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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.
Identifying Functional Mechanisms of Gene and Protein Regulatory Networks in Response to a Broader Range of Environmental Stresses  [PDF]
Cheng-Wei Li,Bor-Sen Chen
Comparative and Functional Genomics , 2010, DOI: 10.1155/2010/408705
Abstract: Cellular responses to sudden environmental stresses or physiological changes provide living organisms with the opportunity for final survival and further development. Therefore, it is an important topic to understand protective mechanisms against environmental stresses from the viewpoint of gene and protein networks. We propose two coupled nonlinear stochastic dynamic models to reconstruct stress-activated gene and protein regulatory networks via microarray data in response to environmental stresses. According to the reconstructed gene/protein networks, some possible mutual interactions, feedforward and feedback loops are found for accelerating response and filtering noises in these signaling pathways. A bow-tie core network is also identified to coordinate mutual interactions and feedforward loops, feedback inhibitions, feedback activations, and cross talks to cope efficiently with a broader range of environmental stresses with limited proteins and pathways.
Theory on the Dynamics of Feedforward Loops in the Transcription Factor Networks  [PDF]
Rajamanickam Murugan
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0041027
Abstract: Feedforward loops (FFLs) consist of three genes which code for three different transcription factors A, B and C where B regulates C and A regulates both B and C. We develop a detailed model to describe the dynamical behavior of various types of coherent and incoherent FFLs in the transcription factor networks. We consider the deterministic and stochastic dynamics of both promoter-states and synthesis and degradation of mRNAs of various genes associated with FFL motifs. Detailed analysis shows that the response times of FFLs strongly dependent on the ratios (wh = γpc/γph where h = a, b, c corresponding to genes A, B and C) between the lifetimes of mRNAs (1/γmh) of genes A, B and C and the protein of C (1/γpc). Under strong binding conditions we can categorize all the possible types of FFLs into groups I, II and III based on the dependence of the response times of FFLs on wh. Group I that includes C1 and I1 type FFLs seem to be less sensitive to the changes in wh. The coherent C1 type seems to be more robust against changes in other system parameters. We argue that this could be one of the reasons for the abundant nature of C1 type coherent FFLs.
Self-organization of gene regulatory network motifs enriched with short transcript's half-life transcription factors  [PDF]
Edwin Wang,Enrico Purisima
Quantitative Biology , 2005, DOI: 10.1016/j.tig.2005.06.013
Abstract: Network motifs, the recurring regulatory structural patterns in networks, are able to self-organize to produce networks. Three major motifs, feedforward loop, single input modules and bi-fan are found in gene regulatory networks. The large ratio of genes to transcription factors (TFs) in genomes leads to a sharing of TFs by motifs and is sufficient to result in network self-organization. We find a common design principle of these motifs: short transcript's half-life (THL) TFs are significantly enriched in motifs and hubs. This enrichment becomes one of the driving forces for the emergence of the network scale-free topology and allows the network to quickly adapt to environmental changes. Most feedforward loops and bi-fans contain at least one short THL TF, which can be seen as a criterion for self-assembling these motifs. We have classified the motifs according to their short THL TF content. We show that the percentage of the different motif subtypes varies in different cellular conditions.
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.
Identifying Functional Mechanisms of Gene and Protein Regulatory Networks in Response to a Broader Range of Environmental Stresses  [PDF]
Cheng-Wei Li,Bor-Sen Chen
International Journal of Genomics , 2010, DOI: 10.1155/2010/408705
Abstract: Cellular responses to sudden environmental stresses or physiological changes provide living organisms with the opportunity for final survival and further development. Therefore, it is an important topic to understand protective mechanisms against environmental stresses from the viewpoint of gene and protein networks. We propose two coupled nonlinear stochastic dynamic models to reconstruct stress-activated gene and protein regulatory networks via microarray data in response to environmental stresses. According to the reconstructed gene/protein networks, some possible mutual interactions, feedforward and feedback loops are found for accelerating response and filtering noises in these signaling pathways. A bow-tie core network is also identified to coordinate mutual interactions and feedforward loops, feedback inhibitions, feedback activations, and cross talks to cope efficiently with a broader range of environmental stresses with limited proteins and pathways. 1. Introduction Eukaryotic cells have developed protective mechanisms in response to external environmental or physiological changes (stresses). For living organisms, cellular response to sudden environmental or physiological changes determines their fate: life or death. Survivors play an essential role in adjusting the adaptation of the whole organism to such changes or just remain uncorrelated with these changes. When unicellular organisms like Saccharomyces cerevisiae suffer from drastic environmental changes, cells may respond swiftly to variations. Therefore, many kinds of signaling pathways exist to construct a protective system to transcriptionally regulate responsible target genes in response to a broader range of environmental stresses. Of these, the high osmolarity glycerol (HOG) pathway, which is the best-understood osmoreponsive system among eukaryotes, is activated by high osmolarity, for example, sorbitol osmotic stress. In contrast to the HOG pathway, the cell-wall integrity pathway is activated by low osmolarity, for example, hypo-osmotic stress. In response to signaling osmotic changes, about 10% of genes are significantly affected in yeast Saccharomyces cerevisiae [1–3]. The mitogen-activated protein kinase (MAPK) pathways play an essential role in response to several environmental changes, for example, growth factors, hormones, cytokines and environmental signals, control stress response, cell growth, morphogenesis, and proliferation. Although some nodes of MAPK pathways and the edges of their connections are suggested [4–6], the way they work and connect together in response to
