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Bistable Circuit

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Alfonso Martinez Arias – One of the best experts on this subject based on the ideXlab platform.

  • fgf mapk signaling sets the switching threshold of a Bistable Circuit controlling cell fate decisions in embryonic stem cells
    Development, 2015
    Co-Authors: Christian Schroter, Jonathan Peter Mackenzie, Alfonso Martinez Arias

    Abstract:

    Intracellular transcriptional regulators and extracellular signaling pathways together regulate the allocation of cell fates during development, but how their molecular activities are integrated to establish the correct proportions of cells with particular fates is not known. Here we study this question in the context of the decision between the epiblast (Epi) and the primitive endoderm (PrE) fate that occurs in the mammalian preimplantation embryo. Using an embryonic stem cell (ESC) model, we discover two successive functions of FGF/MAPK signaling in this decision. First, the pathway needs to be inhibited to make the PrE-like gene expression program accessible for activation by GATA transcription factors in ESCs. In a second step, MAPK signaling levels determine the threshold concentration of GATA factors required for PrE-like differentiation, and thereby control the proportion of cells differentiating along this lineage. Our findings can be explained by a simple mutual repression Circuit modulated by FGF/MAPK signaling. This might be a general network architecture to integrate the activity of signal transduction pathways and transcriptional regulators, and serve to balance proportions of cell fates in several contexts.

  • FGF/MAPK signaling sets the switching threshold of a Bistable Circuit controlling cell fate decisions in embryonic stem cells.
    Development, 2015
    Co-Authors: Christian Schroter, Jonathan Peter Mackenzie, Alfonso Martinez Arias

    Abstract:

    Intracellular transcriptional regulators and extracellular signaling pathways together regulate the allocation of cell fates during development, but how their molecular activities are integrated to establish the correct proportions of cells with particular fates is not known. Here we study this question in the context of the decision between the epiblast (Epi) and the primitive endoderm (PrE) fate that occurs in the mammalian preimplantation embryo. Using an embryonic stem cell (ESC) model, we discover two successive functions of FGF/MAPK signaling in this decision. First, the pathway needs to be inhibited to make the PrE-like gene expression program accessible for activation by GATA transcription factors in ESCs. In a second step, MAPK signaling levels determine the threshold concentration of GATA factors required for PrE-like differentiation, and thereby control the proportion of cells differentiating along this lineage. Our findings can be explained by a simple mutual repression Circuit modulated by FGF/MAPK signaling. This might be a general network architecture to integrate the activity of signal transduction pathways and transcriptional regulators, and serve to balance proportions of cell fates in several contexts.

  • fgf mapk signaling sets the switching threshold of a Bistable Circuit controlling cell fate decisions in es cells
    bioRxiv, 2015
    Co-Authors: Christian Schroter, Jonathan Peter Mackenzie, Alfonso Martinez Arias

    Abstract:

    Intracellular transcriptional regulators and extracellular signaling pathways together regulate the allocation of cell fates during development, but how their molecular activities are integrated to establish the correct proportions of cells with particular fates is not known. Here we study this question in the context of the decision between the epiblast (Epi) and the primitive endoderm (PrE) fate that occurs in the mammalian preimplantation embryo. Using an embryonic stem (ES) cell model, we discover two successive functions of FGF/MAPK signaling in this decision. First, the pathway needs to be inhibited to make the PrE-like gene expression program accessible for activation by GATA transcription factors in ES cells. In a second step, MAPK signaling levels determine the threshold concentration of GATA factors required for PrE-like differentiation, and thereby control the proportion of cells differentiating along this lineage. Our findings can be explained by a simple mutual repression Circuit modulated by FGF/MAPK signaling. This may be a general network architecture to integrate the activity of signal transduction pathways and transcriptional regulators, and serve to balance proportions of cell fates in several contexts.

Christian Schroter – One of the best experts on this subject based on the ideXlab platform.

  • fgf mapk signaling sets the switching threshold of a Bistable Circuit controlling cell fate decisions in embryonic stem cells
    Development, 2015
    Co-Authors: Christian Schroter, Jonathan Peter Mackenzie, Alfonso Martinez Arias

    Abstract:

    Intracellular transcriptional regulators and extracellular signaling pathways together regulate the allocation of cell fates during development, but how their molecular activities are integrated to establish the correct proportions of cells with particular fates is not known. Here we study this question in the context of the decision between the epiblast (Epi) and the primitive endoderm (PrE) fate that occurs in the mammalian preimplantation embryo. Using an embryonic stem cell (ESC) model, we discover two successive functions of FGF/MAPK signaling in this decision. First, the pathway needs to be inhibited to make the PrE-like gene expression program accessible for activation by GATA transcription factors in ESCs. In a second step, MAPK signaling levels determine the threshold concentration of GATA factors required for PrE-like differentiation, and thereby control the proportion of cells differentiating along this lineage. Our findings can be explained by a simple mutual repression Circuit modulated by FGF/MAPK signaling. This might be a general network architecture to integrate the activity of signal transduction pathways and transcriptional regulators, and serve to balance proportions of cell fates in several contexts.

