scholarly journals A synthetic gene circuit for measuring autoregulatory feedback control.

2015 ◽  
Author(s):  
Miquel Angel Schikora-Tamarit ◽  
Carlos Toscano-Ochoa ◽  
Julia Domingo Espinos ◽  
Lorena Espinar ◽  
Lucas Carey
Keyword(s):  
High Throughput ◽  
Negative Feedback ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Feedback Regulation ◽  
Feedback Loops ◽  
Expression Noise ◽  
Negative Feedback Loops

Auto regulatory feedback loops occur in the regulation of molecules ranging from ATP to MAP kinases to zinc. Negative feedback loops can increase a system′s robustness, while positive feedback loops can mediate transitions between cell states. Recent genome-wide experimental and computational studies predict hundreds of novel feedback loops. However, not all physical interactions are regulatory, and many experimental methods cannot detect self-interactions. Our understanding of regulatory feedback loops is therefore hampered by the lack of high-throughput methods to experimentally quantify the presence, strength, and temporal dynamics of auto regulatory feedback loops. Here we present a mathematical and experimental framework for high-throughput quantification of feedback regulation, and apply it to RNA binding proteins (RBPs) in yeast. Our method is able to determine the existence of both direct and indirect positive and negative feedback loops, and to quantify the strength of these loops. We experimentally validate our model using two RBPs which lack native feedback loops, and by the introduction of synthetic feedback loops. We find that the the RBP Puf3 does not natively participate in any direct or indirect feedback regulation, but that replacing the native 3′UTR with that of COX17 generates an auto-regulatory negative feedback loop which reduces gene expression noise. Likewise, the RBP Pub1 does not natively participate in any feedback loops, but a synthetic positive feedback loop involving Pub1 results in increased expression noise. Our results demonstrate a synthetic experimental system for quantifying the existence and strength of feedback loops using a combination of high-throughput experiments and mathematical modeling. This system will be of great use in measuring auto-regulatory feedback by RNA binding proteins, a regulatory motif that is difficult to quantify using existing high-throughput methods.

The principle of homeostasis in the hypothalamus-pituitary-adrenal system: new insight from positive feedback

2007 ◽  
Vol 293 (1) ◽  
pp. R83-R98 ◽  
Author(s):  
A. Peters ◽  
M. Conrad ◽  
C. Hubold ◽  
U. Schweiger ◽  
B. Fischer ◽  
...  
Keyword(s):  
Negative Feedback ◽  
Positive Feedback ◽  
Glucocorticoid Receptors ◽  
Current Knowledge ◽  
Biological Systems ◽  
Feedback Loops ◽  
Endocrine Disorders ◽  
Negative Feedback Loops ◽  
Adrenal System ◽  
Positive And Negative Feedback

Feedback control, both negative and positive, is a fundamental feature of biological systems. Some of these systems strive to achieve a state of equilibrium or “homeostasis”. The major endocrine systems are regulated by negative feedback, a process believed to maintain hormonal levels within a relatively narrow range. Positive feedback is often thought to have a destabilizing effect. Here, we present a “principle of homeostasis,” which makes use of both positive and negative feedback loops. To test the hypothesis that this homeostatic concept is valid for the regulation of cortisol, we assessed experimental data in humans with different conditions (gender, obesity, endocrine disorders, medication) and analyzed these data by a novel computational approach. We showed that all obtained data sets were in agreement with the presented concept of homeostasis in the hypothalamus-pituitary-adrenal axis. According to this concept, a homeostatic system can stabilize itself with the help of a positive feedback loop. The brain mineralocorticoid and glucocorticoid receptors—with their known characteristics—fulfill the key functions in the homeostatic concept: binding cortisol with high and low affinities, acting in opposing manners, and mediating feedback effects on cortisol. This study supports the interaction between positive and negative feedback loops in the hypothalamus-pituitary-adrenal system and in this way sheds new light on the function of dual receptor regulation. Current knowledge suggests that this principle of homeostasis could also apply to other biological systems.

scholarly journals Novel autoregulatory cases of alternative splicing coupled with nonsense-mediated mRNA decay

2018 ◽  
Author(s):  
Dmitri Pervouchine ◽  
Yaroslav Popov ◽  
Andy Berry ◽  
Beatrice Borsari ◽  
Adam Frankish ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Negative Feedback ◽  
Feedback Loop ◽  
Transcriptional Control ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Negative Feedback Loop ◽  
Control Of Gene Expression ◽  
Nonsense Mediated Decay ◽  
Premature Termination Codons

