Stochastic Simulation Algorithm for Gene Regulatory Networks with Multiple Binding Sites

2015 ◽  
Vol 22 (3) ◽  
pp. 218-226 ◽  
Author(s):  
Mattia Petroni ◽  
Nikolaj Zimic ◽  
Miha Mraz ◽  
Miha Moškon
Keyword(s):  
Stochastic Simulation ◽  
Gene Regulatory Networks ◽  
Binding Sites ◽  
Regulatory Networks ◽  
Stochastic Simulation Algorithm ◽  
Simulation Algorithm ◽  
Multiple Binding Sites ◽  
Multiple Binding ◽  
Gene Regulatory

Modeling Gene Regulatory Networks with Delayed Stochastic Dynamics

2010 ◽  
pp. 198-218
Author(s):  
Andre S. Ribeiro ◽  
John J. Grefenstette ◽  
Stuart A. Kauffman
Keyword(s):  
Gene Expression ◽  
Stochastic Simulation ◽  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Stochastic Dynamics ◽  
Single Gene ◽  
Stochastic Simulation Algorithm ◽  
Simulation Algorithm ◽  
Gene Regulatory ◽  
Modeling Strategy

We present a recently developed modeling strategy of gene regulatory networks (GRN) that uses the delayed stochastic simulation algorithm to drive its dynamics. First, we present experimental evidence that led us to use this strategy. Next, we describe the stochastic simulation algorithm (SSA), and the delayed SSA, able to simulate time-delayed events. We then present a model of single gene expression. From this, we present the general modeling strategy of GRN. Specific applications of the approach are presented, beginning with the model of single gene expression which mimics a recent experimental measurement of gene expression at single-protein level, to validate our modeling strategy. We also model a toggle switch with realistic noise and delays, used in cells as differentiation pathway switches. We show that its dynamics differs from previous modeling strategies predictions. As a final example, we model the P53-Mdm2 feedback loop, whose malfunction is associated to 50% of cancers, and can induce cells apoptosis. In the end, we briefly discuss some issues in modeling the evolution of GRNs, and outline some directions for further research.

scholarly journals Stochastic resonances in a distributed genetic broadcasting system: the NF κ B/I κ B paradigm

2018 ◽  
Vol 15 (138) ◽  
pp. 20170809 ◽  
Author(s):  
Zhipeng Wang ◽  
Davit A. Potoyan ◽  
Peter G. Wolynes
Keyword(s):  
Gene Regulatory Networks ◽  
Binding Sites ◽  
Regulatory Networks ◽  
Stochastic Dynamics ◽  
Extracellular Signals ◽  
Broadcasting System ◽  
Gene Regulatory ◽  
And Performance ◽  
The Impact ◽  
Kinetic Regulation

Gene regulatory networks must relay information from extracellular signals to downstream genes in an efficient, timely and coherent manner. Many complex functional tasks such as the immune response require system-wide broadcasting of information not to one but to many genes carrying out distinct functions whose dynamical binding and unbinding characteristics are widely distributed. In such broadcasting networks, the intended target sites are also often dwarfed in number by the even more numerous non-functional binding sites. Taking the genetic regulatory network of NF κ B as an exemplary system we explore the impact of having numerous distributed sites on the stochastic dynamics of oscillatory broadcasting genetic networks pointing out how resonances in binding cycles control the network's specificity and performance. We also show that active kinetic regulation of binding and unbinding through molecular stripping of DNA bound transcription factors can lead to a higher coherence of gene-co-expression and synchronous clearance.

scholarly journals Metabolome, transcriptome, and bioinformatic cis-element analyses point to HNF-4 as a central regulator of gene expression during enterocyte differentiation

2006 ◽  
Vol 27 (2) ◽  
pp. 141-155 ◽  
Author(s):  
Anders Stegmann ◽  
Morten Hansen ◽  
Yulan Wang ◽  
Janus B. Larsen ◽  
Leif R. Lund ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Epithelial Cells ◽  
Gene Regulatory Networks ◽  
Binding Sites ◽  
Regulatory Networks ◽  
Resonance Spectroscopy ◽  
Magic Angle ◽  
Intestinal Epithelial ◽  
Gene Regulatory ◽  
Small Intestinal

