Nested feedback loops in gene regulation

Mengel, Benedicte; Krishna, Sandeep; Jensen, Mogens H.; Trusina, Ala

doi:10.1016/j.physa.2011.06.019

Cited by 11 publications

(9 citation statements)

References 26 publications

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“…For instance, the human NF-kB has feedback regulators comprised of other IkBs (e.g., IkB 3) and also other layers of negative feedback regulators, such as A20, which regulate the upstream nodes, IkB kinases (Hayden and Ghosh, 2008;Werner et al, 2008). The multi-layer negative feedback loops, a topology referred to as ''nested negative feedback loops'' (Mengel et al, 2012), facilitate complex regulation of the NF-kB dynamics. We speculated that we might be able to recapitulate this topology design of nested negative feedback loops to produce unique effects on the oscillatory waveforms.…”

Section: Parameter Tuning In the Initial Circuit Leads To Predictablementioning

confidence: 99%

Design of Tunable Oscillatory Dynamics in a Synthetic NF-κB Signaling Circuit

Zhang

Wang

et al. 2017

Cell Systems

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Although oscillatory circuits are prevalent in transcriptional regulation, it is unclear how a circuit's structure and the specific parameters that describe its components determine the shape of its oscillations. Here, we engineer a minimal, inducible human nuclear factor κB (NF-κB)-based system that is composed of NF-κB (RelA) and degradable inhibitor of NF-κB (IκBα), into the yeast, Saccharomyces cerevisiae. We define an oscillation's waveform quantitatively as a function of signal amplitude, rest time, rise time, and decay time; by systematically tuning RelA concentration, the strength of negative feedback, and the degradation rate of IκBα, we demonstrate that peak shape and frequency of oscillations can be controlled in vivo and predicted mathematically. In addition, we show that nested negative feedback loops can be employed to specifically tune the frequency of oscillations while leaving their peak shape unchanged. In total, this work establishes design principles that enable function-guided design of oscillatory signaling controllers in diverse synthetic biology applications.

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Section: Parameter Tuning In the Initial Circuit Leads To Predictablementioning

confidence: 99%

Design of Tunable Oscillatory Dynamics in a Synthetic NF-κB Signaling Circuit

Zhang

Wang

et al. 2017

Cell Systems

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“…Such nested feedback loops occur in other biological regulatory networks, and may consist of purely negative feedback, mixed positive and negative feedback, or purely positive feedback (Brandman et al , 2005; Tsai et al , 2008; Ray; Igoshin, 2010; Mengel et al , 2012). Interestingly even a simple two-component system may be capable of either positive or negative feedback behavior (Ray; Igoshin, 2010).…”

Section: Additional Sources Of Heterogeneitymentioning

confidence: 99%

“…Interestingly even a simple two-component system may be capable of either positive or negative feedback behavior (Ray; Igoshin, 2010). The presence of negative feedback is often used to drive oscillatory outputs, and the nesting of feedback loops may enhance control over oscillatory period or amplitude (Mengel et al , 2012). In pathways that contain only positive feedback, the nested architecture can provide rapid switching to an output state that is insensitive to noise in the upstream inputs (Brandman et al , 2005).…”

Section: Additional Sources Of Heterogeneitymentioning

confidence: 99%

Origins of heterogeneity in Streptococcus mutans competence: interpreting an environment-sensitive signaling pathway

Hagen¹,

Son

2017

Phys. Biol.

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Bacterial pathogens rely on chemical signaling and environmental cues to regulate disease-causing behavior in complex microenvironments. The human pathogen Streptococcus mutans employs a particularly complex signaling and sensing scheme to regulate genetic competence and other virulence behaviors in the oral biofilms it inhabits. Individual S. mutans cells make the decision to enter the competent state by integrating chemical and physical cues received from their microenvironment along with endogenously produced peptide signals. Studies at the single-cell level, using microfluidics to control the extracellular environment, provide physical insight into how the cells process these inputs to generate complex and often heterogeneous outputs. Fine changes in environmental stimuli can dramatically alter the behavior of the competence circuit. Small shifts in pH can switch the quorum sensing response on or off, while peptide-rich media appear to switch the output from a unimodal to a bimodal behavior. Therefore, depending on environmental cues, the quorum sensing circuitry can either synchronize virulence across the population, or initiate and amplify heterogeneity in that behavior. Much of this complex behavior can be understood within the framework of a quorum sensing system that can operate both as an intercellular signaling mechanism and intracellularly as a noisy bimodal switch.

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“…Though challenges surrounding the modularity and unpredictability of biological systems persist, thanks to fundamental biological research there is an ever-increasing assortment of biological elements that can be used for synthetic designs. Constructs can be built using systems operating on a range of molecular biological levels (for example, using DNA [36], RNA [37] or Protein [14]), as well as at varying time-scales [38], [39], [40] and species concentrations [31]. However, working with this disparate assortment of components requires extensive inter-disciplinary expertise, and can substantially increase the necessity for experimental troubleshooting and system fine-tuning.…”

Section: The Bacterial Chemotaxis System Is a Model Example Of A Natumentioning

confidence: 99%

Design Constraints for Biological Systems That Achieve Adaptation and Disturbance Rejection

Steel

Papachristodoulou

2018

IEEE Trans. Control Netw. Syst.

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Many processes in natural biological systems, such as chemotaxis in bacteria and osmoregulation in yeast, rely on control architectures fundamentally equivalent to commonly used motifs from electrical and control engineering. However, difficulties arise when designing and implementing these architectures in a biological context due to uncertainties inherent in the behaviour of biological systems, and physical limitations of the available parts. In this paper we discuss recent developments in the study of biological control systems, which are increasingly necessary for realisation of complex synthetic biological constructs, focusing on methods for their design and implementation. We establish a range of desirable properties that ease implementation of biological constructs, and apply classical control theory to derive a set of constraints to aid the design of systems that achieve adaptation or disturbance rejection. We demonstrate how these constraints can be used in practice, first deriving the necessary structure for a linear system that achieves adaptation, and then embedding this in a non-linear model of biological relevance that could be built in the laboratory.

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Nested feedback loops in gene regulation

Cited by 11 publications

References 26 publications

Design of Tunable Oscillatory Dynamics in a Synthetic NF-κB Signaling Circuit

Design of Tunable Oscillatory Dynamics in a Synthetic NF-κB Signaling Circuit

Origins of heterogeneity in Streptococcus mutans competence: interpreting an environment-sensitive signaling pathway

Design Constraints for Biological Systems That Achieve Adaptation and Disturbance Rejection

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