The role of configuration and coupling in autoregulatory gene circuits

Wu, Kang; Rao, Christopher V.

doi:10.1111/j.1365-2958.2009.07011.x

Cited by 23 publications

(26 citation statements)

References 43 publications

(52 reference statements)

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“…Based on these results, the authors speculated that natural circuits could evolve using a similar approach - rather than evolve a circuit with a single regulator requiring precise biochemical properties, a more robust and facile solution may be obtained by simply linking together multiple regulators that alone lack the requisite properties. Similarly, others have shown that by changing the regulatory architecture of a circuit one can affect is behavior without commensurate changes in the underlying proteins [54], [55], [56]. We hypothesize that a similar process may have occurred with the SPI1 gene circuit.…”

Section: Discussionmentioning

confidence: 57%

The Role of Coupled Positive Feedback in the Expression of the SPI1 Type Three Secretion System in Salmonella

et al. 2010

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Salmonella enterica serovar Typhimurium is a common food-borne pathogen that induces inflammatory diarrhea and invades intestinal epithelial cells using a type three secretion system (T3SS) encoded within Salmonella pathogenicity island 1 (SPI1). The genes encoding the SPI1 T3SS are tightly regulated by a network of interacting transcriptional regulators involving three coupled positive feedback loops. While the core architecture of the SPI1 gene circuit has been determined, the relative roles of these interacting regulators and associated feedback loops are still unknown. To determine the function of this circuit, we measured gene expression dynamics at both population and single-cell resolution in a number of SPI1 regulatory mutants. Using these data, we constructed a mathematical model of the SPI1 gene circuit. Analysis of the model predicted that the circuit serves two functions. The first is to place a threshold on SPI1 activation, ensuring that the genes encoding the T3SS are expressed only in response to the appropriate combination of environmental and cellular cues. The second is to amplify SPI1 gene expression. To experimentally test these predictions, we rewired the SPI1 genetic circuit by changing its regulatory architecture. This enabled us to directly test our predictions regarding the function of the circuit by varying the strength and dynamics of the activating signal. Collectively, our experimental and computational results enable us to deconstruct this complex circuit and determine the role of its individual components in regulating SPI1 gene expression dynamics.

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Section: Discussionmentioning

confidence: 57%

The Role of Coupled Positive Feedback in the Expression of the SPI1 Type Three Secretion System in Salmonella

et al. 2010

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“…S5A to C in the supplemental material). However, we cannot directly compare these experiments with one another, as the responses to yeast extract and aTc are not orthogonal: as yeast extract concentrations increase, expression from the tetracycline-inducible P tetA promoter (23) decreases, for unknown reasons (see Fig. S5D in the supplemental material).…”

Section: Resultsmentioning

confidence: 99%

“…The data were normalized relative to those from the experiments using 0.2% yeast extract. (D) P tetA promoter activity as a function of aTc and yeast extract measured using mCherry transcriptional fusion in a strain where the repressor TetR is produced independently from the P tetR promoter (23). Data are averages from three independent repeats, and error bars indicate standard deviations.…”

Section: Supplemental Materialsmentioning

confidence: 99%

A Nutrient-Tunable Bistable Switch Controls Motility in Salmonella enterica Serovar Typhimurium

Koirala

Mears

Sim

et al. 2014

mBio

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Many bacteria are motile only when nutrients are scarce. In contrast, Salmonella enterica serovar Typhimurium is motile only when nutrients are plentiful, suggesting that this bacterium uses motility for purposes other than foraging, most likely for host colonization. In this study, we investigated how nutrients affect motility in S. enterica and found that they tune the fraction of motile cells. In particular, we observed coexisting populations of motile and nonmotile cells, with the distribution being determined by the concentration of nutrients in the growth medium. Interestingly, S. enterica responds not to a single nutrient but apparently to a complex mixture of them. Using a combination of experimentation and mathematical modeling, we investigated the mechanism governing this behavior and found that it results from two antagonizing regulatory proteins, FliZ and YdiV. We also found that a positive feedback loop involving the alternate sigma factor FliA is required, although its role appears solely to amplify FliZ expression. We further demonstrate that the response is bistable: that is, genetically identical cells can exhibit different phenotypes under identical growth conditions. Together, these results uncover a new facet of the regulation of the flagellar genes in S. enterica and further demonstrate how bacteria employ phenotypic diversity as a general mechanism for adapting to change in their environment.

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“…Of these hits, ten had an additional frank structural change to a divergent expression pattern originating between lacI and lacZ characters (e.g. in E. cloacae ), likely increasing system sensitivity to lacI repression in these cases [15]. Surprisingly, in other instances, extended window searching revealed the only proximal structural change to be a missing lacA gene.…”

Section: Resultsmentioning

confidence: 99%

Gene Network Homology in Prokaryotes Using a Similarity Search Approach: Queries of Quorum Sensing Signal Transduction

Quan

Bentley

2012

PLoS Comput Biol

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Bacterial cell-cell communication is mediated by small signaling molecules known as autoinducers. Importantly, autoinducer-2 (AI-2) is synthesized via the enzyme LuxS in over 80 species, some of which mediate their pathogenicity by recognizing and transducing this signal in a cell density dependent manner. AI-2 mediated phenotypes are not well understood however, as the means for signal transduction appears varied among species, while AI-2 synthesis processes appear conserved. Approaches to reveal the recognition pathways of AI-2 will shed light on pathogenicity as we believe recognition of the signal is likely as important, if not more, than the signal synthesis. LMNAST (Local Modular Network Alignment Similarity Tool) uses a local similarity search heuristic to study gene order, generating homology hits for the genomic arrangement of a query gene sequence. We develop and apply this tool for the E. coli lac and LuxS regulated (Lsr) systems. Lsr is of great interest as it mediates AI-2 uptake and processing. Both test searches generated results that were subsequently analyzed through a number of different lenses, each with its own level of granularity, from a binary phylogenetic representation down to trackback plots that preserve genomic organizational information. Through a survey of these results, we demonstrate the identification of orthologs, paralogs, hitchhiking genes, gene loss, gene rearrangement within an operon context, and also horizontal gene transfer (HGT). We found a variety of operon structures that are consistent with our hypothesis that the signal can be perceived and transduced by homologous protein complexes, while their regulation may be key to defining subsequent phenotypic behavior.

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The role of configuration and coupling in autoregulatory gene circuits

Cited by 23 publications

References 43 publications

The Role of Coupled Positive Feedback in the Expression of the SPI1 Type Three Secretion System in Salmonella

The Role of Coupled Positive Feedback in the Expression of the SPI1 Type Three Secretion System in Salmonella

A Nutrient-Tunable Bistable Switch Controls Motility in Salmonella enterica Serovar Typhimurium

Gene Network Homology in Prokaryotes Using a Similarity Search Approach: Queries of Quorum Sensing Signal Transduction

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