Bistable responses in bacterial genetic networks: Designs and dynamical consequences

Tiwari, Abhinav; Ray, J. Christian J.; Narula, Jatin; Igoshin, Oleg A.

doi:10.1016/j.mbs.2011.03.004

Cited by 61 publications

(70 citation statements)

References 142 publications

(202 reference statements)

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“…In many other organisms, the cell fate decision has been shown to be controlled by the ultrasensitive activation of the master regulator through positive feedback, resulting in a bistable response. Thus, two stable states of the responses correspond to two distinct cell fates (47)(48)(49)(50)(51)(52)(53). Surprisingly, despite the presence of positive feedback in the phosphorelay architecture, we have found that the phosphorelay response to KinA induction is graded and nonultrasensitive.…”

Section: Discussionmentioning

confidence: 72%

Ultrasensitivity of the Bacillus subtilis sporulation decision

Narula

Devi

Fujita

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Starving Bacillus subtilis cells execute a gene expression program resulting in the formation of stress-resistant spores. Sporulation master regulator, Spo0A, is activated by a phosphorelay and controls the expression of a multitude of genes, including the forespore-specific sigma factor σ F and the mother cell-specific sigma factor σ E . Identification of the system-level mechanism of the sporulation decision is hindered by a lack of direct control over Spo0A activity. This limitation can be overcome by using a synthetic system in which Spo0A activation is controlled by inducing expression of phosphorelay kinase KinA. This induction results in a switch-like increase in the number of sporulating cells at a threshold of KinA. Using a combination of mathematical modeling and single-cell microscopy, we investigate the origin and physiological significance of this ultrasensitive threshold. The results indicate that the phosphorelay is unable to achieve a sufficiently fast and ultrasensitive response via its positive feedback architecture, suggesting that the sporulation decision is made downstream. In contrast, activation of σ F in the forespore and of σ E in the mother cell compartments occurs via a cascade of coherent feed-forward loops, and thereby can produce fast and ultrasensitive responses as a result of KinA induction. Unlike σ F activation, σ E activation in the mother cell compartment only occurs above the KinA threshold, resulting in completion of sporulation. Thus, ultrasensitive σ E activation explains the KinA threshold for sporulation induction. We therefore infer that under uncertain conditions, cells initiate sporulation but postpone making the sporulation decision to average stochastic fluctuations and to achieve a robust population response.cell fate | development | differentiation | stochasticity | network I n response to nutrient deprivation, Bacillus subtilis cells undergo asymmetrical cell division and then follow a cell differentiation program resulting in formation of metabolically inert spores (1, 2) (Fig. 1A). Sporulation requires the execution of a complex gene expression program involving hundreds of "sporulation" genes (3-6). The availability of a large number of genetic mutants that differ from the WT only in their sporulation response makes B. subtilis an ideal model system to study the relationship between gene expression and cell fate specification during bacterial differentiation (7).Progression of the sporulation program is under the control of a large regulatory network (hereafter called the sporulation network). This network involves the sporulation master regulator Spo0A and five alternative sigma factors (σ H , σ F , σ E , σ K , and σ G ) that are activated in precise temporal order (8). Initiation of the sporulation program is controlled by Spo0A (4, 9). The activity and concentration of this master transcription factor are regulated by phosphorelay through both posttranslational and transcriptional interactions (10). Posttranslationally, phosphoryl groups are transferred fro...

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Section: Discussionmentioning

confidence: 72%

Ultrasensitivity of the Bacillus subtilis sporulation decision

Narula

Devi

Fujita

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…As in other fields of engineering, advances have been enabled by the use of small interchangeable modules that are 'functionally equivalent' from an input -output perspective [2]. Bistable circuits-which play a role in essential biological processes, including cell fate specification [3], cell cycle progression [4] and apoptosis [5]-make up a particularly large and diverse functionally equivalent set [6]. Effectively characterizing and comparing these biocircuits is crucial for determining which design is in some sense optimal for a particular context.…”

Section: Introductionmentioning

confidence: 99%

An analytical approach to bistable biological circuit discrimination using real algebraic geometry