The Role of Incoherent MicroRNA-Mediated Feedforward Loops in Noise Buffering  [PDF]
Matteo Osella ,Carla Bosia ,Davide Corá,Michele Caselle
PLOS Computational Biology , 2011, DOI: 10.1371/journal.pcbi.1001101
Abstract: MicroRNAs are endogenous non-coding RNAs which negatively regulate the expression of protein-coding genes in plants and animals. They are known to play an important role in several biological processes and, together with transcription factors, form a complex and highly interconnected regulatory network. Looking at the structure of this network, it is possible to recognize a few overrepresented motifs which are expected to perform important elementary regulatory functions. Among them, a special role is played by the microRNA-mediated feedforward loop in which a master transcription factor regulates a microRNA and, together with it, a set of target genes. In this paper we show analytically and through simulations that the incoherent version of this motif can couple the fine-tuning of a target protein level with an efficient noise control, thus conferring precision and stability to the overall gene expression program, especially in the presence of fluctuations in upstream regulators. Among the other results, a nontrivial prediction of our model is that the optimal attenuation of fluctuations coincides with a modest repression of the target expression. This feature is coherent with the expected fine-tuning function and in agreement with experimental observations of the actual impact of a wide class of microRNAs on the protein output of their targets. Finally, we describe the impact on noise-buffering efficiency of the cross-talk between microRNA targets that can naturally arise if the microRNA-mediated circuit is not considered as isolated, but embedded in a larger network of regulations.
Structural Discrimination of Robustness in Transcriptional Feedforward Loops for Pattern Formation  [PDF]
Guillermo Rodrigo,Santiago F. Elena
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0016904
Abstract: Signaling pathways are interconnected to regulatory circuits for sensing the environment and expressing the appropriate genetic profile. In particular, gradients of diffusing molecules (morphogens) determine cell fate at a given position, dictating development and spatial organization. The feedforward loop (FFL) circuit is among the simplest genetic architectures able to generate one-stripe patterns by operating as an amplitude detection device, where high output levels are achieved at intermediate input ones. Here, using a heuristic optimization-based approach, we dissected the design space containing all possible topologies and parameter values of the FFL circuits. We explored the ability of being sensitive or adaptive to variations in the critical morphogen level where cell fate is switched. We found four different solutions for precision, corresponding to the four incoherent architectures, but remarkably only one mode for adaptiveness, the incoherent type 4 (I4-FFL). We further carried out a theoretical study to unveil the design principle for such structural discrimination, finding that the synergistic action and cooperative binding on the downstream promoter are instrumental to achieve absolute adaptive responses. Subsequently, we analyzed the robustness of these optimal circuits against perturbations in the kinetic parameters and molecular noise, which has allowed us to depict a scenario where adaptiveness, parameter sensitivity and noise tolerance are different, correlated facets of the robustness of the I4-FFL circuit. Strikingly, we showed a strong correlation between the input (environment-related) and the intrinsic (mutation-related) susceptibilities. Finally, we discussed the evolution of incoherent regulations in terms of multifunctionality and robustness.
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.
Stabilizing and Destabilizing Effects of Embedding 3-node Subgraphs on State Space of Boolean Networks  [PDF]
Chikoo Oosawa,Michael A. Savageau,Abdul S. Jarrah,Reinhard C. Laubenbacher,Eduardo D. Sontag
Physics , 2008,
Abstract: We demonstrate the effects of embedding subgraphs using a Boolean network, which is one of the discrete dynamical models for transcriptional regulatory networks. After comparing the dynamical properties of network embedded seven different subgraphs including feedback and feedforward subgraphs, we found that complexity of the state space that increases with longer length of attractors and greater number of attractors is reduced for networks with more feedforward subgraphs. In addition, feedforward subgraphs can also provide higher mutual information with lower entropy in a temporal program of gene expression. Networks with other six subgraphs show opposite effects on dynamics of the networks, is roughly consistent with Thomas's conjecture. These results suggest that feedforward subgraphs are one of the favorable local structures in biological complex networks.
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