AbstractNonsense-mediated decay (NMD) is a eukaryotic mRNA surveillance system that selectively degrades transcripts with premature termination codons (PTC). Many RNA-binding proteins (RBP) regulate their expression levels by a negative feedback loop, in which RBP binds its own pre-mRNA and causes alternative splicing to introduce a PTC. We present a bioinformatic framework to identify novel such autoregulatory feedback loops by combining eCLIP assays for a large panel of RBPs with the data on shRNA inactivation of NMD pathway, and shRNA-depletion of RBPs followed by RNA-seq. We show that RBPs frequently bind their own pre-mRNAs and respond prominently to NMD pathway disruption. Poison and essential exons, i.e., exons that trigger NMD when included in the mRNA or skipped, respectively, respond oppositely to the inactivation of NMD pathway and to the depletion of their host genes, which allows identification of novel autoregulatory mechanisms for a number of human RBPs. For example, SRSF7 binds its own pre-mRNA and facilitates the inclusion of two poison exons; SFPQ binding promotes switching to an alternative distal 3’-UTR that is targeted by NMD; RPS3 activates a poison 5’-splice site in its pre-mRNA that leads to a frame shift; U2AF1 binding activates one of its two mutually exclusive exons, leading to NMD; TBRG4 is regulated by cluster splicing of its two essential exons. Our results indicate that autoregulatory negative feedback loop of alternative splicing and NMD is a generic form of post-transcriptional control of gene expression.

Numerical analysis of a comprehensive model of M-phase control in Xenopus oocyte extracts and intact embryos

1993 ◽  
Vol 106 (4) ◽  
pp. 1153-1168 ◽  
Author(s):  
B. Novak ◽  
J.J. Tyson
Keyword(s):  
Negative Feedback ◽  
Positive Feedback ◽  
Xenopus Oocyte ◽  
Feedback Loop ◽  
Phase Control ◽  
Feedback Loops ◽  
Negative Feedback Loop ◽  
Time Lags ◽  
Tyrosine Residue ◽  
M Phase

To contribute to a deeper understanding of M-phase control in eukaryotic cells, we have constructed a model based on the biochemistry of M-phase promoting factor (MPF) in Xenopus oocyte extracts, where there is evidence for two positive feedback loops (MPF stimulates its own production by activating Cdc25 and inhibiting Wee1) and a negative feedback loop (MPF stimulates its own destruction by indirectly activating the ubiquitin pathway that degrades its cyclin subunit). To uncover the full dynamical possibilities of the control system, we translate the regulatory network into a set of differential equations and study these equations by graphical techniques and computer simulation. The positive feedback loops in the model account for thresholds and time lags in cyclin-induced and MPF-induced activation of MPF, and the model can be fitted quantitatively to these experimental observations. The negative feedback loop is consistent with observed time lags in MPF-induced cyclin degradation. Furthermore, our model indicates that there are two possible mechanisms for autonomous oscillations. One is driven by the positive feedback loops, resulting in phosphorylation and abrupt dephosphorylation of the Cdc2 subunit at an inhibitory tyrosine residue. These oscillations are typical of oocyte extracts. The other type is driven by the negative feedback loop, involving rapid cyclin turnover and negligible phosphorylation of the tyrosine residue of Cdc2. The early mitotic cycles of intact embryos exhibit such characteristics. In addition, by assuming that unreplicated DNA interferes with M-phase initiation by activating the phosphatases that oppose MPF in the positive feedback loops, we can simulate the effect of addition of sperm nuclei to oocyte extracts, and the lengthening of cycle times at the mid-blastula transition of intact embryos.

scholarly journals Positive Feedback Promotes Oscillations in Negative Feedback Loops

PLoS ONE ◽  
2014 ◽  
Vol 9 (8) ◽  
pp. e104761 ◽  
Author(s):  
Bharath Ananthasubramaniam ◽  
Hanspeter Herzel
Keyword(s):  
Negative Feedback ◽  
Positive Feedback ◽  
Feedback Loops ◽  
Negative Feedback Loops

scholarly journals Overlaid positive and negative feedback loops shape dynamical properties of PhoPQ two-component system

