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Exact Probability Landscapes of Stochastic Phenotype Switching in Feed-Forward Loops: Phase Diagrams of Multimodality

Feed-forward loops (FFLs) are among the most ubiquitously found motifs of reaction networks in nature. However, little is known about their stochastic behavior and the variety of network phenotypes they can exhibit. In this study, we provide full characterizations of the properties of stochastic mul...

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Autores principales: Terebus, Anna, Manuchehrfar, Farid, Cao, Youfang, Liang, Jie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8297706/
https://www.ncbi.nlm.nih.gov/pubmed/34306004
http://dx.doi.org/10.3389/fgene.2021.645640
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author Terebus, Anna
Manuchehrfar, Farid
Cao, Youfang
Liang, Jie
author_facet Terebus, Anna
Manuchehrfar, Farid
Cao, Youfang
Liang, Jie
author_sort Terebus, Anna
collection PubMed
description Feed-forward loops (FFLs) are among the most ubiquitously found motifs of reaction networks in nature. However, little is known about their stochastic behavior and the variety of network phenotypes they can exhibit. In this study, we provide full characterizations of the properties of stochastic multimodality of FFLs, and how switching between different network phenotypes are controlled. We have computed the exact steady-state probability landscapes of all eight types of coherent and incoherent FFLs using the finite-butter Accurate Chemical Master Equation (ACME) algorithm, and quantified the exact topological features of their high-dimensional probability landscapes using persistent homology. Through analysis of the degree of multimodality for each of a set of 10,812 probability landscapes, where each landscape resides over 10(5)–10(6) microstates, we have constructed comprehensive phase diagrams of all relevant behavior of FFL multimodality over broad ranges of input and regulation intensities, as well as different regimes of promoter binding dynamics. In addition, we have quantified the topological sensitivity of the multimodality of the landscapes to regulation intensities. Our results show that with slow binding and unbinding dynamics of transcription factor to promoter, FFLs exhibit strong stochastic behavior that is very different from what would be inferred from deterministic models. In addition, input intensity play major roles in the phenotypes of FFLs: At weak input intensity, FFL exhibit monomodality, but strong input intensity may result in up to 6 stable phenotypes. Furthermore, we found that gene duplication can enlarge stable regions of specific multimodalities and enrich the phenotypic diversity of FFL networks, providing means for cells toward better adaptation to changing environment. Our results are directly applicable to analysis of behavior of FFLs in biological processes such as stem cell differentiation and for design of synthetic networks when certain phenotypic behavior is desired.
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spelling pubmed-82977062021-07-23 Exact Probability Landscapes of Stochastic Phenotype Switching in Feed-Forward Loops: Phase Diagrams of Multimodality Terebus, Anna Manuchehrfar, Farid Cao, Youfang Liang, Jie Front Genet Genetics Feed-forward loops (FFLs) are among the most ubiquitously found motifs of reaction networks in nature. However, little is known about their stochastic behavior and the variety of network phenotypes they can exhibit. In this study, we provide full characterizations of the properties of stochastic multimodality of FFLs, and how switching between different network phenotypes are controlled. We have computed the exact steady-state probability landscapes of all eight types of coherent and incoherent FFLs using the finite-butter Accurate Chemical Master Equation (ACME) algorithm, and quantified the exact topological features of their high-dimensional probability landscapes using persistent homology. Through analysis of the degree of multimodality for each of a set of 10,812 probability landscapes, where each landscape resides over 10(5)–10(6) microstates, we have constructed comprehensive phase diagrams of all relevant behavior of FFL multimodality over broad ranges of input and regulation intensities, as well as different regimes of promoter binding dynamics. In addition, we have quantified the topological sensitivity of the multimodality of the landscapes to regulation intensities. Our results show that with slow binding and unbinding dynamics of transcription factor to promoter, FFLs exhibit strong stochastic behavior that is very different from what would be inferred from deterministic models. In addition, input intensity play major roles in the phenotypes of FFLs: At weak input intensity, FFL exhibit monomodality, but strong input intensity may result in up to 6 stable phenotypes. Furthermore, we found that gene duplication can enlarge stable regions of specific multimodalities and enrich the phenotypic diversity of FFL networks, providing means for cells toward better adaptation to changing environment. Our results are directly applicable to analysis of behavior of FFLs in biological processes such as stem cell differentiation and for design of synthetic networks when certain phenotypic behavior is desired. Frontiers Media S.A. 2021-07-08 /pmc/articles/PMC8297706/ /pubmed/34306004 http://dx.doi.org/10.3389/fgene.2021.645640 Text en Copyright © 2021 Terebus, Manuchehrfar, Cao and Liang. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Genetics
Terebus, Anna
Manuchehrfar, Farid
Cao, Youfang
Liang, Jie
Exact Probability Landscapes of Stochastic Phenotype Switching in Feed-Forward Loops: Phase Diagrams of Multimodality
title Exact Probability Landscapes of Stochastic Phenotype Switching in Feed-Forward Loops: Phase Diagrams of Multimodality
title_full Exact Probability Landscapes of Stochastic Phenotype Switching in Feed-Forward Loops: Phase Diagrams of Multimodality
title_fullStr Exact Probability Landscapes of Stochastic Phenotype Switching in Feed-Forward Loops: Phase Diagrams of Multimodality
title_full_unstemmed Exact Probability Landscapes of Stochastic Phenotype Switching in Feed-Forward Loops: Phase Diagrams of Multimodality
title_short Exact Probability Landscapes of Stochastic Phenotype Switching in Feed-Forward Loops: Phase Diagrams of Multimodality
title_sort exact probability landscapes of stochastic phenotype switching in feed-forward loops: phase diagrams of multimodality
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8297706/
https://www.ncbi.nlm.nih.gov/pubmed/34306004
http://dx.doi.org/10.3389/fgene.2021.645640
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