Stochasticity and negative feedback lead to pulsed dynamics and distinct gene activity patterns

Gene expression is an inherently stochastic process that depends on the structure of the biochemical regulatory network in which the gene is embedded. Here we study the interplay between stochastic gene switching and the widespread negative feedback regulatory loop. Using a simple hybrid model, we find that stochasticity in gene switching by itself can induce pulses in the system. Furthermore, we find that our simple model is able to reproduce both exponential and peaked distributions of gene active and inactive times similar to those that have been observed experimentally. Our hybrid modelling approach also allows us to link these patterns to the dynamics of the system for each gene state.

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One Perturbation of the Mother Cell Gene Regulatory Network Suppresses the Effects of Another during Sporulation of Bacillus subtilis

Journal of Bacteriology ◽

10.1128/jb.01285-07 ◽

2007 ◽

Vol 189 (23) ◽

pp. 8467-8473 ◽

Cited By ~ 10

Author(s):

Lijuan Wang ◽

John Perpich ◽

Adam Driks ◽

Lee Kroos

Keyword(s):

Gene Expression ◽

Bacillus Subtilis ◽

Rna Polymerase ◽

Regulatory Network ◽

Mother Cell ◽

Feedback Loop ◽

Network Functions ◽

Regulatory Loop ◽

Cell Gene ◽

Spore Coat Protein

ABSTRACT In the mother cell of sporulating Bacillus subtilis, a regulatory network functions to control gene expression. Four transcription factors act sequentially in the order σE, SpoIIID, σK, GerE. σE and σK direct RNA polymerase to transcribe different regulons. SpoIIID and GerE are DNA-binding proteins that activate or repress transcription of many genes. Several negative regulatory loops add complexity to the network. First, transcriptionally active σK RNA polymerase inhibits early sporulation gene expression, resulting in reduced accumulation of σE and SpoIIID late during sporulation. Second, GerE represses sigK transcription, reducing σK accumulation about twofold. Third, SpoIIID represses cotC, which encodes a spore coat protein, delaying its transcription by σK RNA polymerase. Partially circumventing the first feedback loop, by engineering cells to maintain the SpoIIID level late during sporulation, causes spore defects. Here, the effects of circumventing the second feedback loop, by mutating the GerE binding sites in the sigK promoter region, are reported. Accumulation of pro-σK and σK was increased, but no spore defects were detected. Expression of σK-dependent reporter fusions was altered, increasing the expression of gerE-lacZ and cotC-lacZ and decreasing the expression of cotD-lacZ. Because these effects on gene expression were opposite those observed when the SpoIIID level was maintained late during sporulation, cells were engineered to both maintain the SpoIIID level and have elevated sigK expression late during sporulation. This restored the expression of σK-dependent reporters to wild-type levels, and no spore defects were observed. Hence, circumventing the second feedback loop suppressed the effects of perturbing the first feedback loop. By feeding information back into the network, these two loops appear to optimize target gene expression and increase network robustness. Circumventing the third regulatory loop, by engineering cells to express cotC about 2 h earlier than normal, did not cause a detectable spore defect.

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Investigation of a New Approach to Predict Water Quality Extremes with a Case Study of Chemical Determinands in Stream Water

Water Science & Technology ◽

10.2166/wst.1991.0137 ◽

1991 ◽

Vol 24 (6) ◽

pp. 25-33

Author(s):

A. J. Jakeman ◽

P. G. Whitehead ◽

A. Robson ◽

J. A. Taylor ◽

J. Bai

Keyword(s):

Water Quality ◽

Stream Water ◽

Probability Distributions ◽

Management Strategies ◽

Hybrid Modelling ◽

Trend Model ◽

Environmental Extremes ◽

Modelling Approach

The paper illustrates analysis of the assumptions of the statistical component of a hybrid modelling approach for predicting environmental extremes. This shows how to assess the applicability of the approach to water quality problems. The analysis involves data on stream acidity from the Birkenes catchment in Norway. The modelling approach is hybrid in that it uses: (1) a deterministic or process-based description to simulate (non-stationary) long term trend values of environmental variables, and (2) probability distributions which are superimposed on the trend values to characterise the frequency of shorter term concentrations. This permits assessment of management strategies and of sensitivity to climate variables by adjusting the values of major forcing variables in the trend model. Knowledge of the variability about the trend is provided by: (a) identification of an appropriate parametric form of the probability density function (pdf) of the environmental attribute (e.g. stream acidity variables) whose extremes are of interest, and (b) estimation of pdf parameters using the output of the trend model.

