scholarly journals Bursting noise in gene expression dynamics: linking microscopic and mesoscopic models

2016 ◽  
Vol 13 (114) ◽  
pp. 20150772 ◽  
Author(s):  
Yen Ting Lin ◽  
Tobias Galla
Keyword(s):  
Regulatory Networks ◽  
Coarse Grained ◽  
Relevant Parameter ◽  
Piecewise Deterministic Markov Process ◽  
Biologically Relevant ◽  
Coarse Grained Model ◽  
Mesoscopic Models ◽  
Gene Expression Dynamics ◽  
Gene Regulatory ◽  
Noise In Gene Expression

The dynamics of short-lived mRNA results in bursts of protein production in gene regulatory networks. We investigate the propagation of bursting noise between different levels of mathematical modelling and demonstrate that conventional approaches based on diffusion approximations can fail to capture bursting noise. An alternative coarse-grained model, the so-called piecewise deterministic Markov process (PDMP), is seen to outperform the diffusion approximation in biologically relevant parameter regimes. We provide a systematic embedding of the PDMP model into the landscape of existing approaches, and we present analytical methods to calculate its stationary distribution and switching frequencies.

scholarly journals Repressive gene regulation synchronizes development with cellular metabolism

2019 ◽  
Author(s):  
Justin J. Cassidy ◽  
Sebastian Bernasek ◽  
Rachael Bakker ◽  
Ritika Giri ◽  
Nicolás Peláez ◽  
...  
Keyword(s):  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Animal Species ◽  
Cellular Metabolism ◽  
Error Frequency ◽  
Microrna Family ◽  
Metabolic Conditions ◽  
Gene Expression Dynamics ◽  
Gene Regulatory ◽  
Evolutionary Route

ABSTRACTMetabolic conditions affect the developmental tempo of most animal species. Consequently, developmental gene regulatory networks (GRNs) must faithfully adjust their dynamics to a variable time scale. We find evidence that layered weak repression of genes provides the necessary coupling between GRN output and cellular metabolism. Using a mathematical model that replicates such a scenario, we find that lowering metabolism corrects developmental errors that otherwise occur when different layers of repression are lost. Through mutant analysis, we show that gene expression dynamics are unaffected by loss of repressors, but only when cellular metabolism is reduced. We further show that when metabolism is lowered, formation of a variety of sensory organs inDrosophilais normal despite loss of individual repressors of transcription, mRNA stability, and protein stability. We demonstrate the universality of this phenomenon by experimentally eliminating the entire microRNA family of repressors, and find that all microRNAs are rendered unnecessary when metabolism is reduced. Thus, layered weak repression provides robustness through error frequency suppression, and may provide an evolutionary route to a shorter reproductive cycle.

scholarly journals Evolution of Mendelian Dominance in Gene Regulatory Networks Associated With Phenotypic Robustness

2021 ◽  
Author(s):  
Kenji Okubo ◽  
Kunihiko Kaneko
Keyword(s):  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Target Genes ◽  
Classical Case ◽  
Mendelian Inheritance ◽  
Degree Of Dominance ◽  
Gene Expression Dynamics ◽  
Phenotypic Robustness ◽  
Robustness To Noise ◽  
Gene Regulatory

