Gene perturbation and intervention in context-sensitive stochastic Boolean networks

BMC Systems Biology

Jie Han¹  Jinghang Liang¹  Peican Zhu¹ 

[1] Department of Electrical and Computer Engineering, University of Alberta, Edmonton, AB, Canada

关键词: glioma network;    p53 network;    Steady state distribution;    Context switch;    Intervention;    Gene perturbation;    Context dependent;    Stochastic Boolean networks;    Boolean networks;    Gene regulatory networks;   

Others  :  866361
DOI  :  10.1186/1752-0509-8-60

 received in 2013-02-11, accepted in 2014-04-22,  发布年份 2014

【 摘 要 】

Background

In a gene regulatory network (GRN), gene expressions are affected by noise, and stochastic fluctuations exist in the interactions among genes. These stochastic interactions are context dependent, thus it becomes important to consider noise in a context-sensitive manner in a network model. As a logical model, context-sensitive probabilistic Boolean networks (CSPBNs) account for molecular and genetic noise in the temporal context of gene functions. In a CSPBN with n genes and k contexts, however, a computational complexity of O(nk²2²ⁿ) (or O(nk2ⁿ)) is required for an accurate (or approximate) computation of the state transition matrix (STM) of the size (2ⁿ ∙ k) × (2ⁿ ∙ k) (or 2ⁿ × 2ⁿ). The evaluation of a steady state distribution (SSD) is more challenging. Recently, stochastic Boolean networks (SBNs) have been proposed as an efficient implementation of an instantaneous PBN.

Results

The notion of stochastic Boolean networks (SBNs) is extended for the general model of PBNs, i.e., CSPBNs. This yields a novel structure of context-sensitive SBNs (CSSBNs) for modeling the stochasticity in a GRN. A CSSBN enables an efficient simulation of a CSPBN with a complexity of O(nLk2ⁿ) for computing the state transition matrix, where L is a factor related to the required sequence length in CSSBN for achieving a desired accuracy. A time-frame expanded CSSBN can further efficiently simulate the stationary behavior of a CSPBN and allow for a tunable tradeoff between accuracy and efficiency. The CSSBN approach is more efficient than an analytical method and more accurate than an approximate analysis.

Conclusions

Context-sensitive stochastic Boolean networks (CSSBNs) are proposed as an efficient approach to modeling the effects of gene perturbation and intervention in gene regulatory networks. A CSSBN analysis provides biologically meaningful insights into the oscillatory dynamics of the p53-Mdm2 network in a context-switching environment. It is shown that random gene perturbation has a greater effect on the final distribution of the steady state of a network compared to context switching activities. The CSSBN approach can further predict the steady state distribution of a glioma network under gene intervention. Ultimately, this will help drug discovery and develop effective drug intervention strategies.

【 授权许可】

   
2014 Zhu et al.; licensee BioMed Central Ltd.

【 图 表 】

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