scholarly journals Adaptation and compensation in a bacterial gene regulatory network evolving under antibiotic selection

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Vishwa Patel ◽  
Nishad Matange
Keyword(s):  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
High Pressures ◽  
Regulatory Protein ◽  
Bacterial Gene ◽  
Antibiotic Selection ◽  
E Coli ◽  
Evolutionary Response ◽  
Evolutionary Branch ◽  
Gene Regulatory

Gene regulatory networks allow organisms to generate coordinated responses to environmental challenges. In bacteria, regulatory networks are re-wired and re-purposed during evolution, though the relationship between selection pressures and evolutionary change is poorly understood. In this study, we discover that the early evolutionary response of Escherichia coli to the antibiotic trimethoprim involves derepression of PhoPQ signaling, an Mg2+-sensitive two-component system, by inactivation of the MgrB feedback-regulatory protein. We report that derepression of PhoPQ confers trimethoprim-tolerance to E. coli by hitherto unrecognized transcriptional upregulation of dihydrofolate reductase (DHFR), target of trimethoprim. As a result, mutations in mgrB precede and facilitate the evolution of drug resistance. Using laboratory evolution, genome sequencing, and mutation re-construction, we show that populations of E. coli challenged with trimethoprim are faced with the evolutionary ‘choice’ of transitioning from tolerant to resistant by mutations in DHFR, or compensating for the fitness costs of PhoPQ derepression by inactivating the RpoS sigma factor, itself a PhoPQ-target. Outcomes at this evolutionary branch-point are determined by the strength of antibiotic selection, such that high pressures favor resistance, while low pressures favor cost compensation. Our results relate evolutionary changes in bacterial gene regulatory networks to strength of selection and provide mechanistic evidence to substantiate this link.

scholarly journals Adaptation and Compensation in a Bacterial Gene Regulatory Network Evolving Under Antibiotic Selection

2021 ◽  
Author(s):  
Vishwa Patel ◽  
Nishad Matange
Keyword(s):  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
High Pressures ◽  
Regulatory Protein ◽  
Bacterial Gene ◽  
Antibiotic Selection ◽  
E Coli ◽  
Evolutionary Response ◽  
Evolutionary Branch ◽  
Gene Regulatory

Gene regulatory networks allow organisms to generate coordinated responses to environmental challenges. In bacteria, regulatory networks are re-wired and re-purposed during evolution, though the relationship between selection pressures and evolutionary change is poorly understood. In this study, we discover that early evolutionary response of Escherichia coli to the antibiotic trimethoprim involves de-repression of PhoPQ signalling, a Mg2+-sensitive two-component system, by inactivation of the MgrB feedback-regulatory protein. We report that de-repression of PhoPQ confers trimethoprim-tolerance to E. coli by hitherto unrecognized transcriptional up-regulation of dihydrofolate reductase (DHFR), target of trimethoprim. As a result, mutations in mgrB precede and facilitate the evolution of drug resistance. Using laboratory evolution, genome sequencing and mutation re-construction, we show that populations of E. coli challenged with trimethoprim are faced with the evolutionary "choice" of transitioning from tolerant to resistant by mutations in DHFR, or compensating for the fitness costs of PhoPQ de-repression by inactivating the RpoS sigma factor, itself a PhoPQ-target. Outcomes at this evolutionary branch-point are determined by strength of antibiotic selection, such that high pressures favour resistance, while low pressures favour cost-compensation. Our results relate evolutionary changes in bacterial gene regulatory networks to strength of selection and provide mechanistic evidence to substantiate this link.

scholarly journals Universal attenuators and their interactions with feedback loops in gene regulatory networks

2016 ◽  
Author(s):  
Dianbo Liu ◽  
Luca Albergante ◽  
Timothy J Newman
Keyword(s):  
Gene Expression ◽  
Gene Regulatory Networks ◽  
Gene Networks ◽  
Regulatory Networks ◽  
Human Cancer ◽  
Cancer Cell Line ◽  
Feedback Loops ◽  
Human Cancer Cell ◽  
E Coli ◽  
Gene Regulatory

