scholarly journals Landscape of epithelial-mesenchymal plasticity as an emergent property of coordinated teams in regulatory networks

2021 ◽  
Author(s):  
Kishore Hari ◽  
Varun Ullanat ◽  
Archana Balasubramanian ◽  
Aditi Gopalan ◽  
Mohit Kumar Jolly
Keyword(s):  
Decision Making ◽  
Regulatory Networks ◽  
Feedback Loop ◽  
Emergent Property ◽  
Toggle Switch ◽  
Cell Fates ◽  
Cellular Decision Making ◽  
Inhibitory Feedback ◽  
Decision Making Processes ◽  
Simple Network

Elucidating the principles of cellular decision-making is of fundamental importance. These decisions are often orchestrated by underlying regulatory networks. While we understand the dynamics of simple network motifs, how do large networks lead to a limited number of phenotypes, despite their complexity, remains largely elusive. Here, we investigate five different networks governing epithelial-mesenchymal plasticity and identified a latent design principles in their topology that limits their phenotypic repertoire - the presence of two 'teams' of nodes engaging in a mutually inhibitory feedback loop, forming a toggle switch. These teams are specific to these networks and directly shape the phenotypic landscape and consequently the frequency and stability of terminal phenotypes vs. the intermediary ones. Our analysis reveals that network topology alone can contain information about phenotypic distributions it can lead to, thus obviating the need to simulate them. We unravel topological signatures that can drive canalization of cell-fates during diverse decision-making processes.

scholarly journals Molecular mechanisms creating bistable switches at cell cycle transitions

Open Biology ◽  
2013 ◽  
Vol 3 (3) ◽  
pp. 120179 ◽  
Author(s):  
Anael Verdugo ◽  
P. K. Vinod ◽  
John J. Tyson ◽  
Bela Novak
Keyword(s):  
Cell Cycle ◽  
Mammalian Cells ◽  
Feedback Loop ◽  
Molecular Mechanisms ◽  
Eukaryotic Cell ◽  
Mitotic Checkpoint ◽  
Toggle Switch ◽  
Inhibitory Protein ◽  
Common Features ◽  
Cellular Decision Making

Progression through the eukaryotic cell cycle is characterized by specific transitions, where cells move irreversibly from stage i −1 of the cycle into stage i . These irreversible cell cycle transitions are regulated by underlying bistable switches, which share some common features. An inhibitory protein stalls progression, and an activatory protein promotes progression. The inhibitor and activator are locked in a double-negative feedback loop, creating a one-way toggle switch that guarantees an irreversible commitment to move forward through the cell cycle, and it opposes regression from stage i to stage i −1. In many cases, the activator is an enzyme that modifies the inhibitor in multiple steps, whereas the hypo-modified inhibitor binds strongly to the activator and resists its enzymatic activity. These interactions are the basis of a reaction motif that provides a simple and generic account of many characteristic properties of cell cycle transitions. To demonstrate this assertion, we apply the motif in detail to the G1/S transition in budding yeast and to the mitotic checkpoint in mammalian cells. Variations of the motif might support irreversible cellular decision-making in other contexts.

scholarly journals How can a binary switch within the pars tuberalis control seasonal timing of reproduction?

2018 ◽  
Vol 239 (1) ◽  
pp. R13-R25 ◽  
Author(s):  
Shona H Wood
Keyword(s):  
Decision Making ◽  
Environmental Changes ◽  
Seasonal Reproduction ◽  
Pars Tuberalis ◽  
Seasonal Timing ◽  
Fate Determination ◽  
Cellular Decision Making ◽  
Binary Switch ◽  
Decision Making Processes ◽  
Binary Switching

Life in seasonally changing environments is challenging. Biological systems have to not only respond directly to the environment, but also schedule life history events in anticipation of seasonal changes. The cellular and molecular basis of how these events are scheduled is unknown. Cellular decision-making processes in response to signals above certain thresholds regularly occur i.e. cellular fate determination, apoptosis and firing of action potentials. Binary switches, the result of cellular decision-making processes, are defined as a change in phenotype between two stable states. A recent study presents evidence of a binary switch operating in the pars tuberalis (PT) of the pituitary, seemingly timing seasonal reproduction in sheep. Though, how a binary switch would allow for anticipation of seasonal environmental changes, not just direct responsiveness, is unclear. The purpose of this review is to assess the evidence for a binary switching mechanism timing seasonal reproduction and to hypothesize how a binary switch would allow biological processes to be timed over weeks to years. I draw parallels with mechanisms used in development, cell fate determination and seasonal timing in plants. I propose that the adult PT is a plastic tissue, showing a seasonal cycle of cellular differentiation, and that the underlying processes are likely to be epigenetic. Therefore, considering the mechanisms behind adult cellular plasticity offers a framework to hypothesize how a long-term timer functions within the PT.

