Control Of Gene Regulatory Networks Research Articles

Sub-circuits of a gene regulatory network control a developmental epithelial-mesenchymal transition

Epithelial-mesenchymal transition (EMT) is a fundamental cell state change that transforms epithelial to mesenchymal cells during embryonic development, adult tissue repair and cancer metastasis. EMT includes a complex series of intermediate cell state changes including remodeling of the basement membrane, apical constriction, epithelial de-adhesion, directed motility, loss of apical-basal polarity, and acquisition of mesenchymal adhesion and polarity. Transcriptional regulatory state changes must ultimately coordinate the timing and execution of these cell biological processes. A well-characterized gene regulatory network (GRN) in the sea urchin embryo was used to identify the transcription factors that control five distinct cell changes during EMT. Single transcription factors were perturbed and the consequences followed with in vivo time-lapse imaging or immunostaining assays. The data show that five different sub-circuits of the GRN control five distinct cell biological activities, each part of the complex EMT process. Thirteen transcription factors (TFs) expressed specifically in pre-EMT cells were required for EMT. Three TFs highest in the GRN specified and activated EMT (alx1, ets1, tbr) and the 10 TFs downstream of those (tel, erg, hex, tgif, snail, twist, foxn2/3, dri, foxb, foxo) were also required for EMT. No single TF functioned in all five sub-circuits, indicating that there is no EMT master regulator. Instead, the resulting sub-circuit topologies suggest EMT requires multiple simultaneous regulatory mechanisms: forward cascades, parallel inputs and positive-feedback lock downs. The interconnected and overlapping nature of the sub-circuits provides one explanation for the seamless orchestration by the embryo of cell state changes leading to successful EMT.

Verification and Optimal Control of Context-Sensitive Probabilistic Boolean Networks Using Model Checking and Polynomial Optimization

One of the significant topics in systems biology is to develop control theory of gene regulatory networks (GRNs). In typical control of GRNs, expression of some genes is inhibited (activated) by manipulating external stimuli and expression of other genes. It is expected to apply control theory of GRNs to gene therapy technologies in the future. In this paper, a control method using a Boolean network (BN) is studied. A BN is widely used as a model of GRNs, and gene expression is expressed by a binary value (ON or OFF). In particular, a context-sensitive probabilistic Boolean network (CS-PBN), which is one of the extended models of BNs, is used. For CS-PBNs, the verification problem and the optimal control problem are considered. For the verification problem, a solution method using the probabilistic model checker PRISM is proposed. For the optimal control problem, a solution method using polynomial optimization is proposed. Finally, a numerical example on the WNT5A network, which is related to melanoma, is presented. The proposed methods provide us useful tools in control theory of GRNs.

Optimal Control of Gene Regulatory Networks with Effectiveness of Multiple Drugs: A Boolean Network Approach

Developing control theory of gene regulatory networks is one of the significant topics in the field of systems biology, and it is expected to apply the obtained results to gene therapy technologies in the future. In this paper, a control method using a Boolean network (BN) is studied. A BN is widely used as a model of gene regulatory networks, and gene expression is expressed by a binary value (0 or 1). In the control problem, we assume that the concentration level of a part of genes is arbitrarily determined as the control input. However, there are cases that no gene satisfying this assumption exists, and it is important to consider structural control via external stimuli. Furthermore, these controls are realized by multiple drugs, and it is also important to consider multiple effects such as duration of effect and side effects. In this paper, we propose a BN model with two types of the control inputs and an optimal control method with duration of drug effectiveness. First, a BN model and duration of drug effectiveness are discussed. Next, the optimal control problem is formulated and is reduced to an integer linear programming problem. Finally, numerical simulations are shown.

Short‐term information processing, long‐term responses: Insights by mathematical modeling of signal transduction

How do cells interpret information from their environment and translate it into specific cell fate decisions? We propose that cell fate is already encoded in early signaling events and thus can be predicted from defined signal properties. Specifically, we hypothesize that the time integral of activated key signaling molecules can be correlated to cellular behavior such as proliferation or differentiation. The identification of these decisive key signal mediators and their connection to cell fate is facilitated by mathematical modeling. A possible mechanistic linkage between signaling dynamics and cellular function is the directed control of gene regulatory networks by defined signals. Targeted experiments in combination with mathematical modeling can increase our understanding of how cells process information and realize distinct cell fates.