2021 ◽  
Vol 17 (1) ◽  
pp. e1008130
Author(s):  
Satyajit D Rao ◽  
Oleg A Igoshin
Keyword(s):  
Steady State ◽  
Negative Feedback ◽  
Positive Feedback ◽  
Feedback Loops ◽  
General Mechanism ◽  
Response Dynamics ◽  
Negative Feedback Loops ◽  
Two Component ◽  
Positive And Negative Feedback ◽  
Dynamical Properties

Bacteria use two-component systems (TCSs) to sense environmental conditions and change gene expression in response to those conditions. To amplify cellular responses, many bacterial TCSs are under positive feedback control, i.e. increase their expression when activated. Escherichia coli Mg2+ -sensing TCS, PhoPQ, in addition to the positive feedback, includes a negative feedback loop via the upregulation of the MgrB protein that inhibits PhoQ. How the interplay of these feedback loops shapes steady-state and dynamical responses of PhoPQ TCS to change in Mg2+ remains poorly understood. In particular, how the presence of MgrB feedback affects the robustness of PhoPQ response to overexpression of TCS is unclear. It is also unclear why the steady-state response to decreasing Mg2+ is biphasic, i.e. plateaus over a range of Mg2+ concentrations, and then increases again at growth-limiting Mg2+. In this study, we use mathematical modeling to identify potential mechanisms behind these experimentally observed dynamical properties. The results make experimentally testable predictions for the regime with response robustness and propose a novel explanation of biphasic response constraining the mechanisms for modulation of PhoQ activity by Mg2+ and MgrB. Finally, we show how the interplay of positive and negative feedback loops affects the network’s steady-state sensitivity and response dynamics. In the absence of MgrB feedback, the model predicts oscillations thereby suggesting a general mechanism of oscillatory or pulsatile dynamics in autoregulated TCSs. These results improve the understanding of TCS signaling and other networks with overlaid positive and negative feedback.

scholarly journals Interplay of positive and negative feedback loops governs robustness in multistable biological networks

2021 ◽  
Author(s):  
Anish Hebbar ◽  
Ankush Moger ◽  
Kishore Hari ◽  
Mohit Kumar Jolly
Keyword(s):  
Negative Feedback ◽  
Network Topology ◽  
Positive Feedback ◽  
Biological Networks ◽  
Continuous Model ◽  
Feedback Loops ◽  
Large Networks ◽  
Structural Robustness ◽  
Negative Feedback Loops ◽  
Positive And Negative Feedback

Biological networks are widely reported to be robust to both external and internal perturbations. However, the exact mechanisms and design principles that enable robustness are not yet fully understood. Here we investigated dynamic and structural robustness in biological networks with regards to phenotypic distribution and plasticity. We use two different approaches to simulate these networks: a computationally inexpensive, parameter-independent continuous model, and an ODE-based parameter-agnostic framework (RACIPE), both of which yield similar phenotypic distributions. Using perturbations to network topology and by varying network parameters, we show that multistable biological networks are structurally and dynamically more robust as compared to their randomized counterparts. These features of robustness are governed by an interplay of positive and negative feedback loops embedded in these networks. Using a combination of the number of negative and positive feedback loops weighted by their lengths and sign, we identified a metric that can explain the structural and dynamical robustness of these networks. This metric enabled us to compare networks across multiple sizes, and the network principles thus obtained can be used to identify fragilities in large networks without simulating their dynamics. Our analysis highlights a network topology based approach to quantify robustness in multistable biological networks.

Autoregulatory control of the p53 response by Siah-1L-mediated HIPK2 degradation

2009 ◽  
Vol 390 (10) ◽  
Author(s):  
Marco A. Calzado ◽  
Laureano de la Vega ◽  
Eduardo Muñoz ◽  
M. Lienhard Schmitz
Keyword(s):  
Tumor Suppressor ◽  
Family Member ◽  
Negative Feedback ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Feedback Loops ◽  
Negative Feedback Loop ◽  
Tumor Suppressor P53 ◽  
Ubiquitin E3 Ligase ◽  
P53 Response

