Dataset Information

Inverse perturbation for optimal intervention in gene regulatory networks.

ABSTRACT:

Motivation

Analysis and intervention in the dynamics of gene regulatory networks is at the heart of emerging efforts in the development of modern treatment of numerous ailments including cancer. The ultimate goal is to develop methods to intervene in the function of living organisms in order to drive cells away from a malignant state into a benign form. A serious limitation of much of the previous work in cancer network analysis is the use of external control, which requires intervention at each time step, for an indefinite time interval. This is in sharp contrast to the proposed approach, which relies on the solution of an inverse perturbation problem to introduce a one-time intervention in the structure of regulatory networks. This isolated intervention transforms the steady-state distribution of the dynamic system to the desired steady-state distribution.

Results

We formulate the optimal intervention problem in gene regulatory networks as a minimal perturbation of the network in order to force it to converge to a desired steady-state distribution of gene regulation. We cast optimal intervention in gene regulation as a convex optimization problem, thus providing a globally optimal solution which can be efficiently computed using standard toolboxes for convex optimization. The criteria adopted for optimality is chosen to minimize potential adverse effects as a consequence of the intervention strategy. We consider a perturbation that minimizes (i) the overall energy of change between the original and controlled networks and (ii) the time needed to reach the desired steady-state distribution of gene regulation. Furthermore, we show that there is an inherent trade-off between minimizing the energy of the perturbation and the convergence rate to the desired distribution. We apply the proposed control to the human melanoma gene regulatory network.

Availability

The MATLAB code for optimal intervention in gene regulatory networks can be found online: http://syen.ualr.edu/nxbouaynaya/Bioinformatics2010.html.

SUBMITTER: Bouaynaya N

PROVIDER: S-EPMC3008638 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Publications

Inverse perturbation for optimal intervention in gene regulatory networks.

Bouaynaya Nidhal N Shterenberg Roman R Schonfeld Dan D

Bioinformatics (Oxford, England) 20101108 1

<h4>Motivation</h4>Analysis and intervention in the dynamics of gene regulatory networks is at the heart of emerging efforts in the development of modern treatment of numerous ailments including cancer. The ultimate goal is to develop methods to intervene in the function of living organisms in order to drive cells away from a malignant state into a benign form. A serious limitation of much of the previous work in cancer network analysis is the use of external control, which requires intervention ...[more]

PMID: 21062762

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Project description: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.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.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.

Project description:Most studies of gene regulatory network (GRN) inference have focused extensively on identifying the interaction map of the GRNs. However, in order to predict the cellular behavior, modeling the GRN in terms of logic circuits, i.e., Boolean networks, is necessary. The perturbation techniques, e.g., knock-down and over-expression, should be utilized for identifying the underlying logic behind the interactions. However, we will show that by using only transcriptomic data obtained by single-perturbation experiments, we cannot observe all regulatory interactions, and this invisibility causes ambiguity in our model. Consequently, we need to employ the data of multiple omics layers (genome, transcriptome, and proteome) as well as multiple perturbation experiments to reduce or eliminate ambiguity in our modeling. In this paper, we introduce a multi-step perturbation experiment to deal with ambiguity. Moreover, we perform a thorough analysis to investigate which types of perturbations and omics layers play the most important role in the unambiguous modeling of the GRNs and how much ambiguity will be eliminated by considering more perturbations and more omics layers. Our analysis shows that performing both knock-down and over-expression is necessary in order to achieve the least ambiguous model. Moreover, the more steps of the perturbation are taken, the more ambiguity is eliminated. In addition, we can even achieve an unambiguous model of the GRN by using multi-step perturbation and integrating transcriptomic, protein-protein interaction, and cis-element data. Finally, we demonstrate the effect of utilizing different types of perturbation experiment and integrating multi-omics data on identifying the logic behind the regulatory interactions in a synthetic GRN. In conclusion, relying on the results of only knock-down experiments and not including as many omics layers as possible in the GRN inference, makes the results ambiguous, unreliable, and less accurate.

Dataset Information

Inverse perturbation for optimal intervention in gene regulatory networks.

Motivation

Results

Availability

Publications

Inverse perturbation for optimal intervention in gene regulatory networks.

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