Optimal Control of Gene Regulatory Networks with External Stimuli

Optimal Control of Gene Regulatory Networks with External Stimuli

Scalable approach for effective control of gene regulatory networks

Interactions between genes are realized as gene regulatory networks (GRNs). The control of such networks is essential for investigating issues like different diseases. Control is the process of studying the states and behavior of a given system under different conditions. The system considered in this study is a gene regulatory network (GRN), and one of the most important aspects in the control of GRNs is scalability. Consequently, the objective of this study is to develop a scalable technique that facilitates the control of GRNs. As the approach described in this paper concentrates on the control of GRNs, we argue that it is possible to improve scalability by reducing the number of genes to be considered by the control policy. Consequently, we propose a novel method that considers gene relevancy to estimate genes that are less important for control. This way, it is possible to get a reduced model after identifying genes that can be ignored in model-building. The latter genes are located based on a threshold value which is expected to be provided by a domain expert. Some guidelines are listed to help the domain expert in setting appropriate threshold value. We run experiments using both synthetic and real data, including metastatic melanoma and budding yeast (Saccharomyces cerevisiae). The reported test results identified genes that could be eliminated from each of the investigated GRNs. For instance, test results on budding yeast identified the two genes SWI5 and MCM1 as candidates to be eliminated. This considerably reduces the computation cost and hence demonstrate the applicability and effectiveness of the proposed approach. Employing the proposed reduction strategy results in close to optimal solutions to the control of GRNs, which are otherwise intractable due to the huge state space implied by the large number of genes.

Automated Large-Scale Control of Gene Regulatory Networks

Controlling gene regulatory networks (GRNs) is an important and hard problem. As it is the case in all control problems, the curse of dimensionality is the main issue in real applications. It is possible that hundreds of genes may regulate one biological activity in an organism; this implies a huge state space, even in the case of Boolean models. This is also evident in the literature that shows that only models of small portions of the genome could be used in control applications. In this paper, we empower our framework for controlling GRNs by eliminating the need for expert knowledge to specify some crucial threshold that is necessary for producing effective results. Our framework is characterized by applying the factored Markov decision problem (FMDP) method to the control problem of GRNs. The FMDP is a suitable framework for large state spaces as it represents the probability distribution of state transitions using compact models so that more space and time efficient algorithms could be devised for solving control problems. We successfully mapped the GRN control problem to an FMDP and propose a model reduction algorithm that helps find approximate solutions for large networks by using existing FMDP solvers. The test results reported in this paper demonstrate the efficiency and effectiveness of the proposed approach.

Bayesian Robustness in the Control of Gene Regulatory Networks

The errors originating in the data extraction process, gene selection and network inference prevent the transition probabilities of a gene regulatory network from being accurately estimated. Thus, it is important to study the effect of modeling errors on the final outcome of an intervention strategy and to design robust intervention strategies. Two major approaches applied to the design of robust policies in general are the minimax (worst case) approach and the Bayesian approach. The minimax control approach is typically conservative because it gives too much importance to the scenarios which hardly occur in practice. Consequently, in this paper, we formulate the Bayesian approach for the control of gene regulatory networks. We characterize the errors emanating from the data extraction and inference processes and compare the performance of the minimax and Bayesian designs based on these uncertainties.

Editorial [Hot topic: Genomic Signal Processing: Part 1 (Guest Editors: E.R. Dougherty, X. Cai, Y. Huang, S. Kim and R. Yamaguchi)

