scholarly journals Unexpected links reflect the noise in networks

2013 ◽  
Author(s):  
Anatoly Yambartsev ◽  
Michael Perlin ◽  
Yevgeniy Kovchegov ◽  
Natalia Shulzhenko ◽  
Karina Mine ◽  
...  
Keyword(s):  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
Simulation Analysis ◽  
Biological Processes ◽  
Special Relationship ◽  
False Discovery ◽  
Precise Estimation ◽  
Gene Regulatory ◽  
The Mathematical Model

Gene regulatory networks are commonly used for modeling biological processes and revealing underlying molecular mechanisms. The reconstruction of gene regulatory networks from observational data is a challenging task, especially, considering the large number of involved players (e.g. genes) and much fewer biological replicates available for analysis. Herein, we proposed a new statistical method of estimating the number of erroneous edges that strongly enhances the commonly used inference approaches. This method is based on special relationship between correlation and causality, and allows to identify and to remove approximately half of erroneous edges. Using the mathematical model of Bayesian networks and positive correlation inequalities we established a mathematical foundation for our method. Analyzing real biological datasets, we found a strong correlation between the results of our method and the commonly used false discovery rate (FDR) technique. Furthermore, the simulation analysis demonstrates that in large networks, our new method provides a more precise estimation of the proportion of erroneous links than FDR.

scholarly journals Comprehensive Assessment and Network Analysis of the Emerging Genetic Susceptibility Landscape of Prostate Cancer

2013 ◽  
Vol 12 ◽  
pp. CIN.S12128 ◽  
Author(s):  
Chindo Hicks ◽  
Lucio Miele ◽  
Tejaswi Koganti ◽  
Srinivasan Vijayakumar
Keyword(s):  
Prostate Cancer ◽  
Genetic Susceptibility ◽  
Pathway Analysis ◽  
Gene Regulatory Networks ◽  
Genetic Variants ◽  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
Comprehensive Assessment ◽  
Increased Risk ◽  
Gene Regulatory

Background Recent advances in high-throughput genotyping have made possible identification of genetic variants associated with increased risk of developing prostate cancer using genome-wide associations studies (GWAS). However, the broader context in which the identified genetic variants operate is poorly understood. Here we present a comprehensive assessment, network, and pathway analysis of the emerging genetic susceptibility landscape of prostate cancer. Methods We created a comprehensive catalog of genetic variants and associated genes by mining published reports and accompanying websites hosting supplementary data on GWAS. We then performed network and pathway analysis using single nucleotide polymorphism (SNP)-containing genes to identify gene regulatory networks and pathways enriched for genetic variants. Results We identified multiple gene networks and pathways enriched for genetic variants including IGF-1, androgen biosynthesis and androgen signaling pathways, and the molecular mechanisms of cancer. The results provide putative functional bridges between GWAS findings and gene regulatory networks and biological pathways.

scholarly journals Chip-seq and gene expression data for the identification of functional sub-pathways: a proof of concept in lung cancer

2020 ◽  
Author(s):  
Xanthoula Atsalaki ◽  
Lefteris Koumakis ◽  
George Potamias ◽  
Manolis Tsiknakis
Keyword(s):  
Gene Expression ◽  
Lung Cancer ◽  
Systems Biology ◽  
Gene Expression Data ◽  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
Integrative Approach ◽  
Expression Data ◽  
Gene Regulatory

AbstractHigh-throughput technologies, such as chromatin immunoprecipitation (ChIP) with massively parallel sequencing (ChIP-seq) have enabled cost and time efficient generation of immense amount of genome data. The advent of advanced sequencing techniques allowed biologists and bioinformaticians to investigate biological aspects of cell function and understand or reveal unexplored disease etiologies. Systems biology attempts to formulate the molecular mechanisms in mathematical models and one of the most important areas is the gene regulatory networks (GRNs), a collection of DNA segments that somehow interact with each other. GRNs incorporate valuable information about molecular targets that can be corellated to specific phenotype.In our study we highlight the need to develop new explorative tools and approaches for the integration of different types of -omics data such as ChIP-seq and GRNs using pathway analysis methodologies. We present an integrative approach for ChIP-seq and gene expression data on GRNs. Using public microarray expression samples for lung cancer and healthy subjects along with the KEGG human gene regulatory networks, we identified ways to disrupt functional sub-pathways on lung cancer with the aid of CTCF ChIP-seq data, as a proof of concept.We expect that such a systems biology pipeline could assist researchers to identify corellations and causality of transcription factors over functional or disrupted biological sub-pathways.

scholarly journals Single cell and single nucleus RNA-Seq reveal cellular heterogeneity and homeostatic regulatory networks in adult mouse stria vascularis

