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Theory on the Dynamics of Oscillatory Loops in the Transcription Factor Networks  [PDF]
Rajamanickam Murugan
Quantitative Biology , 2014, DOI: 10.1371/journal.pone.0104328
Abstract: We develop a detailed theoretical framework for various types of transcription factor gene oscillators. We further demonstrate that one can build genetic-oscillators which are tunable and robust against perturbations in the critical control parameters by coupling two or more independent Goodwin-Griffith oscillators through either -OR- or -AND- type logic. Most of the coupled oscillators constructed in the literature so far seem to be of -OR- type. When there are transient perturbations in one of the -OR- type coupled-oscillators, then the overall period of the system remains constant (period-buffering) whereas in case of -AND- type coupling the overall period of the system moves towards the perturbed oscillator. Though there is a period-buffering, the amplitudes of oscillators coupled through -OR- type logic are more sensitive to perturbations in the parameters associated with the promoter state dynamics than -AND- type. Further analysis shows that the period of -AND- type coupled dual-feedback oscillators can be tuned without conceding on the amplitudes. Using these results we derive the basic design principles governing the robust and tunable synthetic gene oscillators without compromising on their amplitudes.
Effects of feedback and feedforward loops on dynamics of transcriptional regulatory model networks  [PDF]
Chikoo Oosawa,Kazuhiro Takemoto,Michael A. Savageau
Physics , 2007,
Abstract: We demonstrate the advantages of feedforward loops using a Boolean network, which is one of the discrete dynamical models for transcriptional regulatory networks. After comparing the dynamical behaviors of network embedded feedback and feedforward loops, we found that feedforward loops can provide higher temporal order (coherence) with lower entropy (randomness) in a temporal program of gene expression. In addition, complexity of the state space that increases with longer length of attractors and greater number of attractors is also reduced for networks with more feedforward loops. Feedback loops show opposite effects on dynamics of the networks. These results suggest that feedforward loops are one of the favorable local structures in biomolecular and neuronal networks.
Stabilizing Gene Regulatory Networks Through Feedforward Loops  [PDF]
Claus Kadelka,David Murrugarra,Reinhard Laubenbacher
Quantitative Biology , 2013, DOI: 10.1063/1.4808248
Abstract: The global dynamics of gene regulatory networks are known to show robustness to perturbations in the form of intrinsic and extrinsic noise, as well as mutations of individual genes. One molecular mechanism underlying this robustness has been identified as the action of so-called microRNAs that operate via feedforward loops. We present results of a computational study, using the modeling framework of stochastic Boolean networks, which explores the role that such network motifs play in stabilizing global dynamics. The paper introduces a new measure for the stability of stochastic networks. The results show that certain types of feedforward loops do indeed buffer the network against stochastic effects.
The role of master regulators in gene regulatory networks  [PDF]
E. Hernández-Lemus,K. Baca-López,R. Lemus,R. García-Herrera
Physics , 2015, DOI: 10.4279/PIP.070011
Abstract: Gene regulatory networks present a wide variety of dynamical responses to intrinsic and extrinsic perturbations. Arguably, one of the most important of such coordinated responses is the one of amplification cascades, in which activation of a few key-responsive transcription factors (termed master regulators, MRs) lead to a large series of transcriptional activation events. This is so since master regulators are transcription factors controlling the expression of other transcription factor molecules and so on. MRs hold a central position related to transcriptional dynamics and control of gene regulatory networks and are often involved in complex feedback and feedforward loops inducing non-trivial dynamics. Recent studies have pointed out to the myocyte enhancing factor 2C (MEF2C, also known as MADS box transcription enhancer factor 2, polypeptide C) as being one of such master regulators involved in the pathogenesis of primary breast cancer. In this work, we perform an integrative genomic analysis of the transcriptional regulation activity of MEF2C and its target genes to evaluate to what extent are these molecules inducing collective responses leading to gene expression deregulation and carcinogenesis. We also analyzed a number of induced dynamic responses, in particular those associated with transcriptional bursts, and nonlinear cascading to evaluate the influence they may have in malignant phenotypes and cancer.