  • FGF/MAPK signaling sets the switching threshold of a Bistable Circuit controlling cell fate decisions in embryonic stem cells.
    Development, 2015
    Co-Authors: Christian Schroter, Jonathan Peter Mackenzie, Alfonso Martinez Arias

    Abstract:

    Intracellular transcriptional regulators and extracellular signaling pathways together regulate the allocation of cell fates during development, but how their molecular activities are integrated to establish the correct proportions of cells with particular fates is not known. Here we study this question in the context of the decision between the epiblast (Epi) and the primitive endoderm (PrE) fate that occurs in the mammalian preimplantation embryo. Using an embryonic stem cell (ESC) model, we discover two successive functions of FGF/MAPK signaling in this decision. First, the pathway needs to be inhibited to make the PrE-like gene expression program accessible for activation by GATA transcription factors in ESCs. In a second step, MAPK signaling levels determine the threshold concentration of GATA factors required for PrE-like differentiation, and thereby control the proportion of cells differentiating along this lineage. Our findings can be explained by a simple mutual repression Circuit modulated by FGF/MAPK signaling. This might be a general network architecture to integrate the activity of signal transduction pathways and transcriptional regulators, and serve to balance proportions of cell fates in several contexts.

  • fgf mapk signaling sets the switching threshold of a Bistable Circuit controlling cell fate decisions in es cells
    bioRxiv, 2015
    Co-Authors: Christian Schroter, Jonathan Peter Mackenzie, Alfonso Martinez Arias

    Abstract:

    Intracellular transcriptional regulators and extracellular signaling pathways together regulate the allocation of cell fates during development, but how their molecular activities are integrated to establish the correct proportions of cells with particular fates is not known. Here we study this question in the context of the decision between the epiblast (Epi) and the primitive endoderm (PrE) fate that occurs in the mammalian preimplantation embryo. Using an embryonic stem (ES) cell model, we discover two successive functions of FGF/MAPK signaling in this decision. First, the pathway needs to be inhibited to make the PrE-like gene expression program accessible for activation by GATA transcription factors in ES cells. In a second step, MAPK signaling levels determine the threshold concentration of GATA factors required for PrE-like differentiation, and thereby control the proportion of cells differentiating along this lineage. Our findings can be explained by a simple mutual repression Circuit modulated by FGF/MAPK signaling. This may be a general network architecture to integrate the activity of signal transduction pathways and transcriptional regulators, and serve to balance proportions of cell fates in several contexts.

Elisa Franco – One of the best experts on this subject based on the ideXlab platform.

  • an analytical approach to Bistable biological Circuit discrimination using real algebraic geometry
    Journal of the Royal Society Interface, 2015
    Co-Authors: Dan Siegalgaskins, Elisa Franco, Tiffany Zhou, Richard M Murray

    Abstract:

    Biomolecular Circuits with two distinct and stable steady states have been identified as essential components in a wide range of biological networks, with a variety of mechanisms and topologies giving rise to their important Bistable property. Understanding the differences between Circuit implementations is an important question, particularly for the synthetic biologist faced with determining which Bistable Circuit design out of many is best for their specific application. In this work we explore the applicability of Sturm’s theorem—a tool from nineteenth-century real algebraic geometry—to comparing ‘functionally equivalent’ Bistable Circuits without the need for numerical simulation. We first consider two genetic toggle variants and two different positive feedback Circuits, and show how specific topological properties present in each type of Circuit can serve to increase the size of the regions of parameter space in which they function as switches. We then demonstrate that a single competitive monomeric activator added to a purely monomeric (and otherwise monostable) mutual repressor Circuit is sufficient for bistability. Finally, we compare our approach with the Routh–Hurwitz method and derive consistent, yet more powerful, parametric conditions. The predictive power and ease of use of Sturm’s theorem demonstrated in this work suggest that algebraic geometric techniques may be underused in biomolecular Circuit analysis.

  • an analytical approach to Bistable biological Circuit discrimination using real algebraic geometry
    bioRxiv, 2015
    Co-Authors: Dan Siegalgaskins, Elisa Franco, Tiffany Zhou, Richard M Murray

    Abstract:

    Biomolecular Circuits with two distinct and stable steady states have been identified as essential components in a wide range of biological networks, with a variety of mechanisms and topologies giving rise to their important Bistable property. Understanding the differences between Circuit implementations is an important question, particularly for the synthetic biologist faced with determining which Bistable Circuit design out of many is best for their specific application. In this work we explore the applicability of Sturm?s theorem–a tool from 19th-century real algebraic geometry–to comparing ?functionally equivalent? Bistable Circuits without the need for numerical simulation. We first consider two genetic toggle variants and two different positive feedback Circuits, and show how specific topological properties present in each type of Circuit can serve to increase the size of the regions of parameter space in which they function as switches. We then demonstrate that a single competitive monomeric activator added to a purely-monomeric (and otherwise monostable) mutual repressor Circuit is sufficient for bistability. Finally, we compare our approach with the Routh-Hurwitz method and derive consistent, yet more powerful, parametric conditions. The predictive power and ease of use of Sturm?s theorem demonstrated in this work suggests that algebraic geometric techniques may be underutilized in biomolecular Circuit analysis.

  • A minimal biomolecular frequency divider
    2015 54th IEEE Conference on Decision and Control (CDC), 2015
    Co-Authors: Christian Cuba Samaniego, Elisa Franco

    Abstract:

    Many cyclic processes such as neuron firing, cardiac functions, and cell division can exhibit integer variations of their period. Period doubling is often triggered by external events, and is an important phenomenon because it can control a change in the time scale of downstream processes. The capacity for period doubling is also relevant in synthetic molecular Circuits where slow and fast modules need to be synchronized. In this paper we describe a rationally designed biomolecular reaction network which operates frequency division of its periodic inputs. The core of this device is a Bistable Circuit, which is toggled between its two stable states by “push” chemical reactions that process the periodic inputs. We thoroughly analyze the behavior of the system deriving an upper bound on the baseline of the inputs it can process, maintaining its output specifications. All the reactions in the system have first or second order rates, and are potentially implementable in vitro using nucleic acids and enzymes. Numerical analysis shows that frequency division is achieved in a range of realistic parameters.