2019 ◽  
Author(s):  
Soumya Korrapati ◽  
Ian Taukulis ◽  
Rafal Olszewski ◽  
Madeline Pyle ◽  
Shoujun Gu ◽  
...  
Keyword(s):  
Single Cell ◽  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
Stria Vascularis ◽  
Cell Types ◽  
Cellular Heterogeneity ◽  
Genetic Mechanisms ◽  
Single Nucleus ◽  
Gene Regulatory

AbstractThe stria vascularis (SV) generates the endocochlear potential (EP) in the inner ear and is necessary for proper hair cell mechanotransduction and hearing. While channels belonging to SV cell types are known to play crucial roles in EP generation, relatively little is known about gene regulatory networks that underlie the ability of the SV to generate and maintain the EP. Using single cell and single nucleus RNA-sequencing, we identify and validate known and rare cell populations in the SV. Furthermore, we establish a basis for understanding molecular mechanisms underlying SV function by identifying potential gene regulatory networks as well as druggable gene targets. Finally, we associate known deafness genes with adult SV cell types. This work establishes a basis for dissecting the genetic mechanisms underlying the role of the SV in hearing and will serve as a basis for designing therapeutic approaches to hearing loss related to SV dysfunction.

Prioritizing candidate disease-related long non-coding RNAs by walking on the heterogeneous lncRNA and disease network

2015 ◽  
Vol 11 (3) ◽  
pp. 760-769 ◽  
Author(s):  
Meng Zhou ◽  
Xiaojun Wang ◽  
Jiawei Li ◽  
Dapeng Hao ◽  
Zhenzhen Wang ◽  
...  
Keyword(s):  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Biological Processes ◽  
Disease Network ◽  
Wide Range ◽  
Gene Regulatory ◽  
Non Coding Rnas

Accumulated evidence has shown that long non-coding RNAs (lncRNA) act as a widespread layer in gene regulatory networks and are involved in a wide range of biological processes.

scholarly journals Local genetic context shapes the function of a gene regulatory network

2021 ◽  
Author(s):  
Anna Nagy-Staroń ◽  
Kathrin Tomasek ◽  
Caroline Caruso Carter ◽  
Elisabeth Sonnleitner ◽  
Bor Kavčič ◽  
...  
Keyword(s):  
Gene Regulatory Network ◽  
Gene Regulatory Networks ◽  
Regulatory Network ◽  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
Transcriptional Unit ◽  
Regulatory Sequences ◽  
Gene Regulatory ◽  
Context Shapes ◽  
Genetic Context

Gene expression levels are influenced by multiple coexisting molecular mechanisms. Some of these interactions, such as those of transcription factors and promoters have been studied extensively. However, predicting phenotypes of gene regulatory networks remains a major challenge. Here, we use a well-defined synthetic gene regulatory network to study how network phenotypes depend on local genetic context, i.e. the genetic neighborhood of a transcription factor and its relative position. We show that one gene regulatory network with fixed topology can display not only quantitatively but also qualitatively different phenotypes, depending solely on the local genetic context of its components. Our results demonstrate that changes in local genetic context can place a single transcriptional unit within two separate regulons without the need for complex regulatory sequences. We propose that relative order of individual transcriptional units, with its potential for combinatorial complexity, plays an important role in shaping phenotypes of gene regulatory networks.

scholarly journals Evolution and multiple roles of the Pancrustacea specific transcription factor zelda in insects

2017 ◽  
Author(s):  
Lupis Ribeiro ◽  
Vitória Tobias-Santos ◽  
Danielle Santos ◽  
Felipe Antunes ◽  
Geórgia Feltran ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Chromatin Accessibility ◽  
Multiple Roles ◽  
Biological Processes ◽  
Regulatory Modules ◽  
Ancestral Function ◽  
Gene Regulatory ◽  
Whole Egg

SummaryGene regulatory networks (GRN) evolve as a result of the coevolutionary process acting on transcription factors and the cis-regulatory modules (CRMs) they bind. The zinc-finger transcription factor (TF) zelda (zld) is essential for maternal zygotic transition (MZT) in Drosophila melanogaster, where it directly binds over thousand CRMs to regulate chromatin accessibility. D. melanogaster displays a long germ type of embryonic development, where all segments are simultaneously generated along the whole egg. However, it remains unclear if zld is also involved in MZT of short-germ insects (including those from basal lineages) or in other biological processes. Here we show that zld is an innovation of the Pancrustacea lineage, being absent in more distant arthropods (e.g. chelicerates) and other organisms. To better understand zld’s ancestral function, we thoroughly investigated its roles in a short-germ beetle, Tribolium castaneum, using molecular biology and computational approaches. Our results demonstrate roles for zld not only during the MZT, but also in posterior segmentation and patterning of imaginal disc derived structures. Further, we also demonstrate that zld is critical for posterior segmentation in the hemipteran Rhodnius prolixus, indicating this function predates the origin of holometabolous insects and was subsequently lost in long-germ insects. Our results unveil new roles of zld in maintaining pluripotent state of progenitor cells at the posterior region and suggest that changes in expression of zld (and probably other pioneer TFs) are critical in the evolution of insect GRNs.

