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A conceptual and computational framework for modelling and understanding the nonequilibrium gene regulatory networks of mouse embryonic stem cells

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A conceptual and computational framework for modelling and understanding the nonequilibrium gene regulatory networks of mouse embryonic stem cells. / Greaves, Richard Brian; Dietmann, Sabine; Smith, Austin; Stepney, Susan; Halley, Julianne Debbie.

In: PLoS Computational Biology, Vol. 13, No. 9, e1005713, 01.09.2017.

Research output: Contribution to journalArticle

Harvard

Greaves, RB, Dietmann, S, Smith, A, Stepney, S & Halley, JD 2017, 'A conceptual and computational framework for modelling and understanding the nonequilibrium gene regulatory networks of mouse embryonic stem cells', PLoS Computational Biology, vol. 13, no. 9, e1005713. https://doi.org/10.1371/journal.pcbi.1005713

APA

Greaves, R. B., Dietmann, S., Smith, A., Stepney, S., & Halley, J. D. (2017). A conceptual and computational framework for modelling and understanding the nonequilibrium gene regulatory networks of mouse embryonic stem cells. PLoS Computational Biology, 13(9), [e1005713]. https://doi.org/10.1371/journal.pcbi.1005713

Vancouver

Greaves RB, Dietmann S, Smith A, Stepney S, Halley JD. A conceptual and computational framework for modelling and understanding the nonequilibrium gene regulatory networks of mouse embryonic stem cells. PLoS Computational Biology. 2017 Sep 1;13(9). e1005713. https://doi.org/10.1371/journal.pcbi.1005713

Author

Greaves, Richard Brian ; Dietmann, Sabine ; Smith, Austin ; Stepney, Susan ; Halley, Julianne Debbie. / A conceptual and computational framework for modelling and understanding the nonequilibrium gene regulatory networks of mouse embryonic stem cells. In: PLoS Computational Biology. 2017 ; Vol. 13, No. 9.

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@article{b1d76425605f453582cc545fe4c0ff44,
title = "A conceptual and computational framework for modelling and understanding the nonequilibrium gene regulatory networks of mouse embryonic stem cells",
abstract = "The capacity of pluripotent embryonic stem cells to differentiate into any cell type in the body makes them invaluable in the field of regenerative medicine. However, because of the complexity of both the core pluripotency network and the process of cell fate computation it is not yet possible to control the fate of stem cells. We present a theoretical model of stem cell fate computation that is based on Halley and Winkler’s Branching Process Theory (BPT) and on Greaves et al.’s agent-based computer simulation derived from that theoretical model. BPT abstracts the complex production and action of a Transcription Factor (TF) into a single critical branching process that may dissipate, maintain, or become supercritical. Here we take the single TF model and extend it to multiple interacting TFs, and build an agent-based simulation of multiple TFs to investigate the dynamics of such coupled systems. We have developed the simulation and the theoretical model together, in an iterative manner, with the aim of obtaining a deeper understanding of stem cell fate computation, in order to influence experimental efforts, which may in turn influence the outcome of cellular differentiation. The model used is an example of self-organization and could be more widely applicable to the modelling of other complex systems. The simulation based on this model, though currently limited in scope in terms of the biology it represents, supports the utility of the Halley and Winkler branching process model in describing the behaviour of stem cell gene regulatory networks. Our simulation demonstrates three key features: (i) the existence of a critical value of the branching process parameter, dependent on the details of the cistrome in question; (ii) the ability of an active cistrome to “ignite” an otherwise fully dissipated cistrome, and drive it to criticality; (iii) how coupling cistromes together can reduce their critical branching parameter values needed to drive them to criticality.",
author = "Greaves, {Richard Brian} and Sabine Dietmann and Austin Smith and Susan Stepney and Halley, {Julianne Debbie}",
note = "{\circledC}2017 Greaves et al.",
year = "2017",
month = "9",
day = "1",
doi = "10.1371/journal.pcbi.1005713",
language = "English",
volume = "13",
journal = "PLoS Computational Biology",
issn = "1553-7358",
publisher = "Public Library of Science",
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}

RIS (suitable for import to EndNote) - Download

TY - JOUR

T1 - A conceptual and computational framework for modelling and understanding the nonequilibrium gene regulatory networks of mouse embryonic stem cells

AU - Greaves, Richard Brian

AU - Dietmann, Sabine

AU - Smith, Austin

AU - Stepney, Susan

AU - Halley, Julianne Debbie

N1 - ©2017 Greaves et al.