Abstract Background: Mendelian inheritance is a fundamental law of genetics. Considering two alleles in a diploid, a phenotype of a heterotype is dominated by a particular homotype according to the law of dominance. This picture is usually based on simple genotype-phenotype mapping in which one gene regulates one phenotype. However, in reality, some interactions between genes can result in deviation from Mendelian dominance. Result: Here, by using the numerical evolution of diploid gene regulatory networks (GRNs), we discuss whether Mendelian dominance evolves beyond the classical case of one-to-one genotype-phenotype mapping. We examine whether complex genotype-phenotype mapping can achieve Mendelian dominance through the evolution of the GRN with interacting genes. Specifically, we extend the GRN model to a diploid case, in which two GRN matrices are added to give gene expression dynamics, and simulate evolution with meiosis and recombination. Our results reveal that Mendelian dominance evolves even under complex genotype-phenotype mapping. This dominance is achieved via a group of genotypes that differ from each other but have a common phenotype given by the expression of target genes. Calculating the degree of dominance shows that it increases through the evolution, correlating closely with the decrease in phenotypic fluctuations and the increase in robustness to initial noise. This evolution of Mendelian dominance is associated with phenotypic robustness against meiosis-induced genome mixing, whereas sexual recombination arising from the mixing of chromosomes from the parents further enhances dominance and robustness. Owing to this dominance, the robustness to genetic differences increases, while the optimal fitness is sustained up to a large difference between the two genomes. Conclusion: Mendelian dominance is achieved by groups of genotypes that are associated with the increase in phenotypic robustness to noise.

Improved Model Checking Techniques for State Space Analysis of Gene Regulatory Networks

2010 ◽  
pp. 386-404
Author(s):  
Hélio C. Pais ◽  
Kenneth L. McMillan ◽  
Ellen M. Sentovich ◽  
Ana T. Freitas ◽  
Arlindo L. Oliveira
Keyword(s):  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Basins Of Attraction ◽  
Model Checker ◽  
Biologically Relevant ◽  
Qualitative Models ◽  
A Cell ◽  
Gene Regulatory ◽  
Improved Model ◽  
High Level

A better understanding of the behavior of a cell, as a system, depends on our ability to model and understand the complex regulatory mechanisms that control gene expression. High level, qualitative models of gene regulatory networks can be used to analyze and characterize the behavior of complex systems, and to provide important insights on the behavior of these systems. In this chapter, we describe a number of additional functionalities that, when supported by a symbolic model checker, make it possible to answer important questions about the nature of the state spaces of gene regulatory networks, such as the nature and size of attractors, and the characteristics of the basins of attraction. We illustrate the type of analysis that can be performed by applying an improved model checker to two well studied gene regulatory models, the network that controls the cell cycle in the yeast S. cerevisiae, and the network that regulates formation of the dorsal-ventral boundary in D. melanogaster. The results show that the insights provided by the analysis can be used to understand and improve the models, and to formulate hypotheses that are biologically relevant and that can be confirmed experimentally.

scholarly journals A multi-modal coarse grained model of DNA flexibility mappable to the atomistic level

2020 ◽  
Vol 48 (5) ◽  
pp. e29-e29 ◽  
Author(s):  
Jürgen Walther ◽  
Pablo D Dans ◽  
Alexandra Balaceanu ◽  
Adam Hospital ◽  
Genís Bayarri ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Coarse Grained ◽  
Web Interface ◽  
Harmonic Model ◽  
Coarse Grained Model ◽  
Mesoscopic Models ◽  
Dynamics Simulations ◽  
Helical Parameters ◽  
High Computational Efficiency

Abstract We present a new coarse grained method for the simulation of duplex DNA. The algorithm uses a generalized multi-harmonic model that can represent any multi-normal distribution of helical parameters, thus avoiding caveats of current mesoscopic models for DNA simulation and representing a breakthrough in the field. The method has been parameterized from accurate parmbsc1 atomistic molecular dynamics simulations of all unique tetranucleotide sequences of DNA embedded in long duplexes and takes advantage of the correlation between helical states and backbone configurations to derive atomistic representations of DNA. The algorithm, which is implemented in a simple web interface and in a standalone package reproduces with high computational efficiency the structural landscape of long segments of DNA untreatable by atomistic molecular dynamics simulations.

scholarly journals Inferring Biologically Relevant Models: Nested Canalyzing Functions

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Franziska Hinkelmann ◽  
Abdul Salam Jarrah
Keyword(s):  
Experimental Data ◽  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Boolean Model ◽  
Biochemical Networks ◽  
Relevant Model ◽  
Biologically Relevant ◽  
Gene Regulatory ◽  
The Given ◽  
Class Of Functions

Inferring dynamic biochemical networks is one of the main challenges in systems biology. Given experimental data, the objective is to identify the rules of interaction among the different entities of the network. However, the number of possible models fitting the available data is huge, and identifying a biologically relevant model is of great interest. Nested canalyzing functions, where variables in a given order dominate the function, have recently been proposed as a framework for modeling gene regulatory networks. Previously, we described this class of functions as an algebraic toric variety. In this paper, we present an algorithm that identifies all nested canalyzing models that fit the given data. We demonstrate our methods using a well-known Boolean model of the cell cycle in budding yeast.