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Stochastic activation and bistability in a Rab GTPase regulatory network

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1921027117 ◽

2020 ◽

Vol 117 (12) ◽

pp. 6540-6549

Author(s):

Urban Bezeljak ◽

Hrushikesh Loya ◽

Beata Kaczmarek ◽

Timothy E. Saunders ◽

Martin Loose

Keyword(s):

Regulatory Network ◽

Regulatory Networks ◽

Membrane Surface ◽

Activity Patterns ◽

Small Gtpases ◽

Signaling Networks ◽

Rab Gtpase ◽

Endomembrane System ◽

In Vitro Reconstitution

The eukaryotic endomembrane system is controlled by small GTPases of the Rab family, which are activated at defined times and locations in a switch-like manner. While this switch is well understood for an individual protein, how regulatory networks produce intracellular activity patterns is currently not known. Here, we combine in vitro reconstitution experiments with computational modeling to study a minimal Rab5 activation network. We find that the molecular interactions in this system give rise to a positive feedback and bistable collective switching of Rab5. Furthermore, we find that switching near the critical point is intrinsically stochastic and provide evidence that controlling the inactive population of Rab5 on the membrane can shape the network response. Notably, we demonstrate that collective switching can spread on the membrane surface as a traveling wave of Rab5 activation. Together, our findings reveal how biochemical signaling networks control vesicle trafficking pathways and how their nonequilibrium properties define the spatiotemporal organization of the cell.

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Study on the Relationship between the miRNA-centered ceRNA Regulatory Network and Fatigue

Journal of Molecular Neuroscience ◽

10.1007/s12031-021-01845-3 ◽

2021 ◽

Author(s):

Xingzhe Yang ◽

Feng Li ◽

Jie Ma ◽

Yan Liu ◽

Xuejiao Wang ◽

...

Keyword(s):

Gene Expression ◽

Gene Regulatory Network ◽

Regulatory Network ◽

Hot Spot ◽

Genetic Research ◽

Noncoding Rnas ◽

Messenger Rnas ◽

Effective Prevention ◽

Gene Regulatory ◽

The Relationship

AbstractIn recent years, the incidence of fatigue has been increasing, and the effective prevention and treatment of fatigue has become an urgent problem. As a result, the genetic research of fatigue has become a hot spot. Transcriptome-level regulation is the key link in the gene regulatory network. The transcriptome includes messenger RNAs (mRNAs) and noncoding RNAs (ncRNAs). MRNAs are common research targets in gene expression profiling. Noncoding RNAs, including miRNAs, lncRNAs, circRNAs and so on, have been developed rapidly. Studies have shown that miRNAs are closely related to the occurrence and development of fatigue. MiRNAs can regulate the immune inflammatory reaction in the central nervous system (CNS), regulate the transmission of nerve impulses and gene expression, regulate brain development and brain function, and participate in the occurrence and development of fatigue by regulating mitochondrial function and energy metabolism. LncRNAs can regulate dopaminergic neurons to participate in the occurrence and development of fatigue. This has certain value in the diagnosis of chronic fatigue syndrome (CFS). CircRNAs can participate in the occurrence and development of fatigue by regulating the NF-κB pathway, TNF-α and IL-1β. The ceRNA hypothesis posits that in addition to the function of miRNAs in unidirectional regulation, mRNAs, lncRNAs and circRNAs can regulate gene expression by competitive binding with miRNAs, forming a ceRNA regulatory network with miRNAs. Therefore, we suggest that the miRNA-centered ceRNA regulatory network is closely related to fatigue. At present, there are few studies on fatigue-related ncRNA genes, and most of these limited studies are on miRNAs in ncRNAs. However, there are a few studies on the relationship between lncRNAs, cirRNAs and fatigue. Less research is available on the pathogenesis of fatigue based on the ceRNA regulatory network. Therefore, exploring the complex mechanism of fatigue based on the ceRNA regulatory network is of great significance. In this review, we summarize the relationship between miRNAs, lncRNAs and circRNAs in ncRNAs and fatigue, and focus on exploring the regulatory role of the miRNA-centered ceRNA regulatory network in the occurrence and development of fatigue, in order to gain a comprehensive, in-depth and new understanding of the essence of the fatigue gene regulatory network.