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.

Interest Groups and the (Non-)Enforcement Powers of EU Agencies: The Case of Energy Regulation

2019 ◽  
Vol 10 (3) ◽  
pp. 458-484
Author(s):  
Martino MAGGETTI
Keyword(s):  
Decision Making ◽  
Interest Groups ◽  
Energy Policy ◽  
Regulatory Networks ◽  
Energy Regulation ◽  
European Network ◽  
Systematic Examination ◽  
Decision Making Processes ◽  
Eu Energy Policy ◽  
The Eu

Some EU agencies have been recently entrusted with enforcement powers, which imply a crucial extension of their regulatory reach. However, other comparable agencies did not receive such powers. This paper explores the case of energy regulation as an instance of these “negative” cases, and suggests that the lack of enforcement powers may have been partially determined by business interest groups. To illustrate this argument, this article firstly relies on official documentation to show that key interest groups were consistently opposed to the option of granting enforcement powers to the EU agency in charge (ACER). Secondly, it is suggested that these interest groups, which have been largely incorporated in regulatory networks during the prehistory of the agency, had access to, and exerted influence in, the governance of EU energy policy, and could plausibly have been able to concretise their preferences. A systematic examination of the representation of interest groups in the European network of energy regulators (CEER/ERGEG) during the period 2004–2011 is undertaken to corroborate this point. The conclusion draws attention to the fact that, although interest groups are less visible than other actors and their presence is less formalised, they could be very influential on decision-making processes within European networks and agencies.

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.

The Drosophila embryonic midline is the site of Spitz processing, and induces activation of the EGF receptor in the ventral ectoderm

Development ◽  
1996 ◽  
Vol 122 (11) ◽  
pp. 3363-3370 ◽  
Author(s):  
M. Golembo ◽  
E. Raz ◽  
B.Z. Shilo
Keyword(s):  
Feedback Loop ◽  
Egf Receptor ◽  
Ectopic Expression ◽  
Cell Fates ◽  
Inhibitory Feedback ◽  
Midline Cells ◽  
Stable Source

The Drosophila EGF receptor (DER) is activated by secreted Spitz to induce different cell fates in the ventral ectoderm. Processing of the precursor transmembrane Spitz to generate the secreted form was shown to be the limiting event, but the cells in which processing takes place and the mechanism that may generate a gradient of secreted Spitz in the ectoderm were not known. The ectodermal defects in single minded (sim) mutant embryos, in which the midline fails to develop, suggested that the midline cells contribute to patterning of the ventral ectoderm. This work shows that the midline provides the site for Spitz expression and processing. The Rhomboid and Star proteins are also expressed and required in the midline. The ectodermal defects of spitz, rho or Star mutant embryos could be rescued by inducing the expression of the respective normal genes only in the midline cells. Rho and Star thus function non-autonomously, and may be required for the production or processing of the Spitz precursor. Secreted Spitz is the only sim-dependent contribution of the midline to patterning the ectoderm, since the ventral defects observed in sim mutant embryos can be overcome by expression of secreted Spitz in the ectoderm. While ectopic expression of secreted Spitz in the ectoderm or mesoderm gave rise to ventralization of the embryo, increased expression of secreted Spitz in the midline did not lead to alterations in ectoderm patterning. A mechanism for adjustment to variable levels of secreted Spitz emanating from the midline may be provided by Argos, which forms an inhibitory feedback loop for DER activation. The production of secreted Spitz in the midline, may provide a stable source for graded DER activation in the ventral ectoderm.

