scholarly journals Operating principles of circular toggle polygons

2020 ◽  
Author(s):  
Souvadra Hati ◽  
Atchuta Srinivas Duddu ◽  
Mohit Kumar Jolly
Keyword(s):  
Decision Making ◽  
Cell Fate ◽  
Network Motif ◽  
Toggle Switch ◽  
Permutation Patterns ◽  
Design Strategies ◽  
Genetic Circuits ◽  
Stable States ◽  
Double Positive ◽  
Cell Fate Decisions

AbstractDecoding the dynamics of cellular decision-making and cell differentiation is a central question in cell and developmental biology. A common network motif involved in many cell-fate decisions is a mutually inhibitory feedback loop between two self-activating ‘master regulators’ A and B, also called as toggle switch. Typically, it can allow for three stable states – (high A, low B), (low A, high B) and (medium A, medium B). A toggle triad – three mutually repressing regulators A, B and C, i.e. three toggle switches arranged circularly (between A and B, between B and C, and between A and C) – can allow for six stable states: three ‘single positive’ and three ‘double positive’ ones. However, the operating principles of larger toggle polygons, i.e. toggle switches arranged circularly to form a polygon, remain unclear. Here, we simulate using both discrete and continuous methods the dynamics of different sized toggle polygons. We observed a pattern in their steady state frequency depending on whether the polygon was an even or odd numbered one. The even-numbered toggle polygons result in two dominant states with consecutive components of the network expressing alternating high and low levels. The odd-numbered toggle polygons, on the other hand, enable more number of states, usually twice the number of components with the states that follow ‘circular permutation’ patterns in their composition. Incorporating self-activations preserved these trends while increasing the frequency of multistability in the corresponding network. Our results offer insights into design principles of circular arrangement of regulatory units involved in cell-fate decision making, and can offer design strategies for synthesizing genetic circuits.

scholarly journals Multistability in cellular differentiation enabled by a network of three mutually repressing master regulators

2020 ◽  
Author(s):  
Atchuta Srinivas Duddu ◽  
Sarthak Sahoo ◽  
Souvadra Hati ◽  
Siddharth Jhunjhunwala ◽  
Mohit Kumar Jolly
Keyword(s):  
Decision Making ◽  
Network Motif ◽  
Design Principles ◽  
Cellular Reprogramming ◽  
Specific Cell ◽  
Toggle Switch ◽  
Double Positive ◽  
Master Regulators ◽  
Cellular Decision Making ◽  
Single Positive

AbstractIdentifying the design principles of complex regulatory networks driving cellular decision-making remains essential to decode embryonic development as well as enhance cellular reprogramming. A well-studied network motif involved in cellular decision-making is a toggle switch – a set of two opposing transcription factors A and B, each of which is a master regulator of a specific cell-fate and can inhibit the activity of the other. A toggle switch can lead to two possible states – (high A, low B) and (low A, high B), and drives the ‘either-or’ choice between these two cell-fates for a common progenitor cell. However, the principles of coupled toggle switches remains unclear. Here, we investigate the dynamics of three master regulators A, B and C inhibiting each other, thus forming three coupled toggle switches to form a toggle triad. Our simulations show that this toggle triad can lead to co-existence of cells into three differentiated ‘single positive’ phenotypes – (high A, low B, low C), (low A, high B, low C), and (low A, low B, high C). Moreover, the hybrid or ‘double positive’ phenotypes – (high A, high B, low C), (low A, high B, high C) and (high A, low B, high C) – can co-exist together with ‘single positive’ phenotypes. Including self-activation loops on A, B and C can increase the frequency of ‘double positive’ states. Finally, we apply our results to understand the cellular decision-making in terms of differentiation of naïve CD4+ T cells into Th1, Th2 and Th17 states, where hybrid Th1/Th2 and hybrid Th1/Th17 cells have been reported in addition to the Th1, Th2 and Th17 ones. Our results offer novel insights into the design principles of a multistable network topology and provides a framework for synthetic biology to design tristable systems.

