Stabilization of perturbed Boolean network attractors through compensatory interactions

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• 作者：Colin Campbell ; Réka Albert
• 关键词：Boolean networks ; Discrete dynamic models ; Signal transduction ; Stability ; Attractors ; Network manipulation ; Interaction modification ; T ; LGL leukemia ; Abscisic acid signaling
• 刊名：BMC Systems Biology
• 出版年：2014
• 出版时间：December 2014
• 年：2014
• 卷：8
• 期：1
• 全文大小：865 KB
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• 刊物主题：Bioinformatics; Systems Biology; Simulation and Modeling; Computational Biology/Bioinformatics; Physiological, Cellular and Medical Topics; Algorithms;
• 出版者：BioMed Central
• ISSN：1752-0509

文摘

Background Understanding and ameliorating the effects of network damage are of significant interest, due in part to the variety of applications in which network damage is relevant. For example, the effects of genetic mutations can cascade through within-cell signaling and regulatory networks and alter the behavior of cells, possibly leading to a wide variety of diseases. The typical approach to mitigating network perturbations is to consider the compensatory activation or deactivation of system components. Here, we propose a complementary approach wherein interactions are instead modified to alter key regulatory functions and prevent the network damage from triggering a deregulatory cascade. Results We implement this approach in a Boolean dynamic framework, which has been shown to effectively model the behavior of biological regulatory and signaling networks. We show that the method can stabilize any single state (e.g., fixed point attractors or time-averaged representations of multi-state attractors) to be an attractor of the repaired network. We show that the approach is minimalistic in that few modifications are required to provide stability to a chosen attractor and specific in that interventions do not have undesired effects on the attractor. We apply the approach to random Boolean networks, and further show that the method can in some cases successfully repair synchronous limit cycles. We also apply the methodology to case studies from drought-induced signaling in plants and T-LGL leukemia and find that it is successful in both stabilizing desired behavior and in eliminating undesired outcomes. Code is made freely available through the software package BooleanNet. Conclusions The methodology introduced in this report offers a complementary way to manipulating node expression levels. A comprehensive approach to evaluating network manipulation should take an "all of the above" perspective; we anticipate that theoretical studies of interaction modification, coupled with empirical advances, will ultimately provide researchers with greater flexibility in influencing system behavior.