Genomic Signal Processing (GSP) has been defined as the analysis, processing, and use of genomic signals for gaining biological knowledge and the translation of that knowledge into systems-based applications, where by genomic signals we mean the measurable events, principally the production of mRNA and protein carried out within the cell. Owing to the defining role of DNA in the production of mRNA, the structural characterization of DNA is inevitably a part of GSP and, interestingly, signal processing methods are utilized in understanding DNA structure. A key goal of translational genomics is to discover families of genes or gene products that can be used to classify disease, thereby leading to molecular-based diagnosis and prognosis. A deeper goal is to characterize genomic and proteomic regulation, thereby leading to a functional understanding of disease and the development of systems-based medical solutions. GSP is growing in importance as an ever larger community is recognizing that accomplishing these goals requires various disciplines within or related to signal processing, including pattern recognition, prediction/estimation theory, information theory, dynamical systems, control theory, network modeling, and communication theory. In sum, systems biology and systems medicine demand deep understanding of systems theory. This inevitably entails the theory and methods of signal processing, which have been so successful in areas such as communications, and the related theory pertaining to the characterization and control of dynamical systems, without which one cannot even imagine our contemporary technological society. The purpose of this special issue is to bring some of the key developments in GSP to the wider genomics community. Owing to its grounding in systems theory and stochastic processes, GSP often requires mathematics beyond the level of that studied in undergraduate electrical engineering, or even undergraduate mathematics and statistics, and, therefore, as originally published in the scientific literature, is not accessible to many researchers in biology and medicine. Because systems biology and systems medicine will, ipso facto, have to rely on mathematical systems theory, this dichotomy is a problem that will have to be addressed in the future, from both educational and research perspectives; nonetheless, in a review format it is possible to communicate many of the basic ideas without recourse to the kind of full rigorous mathematical analyses required in original research. In this issue, the guest editors have tried to accomplish this aim in two ways: first, by specifying the kinds of issues we would like contributors to address, with the requirement that the mathematical details be kept to a minimum (with references to the relevant literature); and, second, by working with the contributors to achieve the goals of the issue through the review process. Although the final scope has been determined by the submissions and acceptances, we believe that a good breadth of subject matter is included in the issue, including the inference, analysis, and control of gene regulatory networks, mass spectrometry for proteomics, sequence analysis, metagenomics, MicroRNA target prediction, clustering, and feature selection and error estimation for classification, where in the cases of classification and clustering the papers pay close attention to performance in the context of small samples, a ubiquitous situation in which many methods in the literature perform poorly.

Robust control of uncertain context-sensitive probabilistic Boolean networks

Uncertainty is an intrinsic phenomenon in control of gene regulatory networks (GRNs). The presence of uncertainty is related to impreciseness of GRN models due to: (1) Errors caused by imperfection of measurement devices and (2) Models' inability to fully capture a complex structure of the GRN. Consequently, there is a discrepancy between actual behaviour of the GRN and what is predicted by its mathematical model. This can result in false control signals, which can drive a cell to an undesirable state. To address the problem of control under uncertainties, a risk-sensitive control paradigm is proposed. Robustness is accomplished by minimisation of the mean exponential cost as opposed to, for instance, minimisation of the mean square cost by risk-neutral controllers. The authors derive an optimal risk-sensitive controller when a GRN is modelled by a context-sensitive probabilistic Boolean network (CSPBN). By using a relation between the relative entropy and free-energy, a relative stability of the cost achieved by the risk-sensitive controller is demonstrated when the distribution of the CSPBN attractors is perturbed, as opposed to the cost of the risk-neutral controller that exhibits increase. The use of the relation between the relative entropy and free-energy to analyse the influence of a particular attractor on the robustness of the controller is studied. The efficiency of the risk-sensitive controller is tested for the CSPBN obtained from the study of malignant melanoma.

Regulation of gene expression in the nervous system

The nervous system contains a multitude of cell types which are specified during development by cascades of transcription factors acting combinatorially. Some of these transcription factors are only active during development, whereas others continue to function in the mature nervous system to maintain appropriate gene-expression patterns in differentiated cells. Underpinning the function of the nervous system is its plasticity in response to external stimuli, and many transcription factors are involved in regulating gene expression in response to neuronal activity, allowing us to learn, remember and make complex decisions. Here we review some of the recent findings that have uncovered the molecular mechanisms that underpin the control of gene regulatory networks within the nervous system. We highlight some recent insights into the gene-regulatory circuits in the development and differentiation of cells within the nervous system and discuss some of the mechanisms by which synaptic transmission influences transcription-factor activity in the mature nervous system. Mutations in genes that are important in epigenetic regulation (by influencing DNA methylation and post-translational histone modifications) have long been associated with neuronal disorders in humans such as Rett syndrome, Huntington's disease and some forms of mental retardation, and recent work has focused on unravelling their mechanisms of action. Finally, the discovery of microRNAs has produced a paradigm shift in gene expression, and we provide some examples and discuss the contribution of microRNAs to maintaining dynamic gene regulatory networks in the brain.