Fundamental Dynamic Units: Feedforward Networks and Adjustable Gates  [PDF]
Herbert Sauro,Song Yang
Quantitative Biology , 2009,
Abstract: The activation/repression of a given gene is typically regulated by multiple transcription factors (TFs) that bind at the gene regulatory region and recruit RNA polymerase (RNAP). The interactions between the promoter region and TFs and between different TFs specify the dynamic responses of the gene under different physiological conditions. By choosing specific regulatory interactions with up to three transcription factors, we designed several functional motifs, each of which is shown to perform a certain function and can be integrated into larger networks. We analyzed three kinds of networks: (i) Motifs derived from incoherent feedforward motifs, which behave as `amplitude filters', or `concentration detectors'. These motifs respond maximally to input transcription factors with concentrations within a certain range. From these motifs homeostatic and pulse generating networks are derived. (ii) Tunable network motifs, which can behave as oscillators or switches for low and high concentrations of an input transcription factor, respectively. (iii) Transcription factor controlled adjustable gates, which switch between AND/OR gate characteristics, depending on the concentration of the input transcription factor. This study has demonstrated the utility of feedforward networks and the flexibility of specific transcriptional binding kinetics in generating new novel behaviors. The flexibility of feedforward networks as dynamic units may explain the apparent frequency that such motifs are found in real biological networks.
Transcription and noise in negative feedback loops  [PDF]
J. C. Nacher,T. Ochiai
Quantitative Biology , 2007,
Abstract: Recently, several studies have investigated the transcription process associated to specific genetic regulatory networks. In this work, we present a stochastic approach for analyzing the dynamics and effect of negative feedback loops (FBL) on the transcriptional noise. First, our analysis allows us to identify a bimodal activity depending of the strength of self-repression coupling D. In the strong coupling region D>>1, the variance of the transcriptional noise is found to be reduced a 28 % more than described earlier. Secondly, the contribution of the noise effect to the abundance of regulating protein becomes manifest when the coefficient of variation is computed. In the strong coupling region, this coefficient is found to be independent of all parameters and in fair agreement with the experimentally observed values. Finally, our analysis reveals that the regulating protein is significantly induced by the intrinsic and external noise in the strong coupling region. In short, it indicates that the existence of inherent noise in FBL makes it possible to produce a basal amount of proteins even though the repression level D is very strong.
Factor analysis for gene regulatory networks and transcription factor activity profiles
Iosifina Pournara, Lorenz Wernisch
BMC Bioinformatics , 2007, DOI: 10.1186/1471-2105-8-61
Abstract: In this paper, we explore the performance of five factor analysis algorithms, Bayesian as well as classical, on problems with biological context using both simulated and real data. Factor analysis (FA) models are used in order to describe a larger number of observed variables by a smaller number of unobserved variables, the factors, whereby all correlation between observed variables is explained by common factors. Bayesian FA methods allow one to infer sparse networks by enforcing sparsity through priors. In contrast, in the classical FA, matrix rotation methods are used to enforce sparsity and thus to increase the interpretability of the inferred factor loadings matrix. However, we also show that Bayesian FA models that do not impose sparsity through the priors can still be used for the reconstruction of a gene regulatory network if applied in conjunction with matrix rotation methods. Finally, we show the added advantage of merging the information derived from all algorithms in order to obtain a combined result.Most of the algorithms tested are successful in reconstructing the connectivity structure as well as the TF profiles. Moreover, we demonstrate that if the underlying network is sparse it is still possible to reconstruct hidden activity profiles of TFs to some degree without prior connectivity information.Factor analysis (FA) as well as principal component analysis (PCA) is used to describe a number of observed variables by a smaller number of unobserved variables. Unlike PCA, FA also includes independent additive measurement errors on the observed variables. FA assumes that the observed variables become uncorrelated given a set of hidden variables called factors. It can also be seen as a clustering method where the variables described by the same factors are highly correlated, thus belonging to the same cluster, while the variables depending on different factors are uncorrelated and placed in different clusters.FA has been successfully used in a number of ar
Phenotypic Robustness and the Assortativity Signature of Human Transcription Factor Networks  [PDF]
Dov A. Pechenick,Joshua L. Payne,Jason H. Moore
PLOS Computational Biology , 2014, DOI: doi/10.1371/journal.pcbi.1003780
Abstract: Many developmental, physiological, and behavioral processes depend on the precise expression of genes in space and time. Such spatiotemporal gene expression phenotypes arise from the binding of sequence-specific transcription factors (TFs) to DNA, and from the regulation of nearby genes that such binding causes. These nearby genes may themselves encode TFs, giving rise to a transcription factor network (TFN), wherein nodes represent TFs and directed edges denote regulatory interactions between TFs. Computational studies have linked several topological properties of TFNs — such as their degree distribution — with the robustness of a TFN's gene expression phenotype to genetic and environmental perturbation. Another important topological property is assortativity, which measures the tendency of nodes with similar numbers of edges to connect. In directed networks, assortativity comprises four distinct components that collectively form an assortativity signature. We know very little about how a TFN's assortativity signature affects the robustness of its gene expression phenotype to perturbation. While recent theoretical results suggest that increasing one specific component of a TFN's assortativity signature leads to increased phenotypic robustness, the biological context of this finding is currently limited because the assortativity signatures of real-world TFNs have not been characterized. It is therefore unclear whether these earlier theoretical findings are biologically relevant. Moreover, it is not known how the other three components of the assortativity signature contribute to the phenotypic robustness of TFNs. Here, we use publicly available DNaseI-seq data to measure the assortativity signatures of genome-wide TFNs in 41 distinct human cell and tissue types. We find that all TFNs share a common assortativity signature and that this signature confers phenotypic robustness to model TFNs. Lastly, we determine the extent to which each of the four components of the assortativity signature contributes to this robustness.