Dynamics of Bacterial Gene Regulatory Networks

2018 ◽  
Vol 47 (1) ◽  
pp. 447-467 ◽  
Author(s):  
David L. Shis ◽  
Matthew R. Bennett, ◽  
Oleg A. Igoshin
Keyword(s):  
Gene Expression ◽  
Gene Regulatory Networks ◽  
Network Architecture ◽  
Regulatory Networks ◽  
Single Cells ◽  
Cell Physiology ◽  
Bacterial Cells ◽  
Bacterial Gene ◽  
Gene Expression Dynamics ◽  
Gene Regulatory

The ability of bacterial cells to adjust their gene expression program in response to environmental perturbation is often critical for their survival. Recent experimental advances allowing us to quantitatively record gene expression dynamics in single cells and in populations coupled with mathematical modeling enable mechanistic understanding on how these responses are shaped by the underlying regulatory networks. Here, we review how the combination of local and global factors affect dynamical responses of gene regulatory networks. Our goal is to discuss the general principles that allow extrapolation from a few model bacteria to less understood microbes. We emphasize that, in addition to well-studied effects of network architecture, network dynamics are shaped by global pleiotropic effects and cell physiology.

scholarly journals Predicting synchronized gene coexpression patterns from fibration symmetries in gene regulatory networks in bacteria

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Ian Leifer ◽  
Mishael Sánchez-Pérez ◽  
Cecilia Ishida ◽  
Hernán A. Makse
Keyword(s):  
Gene Expression ◽  
Gene Regulatory Networks ◽  
Network Structure ◽  
Regulatory Networks ◽  
Conceptual Tool ◽  
E Coli ◽  
Gene Coexpression ◽  
Expression Of Genes ◽  
Gene Expression Dynamics ◽  
Gene Regulatory

Abstract Background Gene regulatory networks coordinate the expression of genes across physiological states and ensure a synchronized expression of genes in cellular subsystems, critical for the coherent functioning of cells. Here we address the question whether it is possible to predict gene synchronization from network structure alone. We have recently shown that synchronized gene expression can be predicted from symmetries in the gene regulatory networks described by the concept of symmetry fibrations. We showed that symmetry fibrations partition the genes into groups called fibers based on the symmetries of their ’input trees’, the set of paths in the network through which signals can reach a gene. In idealized dynamic gene expression models, all genes in a fiber are perfectly synchronized, while less idealized models—with gene input functions differencing between genes—predict symmetry breaking and desynchronization. Results To study the functional role of gene fibers and to test whether some of the fiber-induced coexpression remains in reality, we analyze gene fibrations for the gene regulatory networks of E. coli and B. subtilis and confront them with expression data. We find approximate gene coexpression patterns consistent with symmetry fibrations with idealized gene expression dynamics. This shows that network structure alone provides useful information about gene synchronization, and suggest that gene input functions within fibers may be further streamlined by evolutionary pressures to realize a coexpression of genes. Conclusions Thus, gene fibrations provide a sound conceptual tool to describe tunable coexpression induced by network topology and shaped by mechanistic details of gene expression.

scholarly journals Evolution of Mendelian dominance in gene regulatory networks associated with phenotypic robustness