Abstract The different activities of the tumor suppressor p53 are tightly regulated by various negative and positive feedback loops, which allow accurate control of its function. Here we show that the p53-inducible ubiquitin E3 ligase Siah-1L can bind to the p53 phosphorylating kinase HIPK2 and thus allows its ubiquitination and proteasomal elimination. Siah-1L also eliminates the HIPK family member HIPK3, indicating that its activity is not restricted to one member of the HIPK family. The stimulating effect of HIPK2 on p53-triggered transcription is counteracted by Siah-1L, thus showing the occurrence of another negative feedback loop controlling the p53 response.

scholarly journals Overlaid positive and negative feedback loops shape dynamical properties of PhoPQ two-component system

2020 ◽  
Author(s):  
Satyajit D Rao ◽  
Oleg A Igoshin
Keyword(s):  
Steady State ◽  
Negative Feedback ◽  
Positive Feedback ◽  
Feedback Loops ◽  
Dynamic Responses ◽  
Negative Feedback Loops ◽  
Two Component ◽  
Positive And Negative Feedback ◽  
Gene Regulatory ◽  
Dynamical Properties

AbstractBacteria use two-component systems (TCSs) to sense environmental conditions and change gene expression to adapt to those conditions. To amplify cellular responses, many bacterial TCSs are under positive feedback control, i.e. increase their own expression when activated. In E. coli, Mg2+-sensing TCS, PhoPQ, in addition to the positive feedback includes a negative feedback via upregulation of MgrB protein that inhibits PhoQ. How interplay of these feedback loops shapes steady state and dynamical responses of PhoPQ TCS to change in Mg2+remains poorly understood. In particular, how the presence of MgrB feedback affects the robustness of PhoPQ response to overexpression of TCS is unclear. It is also unclear why the steady state response to decreasing Mg2+is biphasic, i.e. plateaus over a range of Mg2+concentrations and then increases again at growth-limiting Mg2+. In this study, we use mathematical modeling to identify potential mechanisms behind these experimentally observed dynamical properties. The results make experimentally testable predictions for the regime with response robustness and propose novel explanation of biphasic response constraining the mechanisms for modulation of PhoQ activity by Mg2+and MgrB. Finally, we show how interplay of positive and negative feedback loops affect networks steady-state sensitivity and response dynamics. In the absence of MgrB feedback, the model predicts oscillations thereby suggesting a general mechanism of oscillatory or pulsatile dynamics in autoregulated TCSs. These results help better understanding of TCS signaling and other networks with overlaid positive and negative feedback.Author summaryFeedback loops are commonly observed in bacterial gene-regulatory networks to enable proper dynamical responses to stimuli. Positive feedback loops often amplify the response to stimulus, whereas negative feedback loops are known to speed-up the response and increase robustness. Here we demonstrate how combination of positive and negative feedback in network sensing extracellular ion concentrations affects its steady state and dynamic responses. We utilize published experimental data to calibrate mathematical models of the gene regulatory network. The resulting model quantitatively matches experimentally observed behavior and can make predictions on the mechanism of negative feedback control. Our results show the advantages of such a combination feedback loops and predict the effect of their perturbation on the steady state and dynamic responses. This study improves our understanding of how feedback loops shape dynamical properties of signaling networks.

scholarly journals RNA-binding proteins and circadian rhythms in Arabidopsis thaliana

2001 ◽  
Vol 356 (1415) ◽  
pp. 1755-1759 ◽  
Author(s):  
Dorothee Staiger
Keyword(s):  
Arabidopsis Thaliana ◽  
Feedback Loop ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Transcriptional Level ◽  
Reverse Genetic ◽  
Genetic Approach ◽  
Circadian Oscillators ◽  
Clock Proteins ◽  
Reverse Genetic Approach

An Arabidopsis transcript preferentially expressed at the end of the daily light period codes for the RNA–binding protein At GRP7. A reverse genetic approach in Arabidopsis thaliana has revealed its role in the generation of circadian rhythmicity: At GRP7 is part of a negative feedback loop through which it influences the oscillations of its own transcript. Biochemical and genetic experiments indicate a mechanism for this autoregulatory circuit: At grp7 gene transcription is rhythmically activated by the circadian clock during the day. The At GPR7 protein accumulates with a certain delay and represses further accumulation of its transcript, presumably at the post–transcriptional level. In this respect, the At GRP7 feedback loop differs from known circadian oscillators in the fruitfly Drosophila and mammals based on oscillating clock proteins that repress transcription of their own genes with a 24 h rhythm. It is proposed that the At GRP7 feedback loop may act within an output pathway from the Arabidopsis clock.

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