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Transcriptional regulation of gene expression inCorynebacterium glutamicum: the role of global, master and local regulators in the modular and hierarchical gene regulatory network

FEMS Microbiology Reviews ◽

10.1111/j.1574-6976.2010.00228.x ◽

2010 ◽

Vol 34 (5) ◽

pp. 685-737 ◽

Cited By ~ 70

Author(s):

Jasmin Schröder ◽

Andreas Tauch

Keyword(s):

Gene Expression ◽

Transcriptional Regulation ◽

Gene Regulatory Network ◽

Regulatory Network ◽

Regulation Of Gene Expression ◽

Gene Regulatory

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Inference of the Xenopus tropicalis embryonic regulatory network and spatial gene expression patterns

BMC Systems Biology ◽

10.1186/1752-0509-8-3 ◽

2014 ◽

Vol 8 (1) ◽

pp. 3 ◽

Cited By ~ 6

Author(s):

Zhenzhen Zheng ◽

Scott Christley ◽

William T Chiu ◽

Ira L Blitz ◽

Xiaohui Xie ◽

...

Keyword(s):

Gene Expression ◽

Regulatory Network ◽

Expression Patterns ◽

Xenopus Tropicalis ◽

Gene Expression Patterns

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Feedback-Induced Variations of Distribution in a Representative Gene Model

International Journal of Bifurcation and Chaos ◽

10.1142/s0218127415400088 ◽

2015 ◽

Vol 25 (07) ◽

pp. 1540008

Author(s):

Peijiang Liu ◽

Zhanjiang Yuan ◽

Lifang Huang ◽

Tianshou Zhou

Keyword(s):

Gene Expression ◽

Power Law ◽

Positive Feedback ◽

Bimodal Distribution ◽

Stochastic Bifurcation ◽

Protein Distribution ◽

Identical Cell ◽

Induced Changes ◽

Gene Switching ◽

Cell To Cell Variability

Gene expression is inherently noisy, implying that the number of mRNAs or proteins is not invariant rather than follows a distribution. This distribution can not only provide the exact information on the dynamics of gene expression but also describe cell-to-cell variability in a genetically identical cell population. Here, we systematically investigate a two-state model of gene expression, a model paradigm used to study expression dynamics, focusing on the effect of feedback on the type of mRNA or protein distribution. If there is no feedback, then the distribution may be bimodal, power-law tailed, or Poisson-like, depending on gene switching rates. However, we find that feedback can tune or change the type of the distribution in each case and tends to unimodalize the distribution as its strength increases. Specifically, positive feedback can change not only a power-law tailed distribution into a bimodal or Poisson-like distribution but also a bimodal distribution into a Poisson-like distribution (implying that stochastic bifurcation can take place). In addition, it can make a Poisson-like distribution become more peaked but does not change the type of this distribution. In contrast to positive feedback, negative feedback has less influence on the shape of the distributions except for the bimodal case. In all cases, the noise-feedback curve used extensively in previous studies cannot well reflect the feedback-induced changes in the shape of distributions. Feedback-induced variations in distribution would be important for cell survival in fluctuating environments.

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Reconstruction of the Regulatory Network for Bacillus subtilis and Reconciliation with Gene Expression Data

Frontiers in Microbiology ◽

10.3389/fmicb.2016.00275 ◽

2016 ◽

Vol 7 ◽

Cited By ~ 5

Author(s):

José P. Faria ◽

Ross Overbeek ◽

Ronald C. Taylor ◽

Neal Conrad ◽

Veronika Vonstein ◽

...

Keyword(s):

Gene Expression ◽

Bacillus Subtilis ◽

Gene Expression Data ◽

Regulatory Network ◽

Expression Data

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Fuzzy modeling reveals a dynamic self-sustaining network of the GLI transcription factors controlling important metabolic regulators in adult mouse hepatocytes

Molecular BioSystems ◽

10.1039/c5mb00129c ◽

2015 ◽

Vol 11 (8) ◽

pp. 2190-2197 ◽

Cited By ~ 15

Author(s):

Wolfgang Schmidt-Heck ◽

Madlen Matz-Soja ◽

Susanne Aleithe ◽

Eugenia Marbach ◽

Reinhard Guthke ◽

...

Keyword(s):

Fuzzy Logic ◽

Transcription Factors ◽

Regulatory Network ◽

Adult Mouse ◽

Dynamic Features ◽

Hedgehog Signalling ◽

Gli Transcription Factors ◽

Mouse Hepatocytes ◽

Metabolic Regulators ◽

Modelling Approach

The Hedgehog signalling-driven Gli transcription factors in hepatocytes form a regulatory network identified by a fuzzy-logic modelling approach. The network explains dynamic features important for hepatocyte function and fate.

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