Uncovering MicroRNA and Transcription Factor Mediated Regulatory Networks in Glioblastoma  [PDF]
Jingchun Sun,Xue Gong,Benjamin Purow,Zhongming Zhao
PLOS Computational Biology , 2012, DOI: 10.1371/journal.pcbi.1002488
Abstract: Glioblastoma multiforme (GBM) is the most common and lethal brain tumor in humans. Recent studies revealed that patterns of microRNA (miRNA) expression in GBM tissue samples are different from those in normal brain tissues, suggesting that a number of miRNAs play critical roles in the pathogenesis of GBM. However, little is yet known about which miRNAs play central roles in the pathology of GBM and their regulatory mechanisms of action. To address this issue, in this study, we systematically explored the main regulation format (feed-forward loops, FFLs) consisting of miRNAs, transcription factors (TFs) and their impacting GBM-related genes, and developed a computational approach to construct a miRNA-TF regulatory network. First, we compiled GBM-related miRNAs, GBM-related genes, and known human TFs. We then identified 1,128 3-node FFLs and 805 4-node FFLs with statistical significance. By merging these FFLs together, we constructed a comprehensive GBM-specific miRNA-TF mediated regulatory network. Then, from the network, we extracted a composite GBM-specific regulatory network. To illustrate the GBM-specific regulatory network is promising for identification of critical miRNA components, we specifically examined a Notch signaling pathway subnetwork. Our follow up topological and functional analyses of the subnetwork revealed that six miRNAs (miR-124, miR-137, miR-219-5p, miR-34a, miR-9, and miR-92b) might play important roles in GBM, including some results that are supported by previous studies. In this study, we have developed a computational framework to construct a miRNA-TF regulatory network and generated the first miRNA-TF regulatory network for GBM, providing a valuable resource for further understanding the complex regulatory mechanisms in GBM. The observation of critical miRNAs in the Notch signaling pathway, with partial verification from previous studies, demonstrates that our network-based approach is promising for the identification of new and important miRNAs in GBM and, potentially, other cancers.
A Comprehensive Resource of Interacting Protein Regions for Refining Human Transcription Factor Networks  [PDF]
Etsuko Miyamoto-Sato,Shigeo Fujimori,Masamichi Ishizaka,Naoya Hirai,Kazuyo Masuoka,Rintaro Saito,Yosuke Ozawa,Katsuya Hino,Takanori Washio,Masaru Tomita,Tatsuhiro Yamashita,Tomohiro Oshikubo,Hidetoshi Akasaka,Jun Sugiyama,Yasuo Matsumoto,Hiroshi Yanagawa
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0009289
Abstract: Large-scale data sets of protein-protein interactions (PPIs) are a valuable resource for mapping and analysis of the topological and dynamic features of interactome networks. The currently available large-scale PPI data sets only contain information on interaction partners. The data presented in this study also include the sequences involved in the interactions (i.e., the interacting regions, IRs) suggested to correspond to functional and structural domains. Here we present the first large-scale IR data set obtained using mRNA display for 50 human transcription factors (TFs), including 12 transcription-related proteins. The core data set (966 IRs; 943 PPIs) displays a verification rate of 70%. Analysis of the IR data set revealed the existence of IRs that interact with multiple partners. Furthermore, these IRs were preferentially associated with intrinsic disorder. This finding supports the hypothesis that intrinsically disordered regions play a major role in the dynamics and diversity of TF networks through their ability to structurally adapt to and bind with multiple partners. Accordingly, this domain-based interaction resource represents an important step in refining protein interactions and networks at the domain level and in associating network analysis with biological structure and function.
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