of being fixed in the closed state, oscillates between the open and closed states. (c) 2019 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).