scholarly journals Multi-stability in cellular differentiation enabled by a network of three mutually repressing master regulators

2020 ◽  
Vol 17 (170) ◽  
pp. 20200631 ◽  
Author(s):  
Atchuta Srinivas Duddu ◽  
Sarthak Sahoo ◽  
Souvadra Hati ◽  
Siddharth Jhunjhunwala ◽  
Mohit Kumar Jolly
Keyword(s):  
Decision Making ◽  
Network Motif ◽  
Design Principles ◽  
Cellular Reprogramming ◽  
Specific Cell ◽  
Toggle Switch ◽  
Double Positive ◽  
Master Regulators ◽  
Cellular Decision Making ◽  
Single Positive

Identifying the design principles of complex regulatory networks driving cellular decision-making remains essential to decode embryonic development as well as enhance cellular reprogramming. A well-studied network motif involved in cellular decision-making is a toggle switch—a set of two opposing transcription factors A and B, each of which is a master regulator of a specific cell fate and can inhibit the activity of the other. A toggle switch can lead to two possible states—(high A, low B) and (low A, high B)—and drives the ‘either-or' choice between these two cell fates for a common progenitor cell. However, the principles of coupled toggle switches remain unclear. Here, we investigate the dynamics of three master regulators A, B and C inhibiting each other, thus forming three-coupled toggle switches to form a toggle triad. Our simulations show that this toggle triad can lead to co-existence of cells into three differentiated ‘single positive' phenotypes—(high A, low B, low C), (low A, high B, low C) and (low A, low B, high C). Moreover, the hybrid or ‘double positive' phenotypes—(high A, high B, low C), (low A, high B, high C) and (high A, low B, high C)—can coexist together with ‘single positive' phenotypes. Including self-activation loops on A, B and C can increase the frequency of ‘double positive' states. Finally, we apply our results to understand cellular decision-making in terms of differentiation of naive CD4 + T cells into Th1, Th2 and Th17 states, where hybrid Th1/Th2 and hybrid Th1/Th17 cells have been reported in addition to the Th1, Th2 and Th17 ones. Our results offer novel insights into the design principles of a multi-stable network topology and provide a framework for synthetic biology to design tristable systems.

scholarly journals TCF-1 limits the formation of Tc17 cells via repression of the MAF–RORγt axis

2019 ◽  
Vol 216 (7) ◽  
pp. 1682-1699 ◽  
Author(s):  
Lisa A. Mielke ◽  
Yang Liao ◽  
Ella Bridie Clemens ◽  
Matthew A. Firth ◽  
Brigette Duckworth ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Fate ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
T Cell Subsets ◽  
Double Positive ◽  
Cell Fate Decisions ◽  
Healthy Humans ◽  
Tc17 Cells

Interleukin (IL)-17–producing CD8+ T (Tc17) cells have emerged as key players in host-microbiota interactions, infection, and cancer. The factors that drive their development, in contrast to interferon (IFN)-γ–producing effector CD8+ T cells, are not clear. Here we demonstrate that the transcription factor TCF-1 (Tcf7) regulates CD8+ T cell fate decisions in double-positive (DP) thymocytes through the sequential suppression of MAF and RORγt, in parallel with TCF-1–driven modulation of chromatin state. Ablation of TCF-1 resulted in enhanced Tc17 cell development and exposed a gene set signature to drive tissue repair and lipid metabolism, which was distinct from other CD8+ T cell subsets. IL-17–producing CD8+ T cells isolated from healthy humans were also distinct from CD8+IL-17− T cells and enriched in pathways driven by MAF and RORγt. Overall, our study reveals how TCF-1 exerts central control of T cell differentiation in the thymus by normally repressing Tc17 differentiation and promoting an effector fate outcome.