AbstractUsing a combination of mathematical modelling, statistical simulation and large-scale data analysis we study the properties of linear regulatory chains (LRCs) within gene regulatory networks (GRNs). Our modelling indicates that downstream genes embedded within LRCs are highly insulated from the variation in expression of upstream genes, and thus LRCs act as attenuators. This observation implies a progressively weaker functionality of LRCs as their length increases. When analysing the preponderance of LRCs in the GRNs of E. coli K12 and several other organisms, we find that very long LRCs are essentially absent. In both E. coli and M. tuberculosis we find that four-gene LRCs are intimately linked to identical feedback loops that are involved in potentially chaotic stress response, indicating that the dynamics of these potentially destabilising motifs are strongly restrained under homeostatic conditions. The same relationship is observed in a human cancer cell line (K562), and we postulate that four-gene LRCs act as “universal attenuators”. These findings suggest a role for long LRCs in dampening variation in gene expression, thereby protecting cell identity, and in controlling dramatic shifts in cell-wide gene expression through inhibiting chaos-generating motifs.In briefWe present a general principle that linear regulatory chains exponentially attenuate the range of expression in gene regulatory networks. The discovery of a universal interplay between linear regulatory chains and genetic feedback loops in microorganisms and a human cancer cell line is analysed and discussed.HighlightsWithin gene networks, linear regulatory chains act as exponentially strong attenuators of upstream variationBecause of their exponential behaviour, linear regulatory chains beyond a few genes provide no additional functionality and are rarely observed in gene networks across a range of different organismsNovel interactions between four-gene linear regulatory chains and feedback loops were discovered in E. coli, M. tuberculosis and human cancer cells, suggesting a universal mechanism of control.

scholarly journals Mutations in Transcriptional Regulators Allow Selective Engineering of Signal Integration Logic

mBio ◽  
2014 ◽  
Vol 5 (3) ◽  
Author(s):  
Szabolcs Semsey
Keyword(s):  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Regulatory Protein ◽  
Point Mutations ◽  
Building Blocks ◽  
Regulatory Elements ◽  
Regulatory Proteins ◽  
Single Amino Acid ◽  
Signal Integration ◽  
Gene Regulatory

ABSTRACT Bacterial cells monitor their environment by sensing a set of signals. Typically, these environmental signals affect promoter activities by altering the activity of transcription regulatory proteins. Promoters are often regulated by more than one regulatory protein, and in these cases the relevant signals are integrated by certain logic. In this work, we study how single amino acid substitutions in a regulatory protein (GalR) affect transcriptional regulation and signal integration logic at a set of engineered promoters. Our results suggest that point mutations in regulatory genes allow independent evolution of regulatory logic at different promoters. IMPORTANCE Gene regulatory networks are built from simple building blocks, such as promoters, transcription regulatory proteins, and their binding sites on DNA. Many promoters are regulated by more than one regulatory input. In these cases, the inputs are integrated and allow transcription only in certain combinations of input signals. Gene regulatory networks can be easily rewired, because the function of cis-regulatory elements and promoters can be altered by point mutations. In this work, we tested how point mutations in transcription regulatory proteins can affect signal integration logic. We found that such mutations allow context-dependent engineering of signal integration logic at promoters, further contributing to the plasticity of gene regulatory networks.

scholarly journals An Integrated Database of Small RNAs and Their Interplay With Transcriptional Gene Regulatory Networks in Corynebacteria

2021 ◽  
Vol 12 ◽  
Author(s):  
Mariana Teixeira Dornelles Parise ◽  
Doglas Parise ◽  
Flavia Figueira Aburjaile ◽  
Anne Cybelle Pinto Gomide ◽  
Rodrigo Bentes Kato ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Gene Regulatory Networks ◽  
Small Rnas ◽  
Regulatory Networks ◽  
Transcriptional Regulatory Networks ◽  
Bacterial Gene ◽  
Bacterial Gene Expression ◽  
Transcriptional Regulatory ◽  
Animal Pathogens ◽  
Gene Regulatory

Small RNAs (sRNAs) are one of the key players in the post-transcriptional regulation of bacterial gene expression. These molecules, together with transcription factors, form regulatory networks and greatly influence the bacterial regulatory landscape. Little is known concerning sRNAs and their influence on the regulatory machinery in the genus Corynebacterium, despite its medical, veterinary and biotechnological importance. Here, we expand corynebacterial regulatory knowledge by integrating sRNAs and their regulatory interactions into the transcriptional regulatory networks of six corynebacterial species, covering four human and animal pathogens, and integrate this data into the CoryneRegNet database. To this end, we predicted sRNAs to regulate 754 genes, including 206 transcription factors, in corynebacterial gene regulatory networks. Amongst them, the sRNA Cd-NCTC13129-sRNA-2 is predicted to directly regulate ydfH, which indirectly regulates 66 genes, including the global regulator glxR in C. diphtheriae. All of the sRNA-enriched regulatory networks of the genus Corynebacterium have been made publicly available in the newest release of CoryneRegNet(www.exbio.wzw.tum.de/coryneregnet/) to aid in providing valuable insights and to guide future experiments.

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.

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