DNA-binding transcription factors bind to promoters that carry their binding sites. Transcription factors therefore function as nodes in gene regulatory networks. In the present work we used a bioinformatic approach to search for transcription factors that might function as nodes in gene regulatory networks during the differentiation of the small intestinal epithelial cell. In addition we have searched for connections between transcription factors and the villus metabolome. Transcriptome data were generated from mouse small intestinal villus, crypt, and fetal intestinal epithelial cells. Metabolome data were generated from crypt and villus cells. Our results show that genes that are upregulated during fetal to adult and crypt to villus differentiation have an overrepresentation of potential hepatocyte nuclear factor (HNF)-4 binding sites in their promoters. Moreover, metabolome analyses by magic angle spinning 1H nuclear magnetic resonance spectroscopy showed that the villus epithelial cells contain higher concentrations of lipid carbon chains than the crypt cells. These findings suggest a model where the HNF-4 transcription factor influences the villus metabolome by regulating genes that are involved in lipid metabolism. Our approach also identifies transcription factors of importance for crypt functions such as DNA replication (E2F) and stem cell maintenance (c-Myc).

scholarly journals Programmatic access to bacterial regulatory networks with regutools

2020 ◽  
Vol 36 (16) ◽  
pp. 4532-4534
Author(s):  
Joselyn Chávez ◽  
Carmina Barberena-Jonas ◽  
Jesus E Sotelo-Fonseca ◽  
José Alquicira-Hernández ◽  
Heladia Salgado ◽  
...  
Keyword(s):  
Data Structures ◽  
Gene Regulatory Networks ◽  
Binding Sites ◽  
Regulatory Networks ◽  
R Package ◽  
Transcriptional Regulatory Networks ◽  
Dna Binding Sites ◽  
Transcriptional Regulatory ◽  
Gene Regulatory ◽  
Programmatic Access

Abstract Summary RegulonDB has collected, harmonized and centralized data from hundreds of experiments for nearly two decades and is considered a point of reference for transcriptional regulation in Escherichia coli K12. Here, we present the regutools R package to facilitate programmatic access to RegulonDB data in computational biology. regutools gives researchers the possibility of writing reproducible workflows with automated queries to RegulonDB. The regutools package serves as a bridge between RegulonDB data and the Bioconductor ecosystem by reusing the data structures and statistical methods powered by other Bioconductor packages. We demonstrate the integration of regutools with Bioconductor by analyzing transcription factor DNA binding sites and transcriptional regulatory networks from RegulonDB. We anticipate that regutools will serve as a useful building block in our progress to further our understanding of gene regulatory networks. Availability and implementation regutools is an R package available through Bioconductor at bioconductor.org/packages/regutools.

scholarly journals Filtering of Data-Driven Gene Regulatory Networks Using Drosophila melanogaster as a Case Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Yesid Cuesta-Astroz ◽  
Guilherme Gischkow Rucatti ◽  
Leandro Murgas ◽  
Carol D. SanMartín ◽  
Mario Sanhueza ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Drosophila Melanogaster ◽  
Gene Regulatory Networks ◽  
Binding Sites ◽  
Regulatory Networks ◽  
Target Genes ◽  
Regulation Of Gene Expression ◽  
Whole Genomes ◽  
Gene Regulatory