scholarly journals Optimal evolutionary decision-making to store immune memory

2020 ◽  
Author(s):  
Oskar H Schnaack ◽  
Armita Nourmohammad
Keyword(s):  
Decision Making ◽  
Immune System ◽  
Cell Fate ◽  
Adaptive Immune System ◽  
Memory Formation ◽  
Immune Memory ◽  
Central Feature ◽  
Cell Fate Decisions ◽  
Adaptive Immune ◽  
Immune Receptors

The adaptive immune system in vertebrates consists of highly diverse immune receptors to mount specific responses against a multitude of pathogens. A central feature of the adaptive immune system is the ability to form a memory to act more efficiently in future encounters with similar pathogens. However, memory formation especially in B-cells is one of the least understood cell fate decisions in the immune system. Here, we present a framework to characterize optimal strategies to store memory in order to maximize the utility of immune response to counter evolving pathogens throughout an organism’s lifetime. To do so, we have incorporated the kinetics and energetics of memory response as ingredients of non-equilibrium decision-making between an adaptive exploration to mount a specific and novel response or exploitation of existing memory that can be activated rapidly yet with a reduced specificity against evolved pathogens. To achieve a long-term benefit for the host, we show that memory generation should be actively regulated and dependent on immune receptors’ affinity, with a preference for cross-reactive receptors with a moderate affinity against pathogens as opposed to high affinity receptors— a recipe that is consistent with recent experimental findings [1, 2]. Moreover, we show that the specificity of memory should depend on the organism’s lifespan, and shorter-lived organisms with fewer pathogenic encounters throughout their lifetime should store more cross-reactive memory. Overall, our framework provides a baseline to gauge the efficacy of immune memory formation in light of an organism’s coevolutionary history with pathogens.

scholarly journals Cell-to-cell ATP differences can modulate cellular decision-making

2020 ◽  
Vol 2 (7A) ◽  
Author(s):  
Ryan Kerr ◽  
Sara Jabbari ◽  
Iain Johnston
Keyword(s):  
Decision Making ◽  
Cell Fate ◽  
Regulatory Network ◽  
Phenotypic Diversity ◽  
Biological Systems ◽  
Energy Budgets ◽  
Specific Cell ◽  
Cell Fate Decisions ◽  
Cellular Decision Making ◽  
Intracellular Energy

Cells generate phenotypic diversity both during development and in response to stressful and changing environments, aiding survival. Functionally vital cell fate decisions from a range of phenotypic choices are made by regulatory networks, the dynamics of which rely on gene expression and hence depend on the cellular energy budget (and particularly ATP levels). However, despite pronounced cell-to-cell ATP differences observed across biological systems, the influence of energy availability on regulatory network dynamics is often overlooked as a cellular decision-making modulator, limiting our knowledge of how energy budgets affect cell behaviour. Here, we consider a mathematical model of a highly generalisable, ATP-dependent, decision-making regulatory network, and show that cell-to-cell ATP variability changes the sets of decisions a cell can make. Our model shows that increasing intracellular energy levels can increase the number of supported stable phenotypes, corresponding to increased decision-making capacity. Model cells with sub-threshold intracellular energy are limited to a singular phenotype, forcing the adoption of a specific cell fate. We suggest that energetic differences between cells may be an important consideration to help explain observed variability in cellular decision-making across a broad range of biological systems, including bacteria and the blood stem cell system.

scholarly journals Intracellular Energy Variability Modulates Cellular Decision-Making Capacity

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Ryan Kerr ◽  
Sara Jabbari ◽  
Iain G. Johnston
Keyword(s):  
Decision Making ◽  
Cell Fate ◽  
Regulatory Network ◽  
Phenotypic Diversity ◽  
Biological Systems ◽  
Specific Cell ◽  
Cell Fate Decisions ◽  
Cellular Decision Making ◽  
Decision Making Capacity ◽  
Intracellular Energy