Siegal-Gaskins

Franco

Zhou

et al. 2015

J. R. Soc. Interface.

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Biomolecular circuits with two distinct and stable steady states have been identified as essential components in a wide range of biological networks, with a variety of mechanisms and topologies giving rise to their important bistable property. Understanding the differences between circuit implementations is an important question, particularly for the synthetic biologist faced with determining which bistable circuit design out of many is best for their specific application. In this work we explore the applicability of Sturm's theorem-a tool from nineteenth-century real algebraic geometryto comparing 'functionally equivalent' bistable circuits without the need for numerical simulation. We first consider two genetic toggle variants and two different positive feedback circuits, and show how specific topological properties present in each type of circuit can serve to increase the size of the regions of parameter space in which they function as switches. We then demonstrate that a single competitive monomeric activator added to a purely monomeric (and otherwise monostable) mutual repressor circuit is sufficient for bistability. Finally, we compare our approach with the Routh-Hurwitz method and derive consistent, yet more powerful, parametric conditions. The predictive power and ease of use of Sturm's theorem demonstrated in this work suggest that algebraic geometric techniques may be underused in biomolecular circuit analysis.

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“…However, a binary or greatly delayed response is not likely preferred by all signaling systems; rather, a continuous well-defined output in relation to input signals allows cells to make accurate and prompt adjustments. It has been suggested that most TCSs tend to be monostable and the TCS autoregulatory architecture is distinct from conventional positive feedback loops due to the negative phosphatase activities of bifunctional HKs [6], [7], [14]. Constitutively expressed TCSs often complement the loss of autoregulated systems without causing apparent differences in steady-state outputs under laboratory conditions [7], [15]–[19].…”

Section: Introductionmentioning

confidence: 99%

Evolutionary Tuning of Protein Expression Levels of a Positively Autoregulated Two-Component System

Gao

Stock

2013

PLoS Genet

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Cellular adaptation relies on the development of proper regulatory schemes for accurate control of gene expression levels in response to environmental cues. Over- or under-expression can lead to diminished cell fitness due to increased costs or insufficient benefits. Positive autoregulation is a common regulatory scheme that controls protein expression levels and gives rise to essential features in diverse signaling systems, yet its roles in cell fitness are less understood. It remains largely unknown how much protein expression is ‘appropriate’ for optimal cell fitness under specific extracellular conditions and how the dynamic environment shapes the regulatory scheme to reach appropriate expression levels. Here, we investigate the correlation of cell fitness and output response with protein expression levels of the E. coli PhoB/PhoR two-component system (TCS). In response to phosphate (Pi)-depletion, the PhoB/PhoR system activates genes involved in phosphorus assimilation as well as genes encoding themselves, similarly to many other positively autoregulated TCSs. We developed a bacteria competition assay in continuous cultures and discovered that different Pi conditions have conflicting requirements of protein expression levels for optimal cell fitness. Pi-replete conditions favored cells with low levels of PhoB/PhoR while Pi-deplete conditions selected for cells with high levels of PhoB/PhoR. These two levels matched PhoB/PhoR concentrations achieved via positive autoregulation in wild-type cells under Pi-replete and -deplete conditions, respectively. The fitness optimum correlates with the wild-type expression level, above which the phosphorylation output saturates, thus further increase in expression presumably provides no additional benefits. Laboratory evolution experiments further indicate that cells with non-ideal protein levels can evolve toward the optimal levels with diverse mutational strategies. Our results suggest that the natural protein expression levels and feedback regulatory schemes of TCSs are evolved to match the phosphorylation output of the system, which is determined by intrinsic activities of TCS proteins.

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Bistable responses in bacterial genetic networks: Designs and dynamical consequences

Cited by 61 publications

References 142 publications

Ultrasensitivity of the Bacillus subtilis sporulation decision

Ultrasensitivity of the Bacillus subtilis sporulation decision

An analytical approach to bistable biological circuit discrimination using real algebraic geometry

Evolutionary Tuning of Protein Expression Levels of a Positively Autoregulated Two-Component System

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