scholarly journals Local genetic context shapes the function of a gene regulatory network

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Anna Nagy-Staron ◽  
Kathrin Tomasek ◽  
Caroline Caruso Carter ◽  
Elisabeth Sonnleitner ◽  
Bor Kavčič ◽  
...  
Keyword(s):  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
Transcriptional Unit ◽  
Regulatory Sequences ◽  
Fixed Topology ◽  
Gene Regulatory ◽  
Context Shapes ◽  
Genetic Context ◽  
Gene Expression Levels

Gene expression levels are influenced by multiple coexisting molecular mechanisms. Some of these interactions such as those of transcription factors and promoters have been studied extensively. However, predicting phenotypes of gene regulatory networks (GRNs) remains a major challenge. Here, we use a well-defined synthetic GRN to study in Escherichia coli how network phenotypes depend on local genetic context, i.e. the genetic neighborhood of a transcription factor and its relative position. We show that one GRN with fixed topology can display not only quantitatively but also qualitatively different phenotypes, depending solely on the local genetic context of its components. Transcriptional read-through is the main molecular mechanism that places one transcriptional unit (TU) within two separate regulons without the need for complex regulatory sequences. We propose that relative order of individual TUs, with its potential for combinatorial complexity, plays an important role in shaping phenotypes of GRNs.

scholarly journals The mechanisms of gene regulatory networks constrain evolution: A lesson from synthetic circuits

2017 ◽  
Author(s):  
Yolanda Schaerli ◽  
Alba Jiménez ◽  
José M. Duarte ◽  
Ljiljana Mihajlovic ◽  
Julien Renggli ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Regulatory Networks ◽  
Phenotypic Variation ◽  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
Raw Material ◽  
Darwinian Evolution ◽  
Regulatory Mechanisms ◽  
Gene Regulatory ◽  
Organismal Development

AbstractPhenotypic variation is the raw material of adaptive Darwinian evolution. The phenotypic variation found in organismal development is biased towards certain phenotypes, but the molecular mechanisms behind such restrictions are still poorly understood. Gene regulatory networks have been proposed as one cause of constrained phenotypic variation. However, most of the evidence for this is theoretical rather than experimental. Here, we study evolutionary biases in two synthetic gene regulatory circuits expressed inE. colithat produce a gene expression stripe - a pivotal pattern in embryonic development. The two parental circuits produce the same phenotype, but create it through different regulatory mechanisms. We show that mutations cause distinct novel phenotypes in the two networks and use a combination of experimental measurements, mathematical modelling and DNA sequencing to understand why mutations bring forth only some but not other novel gene expression phenotypes. Our results reveal that the regulatory mechanisms of networks restrict the possible phenotypic variation upon mutation. Consequently, seemingly equivalent networks can indeed be distinct in how they constrain the outcome of further evolution.

scholarly journals Gene Regulatory Networks Generating the Phenomena of Additivity, Dominance and Epistasis

Genetics ◽  
2000 ◽  
Vol 155 (2) ◽  
pp. 969-980 ◽  
Author(s):  
Stig W Omholt ◽  
Erik Plahte ◽  
Leiv Øyehaug ◽  
Kefang Xiang
Keyword(s):  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Feedback Loop ◽  
Molecular Mechanisms ◽  
Gene Action ◽  
Gene Dosage ◽  
Dominant Negative ◽  
Protein Activity ◽  
Genetic Dominance ◽  
Gene Regulatory

Abstract We show how the phenomena of genetic dominance, overdominance, additivity, and epistasis are generic features of simple diploid gene regulatory networks. These regulatory network models are together sufficiently complex to catch most of the suggested molecular mechanisms responsible for generating dominant mutations. These include reduced gene dosage, expression or protein activity (haploinsufficiency), increased gene dosage, ectopic or temporarily altered mRNA expression, increased or constitutive protein activity, and dominant negative effects. As classical genetics regards the phenomenon of dominance to be generated by intralocus interactions, we have studied two one-locus models, one with a negative autoregulatory feedback loop, and one with a positive autoregulatory feedback loop. To include the phenomena of epistasis and downstream regulatory effects, a model of a three-locus signal transduction network is also analyzed. It is found that genetic dominance as well as overdominance may be an intra- as well as interlocus interaction phenomenon. In the latter case the dominance phenomenon is intimately connected to either feedback-mediated epistasis or downstream-mediated epistasis. It appears that in the intra- as well as the interlocus case there is considerable room for additive gene action, which may explain to some degree the predictive power of quantitative genetic theory, with its emphasis on this type of gene action. Furthermore, the results illuminate and reconcile the prevailing explanations of heterosis, and they support the old conjecture that the phenomenon of dominance may have an evolutionary explanation related to life history strategy.

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