AbstractCells generate phenotypic diversity both during development and in response to stressful and changing environments, aiding survival. Functionally vital cell fate decisions from a range of phenotypic choices are made by regulatory networks, the dynamics of which rely on gene expression and hence depend on the cellular energy budget (and particularly ATP levels). However, despite pronounced cell-to-cell ATP differences observed across biological systems, the influence of energy availability on regulatory network dynamics is often overlooked as a cellular decision-making modulator, limiting our knowledge of how energy budgets affect cell behaviour. Here, we consider a mathematical model of a highly generalisable, ATP-dependent, decision-making regulatory network, and show that cell-to-cell ATP variability changes the sets of decisions a cell can make. Our model shows that increasing intracellular energy levels can increase the number of supported stable phenotypes, corresponding to increased decision-making capacity. Model cells with sub-threshold intracellular energy are limited to a singular phenotype, forcing the adoption of a specific cell fate. We suggest that energetic differences between cells may be an important consideration to help explain observed variability in cellular decision-making across biological systems.

scholarly journals Quantifying Waddington landscapes and paths of non-adiabatic cell fate decisions for differentiation, reprogramming and transdifferentiation

2013 ◽  
Vol 10 (89) ◽  
pp. 20130787 ◽  
Author(s):  
Chunhe Li ◽  
Jin Wang
Keyword(s):  
Decision Making ◽  
Stem Cell ◽  
Cell Fate ◽  
Intermediate State ◽  
Regulatory Networks ◽  
Experimental Studies ◽  
Cell Fate Decision ◽  
Cell Fate Decisions ◽  
Decision Making Processes ◽  
Fate Decision

Cellular differentiation, reprogramming and transdifferentiation are determined by underlying gene regulatory networks. Non-adiabatic regulation via slow binding/unbinding to the gene can be important in these cell fate decision-making processes. Based on a stem cell core gene network, we uncovered the stem cell developmental landscape. As the binding/unbinding speed decreases, the landscape topography changes from bistable attractors of stem and differentiated states to more attractors of stem and other different cell states as well as substates. Non-adiabaticity leads to more differentiated cell types and provides a natural explanation for the heterogeneity observed in the experiments. We quantified Waddington landscapes with two possible cell fate decision mechanisms by changing the regulation strength or regulation timescale (non-adiabaticity). Transition rates correlate with landscape topography through barrier heights between different states and quantitatively determine global stability. We found the optimal speeds of these cell fate decision-making processes. We quantified biological paths and predict that differentiation and reprogramming go through an intermediate state (IM1), whereas transdifferentiation goes through another intermediate state (IM2). Some predictions are confirmed by recent experimental studies.

scholarly journals Phase separation drives decision making in cell division

2020 ◽  
Vol 295 (39) ◽  
pp. 13419-13431 ◽  
Author(s):  
Xing Liu ◽  
Xu Liu ◽  
Haowei Wang ◽  
Zhen Dou ◽  
Ke Ruan ◽  
...  
Keyword(s):  
Decision Making ◽  
Phase Separation ◽  
Cell Division ◽  
Cell Fate ◽  
Lipid Bilayers ◽  
New Paradigm ◽  
Research Directions ◽  
Cell Fate Decisions ◽  
New Research ◽  
Centromere Assembly

Liquid–liquid phase separation (LLPS) of biomolecules drives the formation of subcellular compartments with distinct physicochemical properties. These compartments, free of lipid bilayers and therefore called membraneless organelles, include nucleoli, centrosomes, heterochromatin, and centromeres. These have emerged as a new paradigm to account for subcellular organization and cell fate decisions. Here we summarize recent studies linking LLPS to mitotic spindle, heterochromatin, and centromere assembly and their plasticity controls in the context of the cell division cycle, highlighting a functional role for phase behavior and material properties of proteins assembled onto heterochromatin, centromeres, and central spindles via LLPS. The techniques and tools for visualizing and harnessing membraneless organelle dynamics and plasticity in mitosis are also discussed, as is the potential for these discoveries to promote new research directions for investigating chromosome dynamics, plasticity, and interchromosome interactions in the decision-making process during mitosis.