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 Dynamics of a hepatocyte-cholangiocyte decision-making gene regulatory network during liver development and regeneration

2021 ◽  
Author(s):  
Sarthak Sahoo ◽  
Ashutosh Mishra ◽  
Anna Mae Diehl ◽  
Mohit Kumar Jolly
Keyword(s):  
Decision Making ◽  
Gene Regulatory Network ◽  
Regulatory Network ◽  
Regulatory Networks ◽  
Developmental Stages ◽  
Cellular Reprogramming ◽  
Liver Development ◽  
Cell Fates ◽  
Dynamic Simulations ◽  
Gene Regulatory

AbstractLiver is one of the few organs with immense regenerative potential even at adulthood in mammals. It is composed of primarily two cell types: hepatocytes and cholangiocytes, that can trans-differentiate to one another either directly or through intermediate progenitor states, contributing to remarkable regenerative potential of the liver. However, the dynamical features of decision-making between these cell-fates during liver development and regeneration remains elusive. Here, we identify a core gene regulatory network comprising c/EBPα, TGFBR2 and SOX9 that underlies liver development and injury-induced reprogramming. Dynamic simulations for this network reveal its multistable nature, enabling three distinct cell states – hepatocytes, cholangiocytes and liver progenitor cells (hepatoblasts/oval cells) – and stochastic switching among them. Predicted expression signature for these three states are validated through multiple bulk and single-cell transcriptomic datasets collected across developmental stages and injury-induced liver repair. This network can also explain the experimentally observed spatial organisation of phenotypes in liver parenchyma and predict strategies for efficient cellular reprogramming among these cell-fates. Our analysis elucidates how the emergent multistable dynamics of underlying gene regulatory networks drive diverse cell-state decisions in liver development and regeneration.

Argos transcription is induced by the Drosophila EGF receptor pathway to form an inhibitory feedback loop

Development ◽  
1996 ◽  
Vol 122 (1) ◽  
pp. 223-230 ◽  
Author(s):  
M. Golembo ◽  
R. Schweitzer ◽  
M. Freeman ◽  
B.Z. Shilo
Keyword(s):  
Cell Culture ◽  
Signaling Pathways ◽  
Feedback Loop ◽  
Egf Receptor ◽  
Cell Fates ◽  
Inhibitory Feedback

Argos is a secreted molecule with an atypical EGF motif. It was recently shown to function as an inhibitor of the signaling triggered by the Drosophila EGF receptor (DER). In this work, we determine the contribution of Argos to the establishment of cell fates in the embryonic ventral ectoderm. Graded activation of DER is essential for patterning the ventral ectoderm. argos mutant embryos show expansion of ventral cell fates suggesting hyperactivation of the DER pathway. In the embryonic ventral ectoderm, argos is expressed in the ventralmost row of cells. We show that argos expression in the ventral ectoderm is induced by the DER pathway: argos is not expressed in DER mutant embryos, while it is ectopically expressed in the entire ventral ectoderm following ubiquitous activation of the DER pathway. argos expression appears to be triggered directly by the DER pathway, since induction can also be observed in cell culture, following activation of DER by its ligand, Spitz. Argos therefore functions in a sequential manner, to restrict the duration and level of DER signaling. This type of inhibitory feedback loop may represent a general paradigm for signaling pathways inducing diverse cell fates within a population of non-committed cells.

scholarly journals Engineering of a synthetic quadrastable gene network to approach Waddington landscape and cell fate determination

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Fuqing Wu ◽  
Ri-Qi Su ◽  
Ying-Cheng Lai ◽  
Xiao Wang
Keyword(s):  
Cell Fate ◽  
Regulatory Networks ◽  
Cell Fate Determination ◽  
Final States ◽  
Cell Fates ◽  
Fate Determination ◽  
Cellular Decision Making ◽  
Distinct Cell ◽  
Model Predictions ◽  
Gene Regulatory

The process of cell fate determination has been depicted intuitively as cells travelling and resting on a rugged landscape, which has been probed by various theoretical studies. However, few studies have experimentally demonstrated how underlying gene regulatory networks shape the landscape and hence orchestrate cellular decision-making in the presence of both signal and noise. Here we tested different topologies and verified a synthetic gene circuit with mutual inhibition and auto-activations to be quadrastable, which enables direct study of quadruple cell fate determination on an engineered landscape. We show that cells indeed gravitate towards local minima and signal inductions dictate cell fates through modulating the shape of the multistable landscape. Experiments, guided by model predictions, reveal that sequential inductions generate distinct cell fates by changing landscape in sequence and hence navigating cells to different final states. This work provides a synthetic biology framework to approach cell fate determination and suggests a landscape-based explanation of fixed induction sequences for targeted differentiation.

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