2021 ◽  
Author(s):  
Kenji Okubo ◽  
Kunihiko Kaneko
Keyword(s):  
Gene Expression ◽  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Target Genes ◽  
Gene Expression Pattern ◽  
Mendelian Inheritance ◽  
Gene Expression Dynamics ◽  
Phenotypic Robustness ◽  
Robustness To Noise ◽  
Gene Regulatory

AbstractMendelian inheritance is a fundamental law of genetics. Considering two alleles in a diploid, a phenotype of a heterotype is dominated by a particular homotype according to the law of dominance. This picture is usually based on simple genotype-phenotype mapping in which one gene regulates one phenotype. However, in reality, some interactions between genes can result in deviation from Mendelian dominance.Here, by using the numerical evolution of diploid gene regulatory networks (GRNs), we discuss whether Mendelian dominance evolves beyond the classical case of one-to-one genotype-phenotype mapping. We examine whether complex genotype-phenotype mapping can achieve Mendelian dominance through the evolution of the GRN with interacting genes. Specifically, we extend the GRN model to a diploid case, in which two GRN matrices are added to give gene expression dynamics, and simulate evolution with meiosis and recombination. Our results reveal that Mendelian dominance evolves even under complex genotype-phenotype mapping. This dominance is achieved via a group of genotypes that differ from each other but have a common phenotype given by the expression of target genes. Calculating the degree of dominance shows that it increases through the evolution, correlating closely with the decrease in phenotypic fluctuations and the increase in robustness to initial noise. This evolution of Mendelian dominance is associated with phenotypic robustness against meiosis-induced genome mixing, whereas sexual recombination arising from the mixing of chromosomes from the parents further enhances dominance and robustness. Owing to this dominance, the robustness to genetic differences increases, while the optimal fitness is sustained up to a large difference between the two genomes. In summary, Mendelian dominance is achieved by groups of genotypes that are associated with the increase in phenotypic robustness to noise.Author summaryMendelian dominance is one of the most fundamental laws in genetics. When two conflicting characters occur in a single diploid, the dominant character is always chosen. Assuming that one gene makes one character, this law is simple to grasp. However, in reality, phenotypes are generated via interactions between several genes, which may alter Mendel’s dominance law. The evolution of robustness to noise and mutations has been investigated extensively using complex expression dynamics with gene regulatory networks. Here, we applied gene-expression dynamics with complex interactions to the case of a diploid and simulated the evolution of the gene regulatory network to generate the optimal phenotype given by a certain gene expression pattern. Interestingly, after evolution, Mendelian dominance is achieved via a group of genes. This group-based Mendelian dominance is shaped by phenotype insensitivity to genome mixing by meiosis and evolves concurrently with the robustness to noise. By focusing on the influence of phenotypic robustness, which has received considerable attention recently, our result provides a novel perspective as to why Mendel’s law of dominance is commonly observed.

scholarly journals TReNCo: Topologically associating domain (TAD) aware regulatory network construction

2021 ◽  
Author(s):  
Christopher Bennett ◽  
Viren Amin ◽  
Daehwan Kim ◽  
Murat Cobanoglu ◽  
Venkat Malladi
Keyword(s):  
Gene Regulatory Networks ◽  
Regulatory Network ◽  
Regulatory Networks ◽  
Cardiac Development ◽  
Network Construction ◽  
Biologically Relevant ◽  
Topologically Associated Domains ◽  
Gene Regulatory ◽  
Context Specific ◽  
Tf Gene

AbstractThere has long been a desire to understand, describe, and model gene regulatory networks controlling numerous biologically meaningful processes like differentiation. Despite many notable improvements to models over the years, many models do not accurately capture subtle biological and chemical characteristics of the cell such as high-order chromatin domains of the chromosomes. Topologically Associated Domains (TAD) are one of these genomic regions that are enriched for contacts within themselves. Here we present TAD-aware Regulatory Network Construction or TReNCo, a memory-lean method utilizing epigenetic marks of enhancer and promoter activity, and gene expression to create context-specific transcription factor-gene regulatory networks. TReNCo utilizes common assay’s, ChIP-seq, RNA-seq, and TAD boundaries as a hard cutoff, instead of distance based, to efficiently create context-specific TF-gene regulatory networks. We used TReNCo to define the enhancer landscape and identify transcription factors (TFs) that drive the cardiac development of the mouse. Our results show that we are able to build specialized adjacency regulatory network graphs containing biologically relevant connections and time dependent dynamics.