Synthetic biology for improving cell fate decisions and tissue engineering outcomes

2019 ◽  
Vol 3 (5) ◽  
pp. 631-643 ◽  
Author(s):  
Adam M. Vogel ◽  
Kylie M. Persson ◽  
Travis R. Seamons ◽  
Tara L. Deans
Keyword(s):  
Tissue Engineering ◽  
Stem Cells ◽  
Synthetic Biology ◽  
Cell Fate ◽  
Genome Engineering ◽  
Future Research ◽  
Genetic Circuits ◽  
Cell Fate Decisions ◽  
Work Done ◽  
The Way

Synthetic biology is a relatively new field of science that combines aspects of biology and engineering to create novel tools for the construction of biological systems. Using tools within synthetic biology, stem cells can then be reprogrammed and differentiated into a specified cell type. Stem cells have already proven to be largely beneficial in many different therapies and have paved the way for tissue engineering and regenerative medicine. Although scientists have made great strides in tissue engineering, there still remain many questions to be answered in regard to regeneration. Presented here is an overview of synthetic biology, common tools built within synthetic biology, and the way these tools are being used in stem cells. Specifically, this review focuses on how synthetic biologists engineer genetic circuits to dynamically control gene expression while also introducing emerging topics such as genome engineering and synthetic transcription factors. The findings mentioned in this review show the diverse use of stem cells within synthetic biology and provide a foundation for future research in tissue engineering with the use of synthetic biology tools. Overall, the work done using synthetic biology in stem cells is in its early stages, however, this early work is leading to new approaches for repairing diseased and damaged tissues and organs, and further expanding the field of tissue engineering.

scholarly journals Interrogating the Topological Robustness of Gene Regulatory Circuits

2016 ◽  
Author(s):  
Bin Huang ◽  
Mingyang Lu ◽  
Dongya Jia ◽  
Eshel Ben-Jacob ◽  
Herbert Levine ◽  
...  
Keyword(s):  
Cell Fate ◽  
Epithelial To Mesenchymal Transition ◽  
Dynamical Behavior ◽  
Computational Method ◽  
Toggle Switch ◽  
Stable States ◽  
Generic Properties ◽  
Mesenchymal Transition ◽  
Cellular Environment ◽  
Gene Regulatory

AbstractOne of the most important roles of cells is performing their cellular tasks properly for survival. Cells usually achieve robust functionality, for example cell-fate decision-making and signal transduction, through multiple layers of regulation involving many genes. Despite the combinatorial complexity of gene regulation, its quantitative behavior has been typically studied on the basis of experimentally-verified core gene regulatory circuitry, composed of a small set of important elements. It is still unclear how such a core circuit operates in the presence of many other regulatory molecules and in a crowded and noisy cellular environment. Here we report a new computational method, named random circuit perturbation (RACIPE), for interrogating the robust dynamical behavior of a gene regulatory circuit even without accurate measurements of circuit kinetic parameters. RACIPE generates an ensemble of random kinetic models corresponding to a fixed circuit topology, and utilizes statistical tools to identify generic properties of the circuit. By applying RACIPE to simple toggle-switch-like motifs, we observed that the stable states of all models converge to experimentally observed gene state clusters even when the parameters are strongly perturbed. RACIPE was further applied to a proposed 22-gene network of the Epithelial-to-Mesenchymal transition (EMT), from which we identified four experimentally observed gene states, including the states that are associated with two different types of hybrid Epithelial/Mesenchymal phenotypes. Our results suggest that dynamics of a gene circuit is mainly determined by its topology, not by detailed circuit parameters. Our work provides a theoretical foundation for circuit-based systems biology modeling. We anticipate RACIPE to be a powerful tool to predict and decode circuit design principles in an unbiased manner, and to quantitatively evaluate the robustness and heterogeneity of gene expression.

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