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 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 ◽  
Author(s):  
Ryan Kerr ◽  
Sara Jabbari ◽  
Iain G. Johnston
Keyword(s):  
Decision Making ◽  
Cell Fate ◽  
Phenotypic Diversity ◽  
Energy Levels ◽  
Specific Cell ◽  
Energy Availability ◽  
Cellular Decision Making ◽  
Decision Making Capacity ◽  
A Cell ◽  
Intracellular Energy

ABSTRACTCells are able to generate phenotypic diversity both during development and in response to stressful and changing environments, aiding survival. The biologically and medically vital process of a cell assuming a functionally important fate from a range of phenotypic possibilities can be thought of as a cell decision. To make these decisions, a cell relies on energy dependent pathways of signalling and expression. However, energy availability is often overlooked as a modulator of cellular decision-making. As cells can vary dramatically in energy availability, this limits our knowledge of how this key biological axis affects cell behaviour. Here, we consider the energy dependence of a highly generalisable decision-making regulatory network, and show that energy variability changes the sets of decisions a cell can make and the ease with which they can be made. Increasing intracellular energy levels can increase the number of stable phenotypes it can generate, corresponding to increased decision-making capacity. For this decision-making architecture, a cell with intracellular energy below a threshold is limited to a singular phenotype, potentially forcing the adoption of a specific cell fate. We suggest that common energetic differences between cells may explain some of the observed variability in cellular decision-making, and demonstrate the importance of considering energy levels in several diverse biological decision-making phenomena.

scholarly journals A BMP regulatory network controls ectodermal cell fate decisions at the neural plate border

Development ◽  
2013 ◽  
Vol 140 (21) ◽  
pp. 4435-4444 ◽  
Author(s):  
S. Reichert ◽  
R. A. Randall ◽  
C. S. Hill
Keyword(s):  
Cell Fate ◽  
Regulatory Network ◽  
Neural Plate ◽  
Cell Fate Decisions ◽  
Neural Plate Border

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 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 Disruption of a GATA2, TAL1, ERG regulatory circuit promotes erythroid transition in healthy and leukemic stem cells

Blood ◽  
2021 ◽  
Author(s):  
Julie A I Thoms ◽  
Peter Truong ◽  
Shruthi Subramanian ◽  
Kathy Knezevic ◽  
Gregory Harvey ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Fate ◽  
Prognostic Significance ◽  
Regulatory Elements ◽  
Leukemic Cells ◽  
State Transitions ◽  
Specific Cell ◽  
Hematopoietic Stem ◽  
Cell Fate Decisions ◽  
Gene Regulatory

Changes in gene regulation and expression govern orderly transitions from hematopoietic stem cells to terminally differentiated blood cell types. These transitions are disrupted during leukemic transformation but knowledge of the gene regulatory changes underpinning this process is elusive. We hypothesised that identifying core gene regulatory networks in healthy hematopoietic and leukemic cells could provide insights into network alterations that perturb cell state transitions. A heptad of transcription factors (LYL1, TAL1, LMO2, FLI1, ERG, GATA2, RUNX1) bind key hematopoietic genes in human CD34+ haematopoietic stem and progenitor cells (HSPCs) and have prognostic significance in acute myeloid leukemia (AML). These factors also form a densely interconnected circuit by binding combinatorially at their own, and each other's, regulatory elements. However, their mutual regulation during normal haematopoiesis and in AML cells, and how perturbation of their expression levels influences cell fate decisions remains unclear. Here, we integrated bulk and single cell data and found that the fully connected heptad circuit identified in healthy HSPCs persists with only minor alterations in AML, and that chromatin accessibility at key heptad regulatory elements was predictive of cell identity in both healthy progenitors and in leukemic cells. The heptad factors GATA2, TAL1 and ERG formed an integrated sub-circuit that regulates stem cell to erythroid transition in both healthy and leukemic cells. Components of this triad could be manipulated to facilitate erythroid transition providing a proof of concept that such regulatory circuits could be harnessed to promote specific cell type transitions and overcome dysregulated haematopoiesis.

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 Logical modeling of lymphoid and myeloid cell specification and transdifferentiation

2017 ◽  
Vol 114 (23) ◽  
pp. 5792-5799 ◽  
Author(s):  
Samuel Collombet ◽  
Chris van Oevelen ◽  
Jose Luis Sardina Ortega ◽  
Wassim Abou-Jaoudé ◽  
Bruno Di Stefano ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Cell Fate ◽  
Regulatory Network ◽  
Developmental Process ◽  
Ectopic Expression ◽  
Myeloid Cell ◽  
Hematopoietic Stem ◽  
Chip Sequencing ◽  
Cell Fate Decisions ◽  
Public Data

Blood cells are derived from a common set of hematopoietic stem cells, which differentiate into more specific progenitors of the myeloid and lymphoid lineages, ultimately leading to differentiated cells. This developmental process is controlled by a complex regulatory network involving cytokines and their receptors, transcription factors, and chromatin remodelers. Using public data and data from our own molecular genetic experiments (quantitative PCR, Western blot, EMSA) or genome-wide assays (RNA-sequencing, ChIP-sequencing), we have assembled a comprehensive regulatory network encompassing the main transcription factors and signaling components involved in myeloid and lymphoid development. Focusing on B-cell and macrophage development, we defined a qualitative dynamical model recapitulating cytokine-induced differentiation of common progenitors, the effect of various reported gene knockdowns, and the reprogramming of pre-B cells into macrophages induced by the ectopic expression of specific transcription factors. The resulting network model can be used as a template for the integration of new hematopoietic differentiation and transdifferentiation data to foster our understanding of lymphoid/myeloid cell-fate decisions.

scholarly journals Arkadia via SNON enables NODAL-SMAD2/3 signaling effectors to transcribe different genes depending on their levels

2018 ◽  
Author(s):  
Jonathon M. Carthy ◽  
Marilia Ioannou ◽  
Vasso Episkopou
Keyword(s):  
Cell Fate ◽  
Target Genes ◽  
Embryonic Stem ◽  
Null Mouse ◽  
Specific Cell ◽  
Cell Fates ◽  
Mammalian Embryo ◽  
Cell Fate Decisions ◽  
Dependent Cell ◽  
Anterior Posterior

AbstractHow cells assess levels of signaling and select to transcribe different target genes depending on the levels of activated effectors remains elusive. High NODAL-signalling levels specify anterior/head, lower specify posterior, and complete loss abolishes anterior-posterior patterning in the mammalian embryo. Here we show that cells assess NODAL-activated SMAD2 and SMAD3 (SMAD2/3) effector-levels by complex formation and pairing each effector with the co-repressor SNON, which is present in the cell before signaling. These complexes enable the E3-ubiquitin ligase Arkadia (RNF111) to degrade SNON. High SMAD2/3 levels can saturate and remove SNON, leading to derepression and activation of a subset of targets (high targets) that are highly susceptible to SNON repression. However, low SMAD2/3 levels can only reduce SNON preventing derepression/activation of high targets. Arkadia degrades SNON transiently only upon signaling exposure, leading to dynamic signaling-responses, which most likely initiate level-specific cell-fate decisions. Arkadia-null mouse embryos and Embryonic Stem Cells (ESC) cannot develop anterior tissues and head. However, SnoN/Arkadia, double-null embryos and ESCs are rescued confirming that Arkadia removes SNON, to achieve level-dependent cell-fatesOne Sentence SummarySignaling intensity induces equivalent degradation of a transcriptional repressor leading to level-dependent responses.

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