Gene Regulatory Networks (GRNs) allow the study of regulation of gene expression of whole genomes. Among the most relevant advantages of using networks to depict this key process, there is the visual representation of large amounts of information and the application of graph theory to generate new knowledge. Nonetheless, despite the many uses of GRNs, it is still difficult and expensive to assign Transcription Factors (TFs) to the regulation of specific genes. ChIP-Seq allows the determination of TF Binding Sites (TFBSs) over whole genomes, but it is still an expensive technique that can only be applied one TF at a time and requires replicates to reduce its noise. Once TFBSs are determined, the assignment of each TF and its binding sites to the regulation of specific genes is not trivial, and it is often performed by carrying out site-specific experiments that are unfeasible to perform in all possible binding sites. Here, we addressed these relevant issues with a two-step methodology using Drosophila melanogaster as a case study. First, our protocol starts by gathering all transcription factor binding sites (TFBSs) determined with ChIP-Seq experiments available at ENCODE and FlyBase. Then each TFBS is used to assign TFs to the regulation of likely target genes based on the TFBS proximity to the transcription start site of all genes. In the final step, to try to select the most likely regulatory TF from those previously assigned to each gene, we employ GENIE3, a random forest-based method, and more than 9,000 RNA-seq experiments from D. melanogaster. Following, we employed known TF protein-protein interactions to estimate the feasibility of regulatory events in our filtered networks. Finally, we show how known interactions between co-regulatory TFs of each gene increase after the second step of our approach, and thus, the consistency of the TF-gene assignment. Also, we employed our methodology to create a network centered on the Drosophila melanogaster gene Hr96 to demonstrate the role of this transcription factor on mitochondrial gene regulation.

scholarly journals Genome-Wide Transcription Factor DNA Binding Sites and Gene Regulatory Networks in Clostridium thermocellum

2021 ◽  
Vol 12 ◽  
Author(s):  
Skyler D. Hebdon ◽  
Alida T. Gerritsen ◽  
Yi-Pei Chen ◽  
Joan G. Marcano ◽  
Katherine J. Chou
Keyword(s):  
Dna Binding ◽  
Genetic Engineering ◽  
Gene Regulatory Networks ◽  
Binding Sites ◽  
Clostridium Thermocellum ◽  
Regulatory Networks ◽  
Cellulosic Biomass ◽  
Global Network ◽  
Genome Wide ◽  
Gene Regulatory

Clostridium thermocellum is a thermophilic bacterium recognized for its natural ability to effectively deconstruct cellulosic biomass. While there is a large body of studies on the genetic engineering of this bacterium and its physiology to-date, there is limited knowledge in the transcriptional regulation in this organism and thermophilic bacteria in general. The study herein is the first report of a large-scale application of DNA-affinity purification sequencing (DAP-seq) to transcription factors (TFs) from a bacterium. We applied DAP-seq to > 90 TFs in C. thermocellum and detected genome-wide binding sites for 11 of them. We then compiled and aligned DNA binding sequences from these TFs to deduce the primary DNA-binding sequence motifs for each TF. These binding motifs are further validated with electrophoretic mobility shift assay (EMSA) and are used to identify individual TFs’ regulatory targets in C. thermocellum. Our results led to the discovery of novel, uncharacterized TFs as well as homologues of previously studied TFs including RexA-, LexA-, and LacI-type TFs. We then used these data to reconstruct gene regulatory networks for the 11 TFs individually, which resulted in a global network encompassing the TFs with some interconnections. As gene regulation governs and constrains how bacteria behave, our findings shed light on the roles of TFs delineated by their regulons, and potentially provides a means to enable rational, advanced genetic engineering of C. thermocellum and other organisms alike toward a desired phenotype.

scholarly journals Cross-species analysis of melanoma enhancer logic using deep learning

2019 ◽  
Author(s):  
Liesbeth Minnoye ◽  
Ibrahim Ihsan Taskiran ◽  
David Mauduit ◽  
Maurizio Fazio ◽  
Linde Van Aerschot ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Melanoma Cell ◽  
Gene Regulatory Networks ◽  
Binding Sites ◽  
Regulatory Networks ◽  
Transcription Factor Binding Sites ◽  
Transcription Factor Binding ◽  
Factor Binding ◽  
Depth Analysis ◽  
Gene Regulatory

AbstractGenomic enhancers form the central nodes of gene regulatory networks by harbouring combinations of transcription factor binding sites. Deciphering the combinatorial code by which these binding sites are assembled within enhancers is indispensable to understand their regulatory involvement in establishing a cell’s phenotype, especially within biological systems with dysregulated gene regulatory networks, such as melanoma. In order to unravel the enhancer logic of the two most common melanoma cell states, namely the melanocytic and mesenchymal-like state, we combined comparative epigenomics with machine learning. By profiling chromatin accessibility using ATAC-seq on a cohort of 27 melanoma cell lines across six different species, we demonstrate the conservation of the two main melanoma states and their underlying master regulators. To perform an in-depth analysis of the enhancer architecture, we trained a deep neural network, called DeepMEL, to classify melanoma enhancers not only in the human genome, but also in other species. DeepMEL revealed the presence, organisation and positional specificity of important transcription factor binding sites. Together, this extensive analysis of the melanoma enhancer code allowed us to propose the concept of a core regulatory complex binding to melanocytic enhancers, consisting of SOX10, TFAP2A, MITF and RUNX, and to disentangle their individual roles in regulating enhancer accessibility and activity.