scholarly journals A systems biology approach uncovers the core gene regulatory network governing iridophore fate choice from the neural crest

2018 ◽  
Author(s):  
K. Petratou ◽  
T. Subkhankulova ◽  
J. A. Lister ◽  
A. Rocco ◽  
H. Schwetlick ◽  
...  
Keyword(s):  
Gene Expression ◽  
Neural Crest ◽  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
Pigment Cells ◽  
The Core ◽  
Gene Expression Dynamics ◽  
Qualitative Nature ◽  
Gene Regulatory ◽  
Parameter Values

AbstractMultipotent neural crest (NC) progenitors generate an astonishing array of derivatives, including neuronal, skeletal components and pigment cells (chromatophores), but the molecular mechanisms allowing balanced selection of each fate remain unknown. In zebrafish, melanocytes, iridophores and xanthophores, the three chromatophore lineages, are thought to share progenitors and so lend themselves to investigating the complex gene regulatory networks (GRNs) underlying fate segregation of NC progenitors. Although the core GRN governing melanocyte specification has been previously established, those guiding iridophore and xanthophore development remain elusive. Here we focus on the iridophore GRN, where mutant phenotypes identify the transcription factors Sox10, Tfec and Mitfa and the receptor tyrosine kinase, Ltk, as key players. We present expression data, as well as loss and gain of function results, guiding the derivation of an initial iridophore specification GRN. Moreover, we use an iterative process of mathematical modelling, supplemented with a novel, Monte Carlo screening algorithm suited to the qualitative nature of the experimental data, to allow for rigorous predictive exploration of the GRN dynamics. Predictions were experimentally evaluated and testable hypotheses were derived to construct an improved version of the GRN, which we showed produced outputs consistent with experimentally observed gene expression dynamics. Our study reveals multiple important regulatory features, notably a sox10-dependent positive feedback loop between tfec and ltk driving iridophore specification; the molecular basis of sox10 maintenance throughout iridophore development; and the cooperation between sox10 and tfec in driving expression of pnp4a, a key differentiation gene. We also assess a candidate repressor of mitfa, a melanocyte-specific target of sox10. Surprisingly, our data challenge the reported role of Foxd3, an established mitfa repressor, in iridophore regulation. Our study builds upon our previous systems biology approach, by incorporating physiologically-relevant parameter values and rigorous evaluation of parameter values within a qualitative data framework, to establish for the first time the core GRN guiding specification of the iridophore lineage.Author SummaryMultipotent neural crest (NC) progenitors generate an astonishing array of derivatives, including neuronal, skeletal components and pigment cells, but the molecular mechanisms allowing balanced selection of each fate remain unknown. In zebrafish, melanocytes, iridophores and xanthophores, the three chromatophore lineages, are thought to share progenitors and so lend themselves to investigating the complex gene regulatory networks (GRNs) underlying fate segregation of NC progenitors. Although the core GRN governing melanocyte specification has been previously established, those guiding iridophore and xanthophore development remain elusive. Here we present expression data, as well as loss and gain of function results, guiding the derivation of a core iridophore specification GRN. Moreover, we use a process of mathematical modelling and rigorous computational exploration of the GRN to predict gene expression dynamics, assessing them by criteria suited to the qualitative nature of our current understanding of iridophore development. Predictions were experimentally evaluated and testable hypotheses were derived to construct an improved version of the GRN, which we showed produced outputs consistent with experimentally observed gene expression dynamics. The core iridophore GRN defined here is a key stepping stone towards exploring how chromatophores fate decisions are made in multipotent NC progenitors.

Sign in / Sign up

Export Citation Format

Share Document