PY - 2017/9/1

Y1 - 2017/9/1

N2 - The capacity of pluripotent embryonic stem cells to differentiate into any cell type in the body makes them invaluable in the field of regenerative medicine. However, because of the complexity of both the core pluripotency network and the process of cell fate computation it is not yet possible to control the fate of stem cells. We present a theoretical model of stem cell fate computation that is based on Halley and Winkler’s Branching Process Theory (BPT) and on Greaves et al.’s agent-based computer simulation derived from that theoretical model. BPT abstracts the complex production and action of a Transcription Factor (TF) into a single critical branching process that may dissipate, maintain, or become supercritical. Here we take the single TF model and extend it to multiple interacting TFs, and build an agent-based simulation of multiple TFs to investigate the dynamics of such coupled systems. We have developed the simulation and the theoretical model together, in an iterative manner, with the aim of obtaining a deeper understanding of stem cell fate computation, in order to influence experimental efforts, which may in turn influence the outcome of cellular differentiation. The model used is an example of self-organization and could be more widely applicable to the modelling of other complex systems. The simulation based on this model, though currently limited in scope in terms of the biology it represents, supports the utility of the Halley and Winkler branching process model in describing the behaviour of stem cell gene regulatory networks. Our simulation demonstrates three key features: (i) the existence of a critical value of the branching process parameter, dependent on the details of the cistrome in question; (ii) the ability of an active cistrome to “ignite” an otherwise fully dissipated cistrome, and drive it to criticality; (iii) how coupling cistromes together can reduce their critical branching parameter values needed to drive them to criticality.

AB - The capacity of pluripotent embryonic stem cells to differentiate into any cell type in the body makes them invaluable in the field of regenerative medicine. However, because of the complexity of both the core pluripotency network and the process of cell fate computation it is not yet possible to control the fate of stem cells. We present a theoretical model of stem cell fate computation that is based on Halley and Winkler’s Branching Process Theory (BPT) and on Greaves et al.’s agent-based computer simulation derived from that theoretical model. BPT abstracts the complex production and action of a Transcription Factor (TF) into a single critical branching process that may dissipate, maintain, or become supercritical. Here we take the single TF model and extend it to multiple interacting TFs, and build an agent-based simulation of multiple TFs to investigate the dynamics of such coupled systems. We have developed the simulation and the theoretical model together, in an iterative manner, with the aim of obtaining a deeper understanding of stem cell fate computation, in order to influence experimental efforts, which may in turn influence the outcome of cellular differentiation. The model used is an example of self-organization and could be more widely applicable to the modelling of other complex systems. The simulation based on this model, though currently limited in scope in terms of the biology it represents, supports the utility of the Halley and Winkler branching process model in describing the behaviour of stem cell gene regulatory networks. Our simulation demonstrates three key features: (i) the existence of a critical value of the branching process parameter, dependent on the details of the cistrome in question; (ii) the ability of an active cistrome to “ignite” an otherwise fully dissipated cistrome, and drive it to criticality; (iii) how coupling cistromes together can reduce their critical branching parameter values needed to drive them to criticality.

U2 - 10.1371/journal.pcbi.1005713

DO - 10.1371/journal.pcbi.1005713

M3 - Article

VL - 13

JO - PLoS Computational Biology

JF - PLoS Computational Biology

SN - 1553-7358

IS - 9

M1 - e1005713

ER -