scholarly journals Variable levels of drift in tunicate cardiopharyngeal gene regulatory elements

EvoDevo ◽  
2019 ◽  
Vol 10 (1) ◽  
Author(s):  
William Colgan ◽  
Alexis Leanza ◽  
Ariel Hwang ◽  
Melissa B. DeBiasse ◽  
Isabel Llosa ◽  
...  
Keyword(s):  
Gene Regulatory Networks ◽  
Binding Sites ◽  
Regulatory Network ◽  
Network Architecture ◽  
Regulatory Networks ◽  
Regulatory Elements ◽  
Structural Constraints ◽  
Developmental Systems ◽  
Gene Regulatory ◽  
Developmental Systems Drift

Abstract Background Mutations in gene regulatory networks often lead to genetic divergence without impacting gene expression or developmental patterning. The rules governing this process of developmental systems drift, including the variable impact of selective constraints on different nodes in a gene regulatory network, remain poorly delineated. Results Here we examine developmental systems drift within the cardiopharyngeal gene regulatory networks of two tunicate species, Corella inflata and Ciona robusta. Cross-species analysis of regulatory elements suggests that trans-regulatory architecture is largely conserved between these highly divergent species. In contrast, cis-regulatory elements within this network exhibit distinct levels of conservation. In particular, while most of the regulatory elements we analyzed showed extensive rearrangements of functional binding sites, the enhancer for the cardiopharyngeal transcription factor FoxF is remarkably well-conserved. Even minor alterations in spacing between binding sites lead to loss of FoxF enhancer function, suggesting that bound trans-factors form position-dependent complexes. Conclusions Our findings reveal heterogeneous levels of divergence across cardiopharyngeal cis-regulatory elements. These distinct levels of divergence presumably reflect constraints that are not clearly associated with gene function or position within the regulatory network. Thus, levels of cis-regulatory divergence or drift appear to be governed by distinct structural constraints that will be difficult to predict based on network architecture.

scholarly journals Programmatic access to bacterial regulatory networks with regutools

2020 ◽  
Author(s):  
Joselyn Chávez ◽  
Carmina Barberena-Jonas ◽  
Jesus E. Sotelo-Fonseca ◽  
José Alquicira-Hernández ◽  
Heladia Salgado ◽  
...  
Keyword(s):  
Data Structures ◽  
Gene Regulatory Networks ◽  
Binding Sites ◽  
Regulatory Networks ◽  
Transcriptional Regulatory Networks ◽  
Link Type ◽  
Dna Binding Sites ◽  
Transcriptional Regulatory ◽  
Gene Regulatory ◽  
Programmatic Access

AbstractSummaryRegulonDB has collected, harmonized and centralized data from hundreds of experiments for nearly two decades and is considered a point of reference for transcriptional regulation in Escherichia coli K12. Here, we present the regutools R package to facilitate programmatic access to RegulonDB data in computational biology. regutools gives researchers the possibility of writing reproducible workflows with automated queries to RegulonDB. The regutools package serves as a bridge between RegulonDB data and the Bioconductor ecosystem by reusing the data structures and statistical methods powered by other Bioconductor packages. We demonstrate the integration of regutools with Bioconductor by analyzing transcription factor DNA binding sites and transcriptional regulatory networks from RegulonDB. We anticipate that regutools will serve as a useful building block in our progress to further our understanding of gene regulatory networks.Availability and Implementationregutools is an R package available through Bioconductor at bioconductor.org/packages/regutools.Contactgithub.com/ComunidadBioInfo/regutools, [email protected], [email protected].

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