Context-specific network modeling identifies new crosstalk in β-adrenergic cardiac hypertrophy
Cardiac hypertrophy is a context-dependent phenomenon wherein a myriad of biochemical and biomechanical factors regulate myocardial growth through a complex large-scale signaling network. Although numerous studies have investigated hypertrophic signaling pathways, less is known about hypertrophy sig...
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| Veröffentlicht in: | PLoS computational biology 2020-12, Vol.16 (12), p.e1008490-e1008490 |
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| description | Cardiac hypertrophy is a context-dependent phenomenon wherein a myriad of biochemical and biomechanical factors regulate myocardial growth through a complex large-scale signaling network. Although numerous studies have investigated hypertrophic signaling pathways, less is known about hypertrophy signaling as a whole network and how this network acts in a context-dependent manner. Here, we developed a systematic approach, CLASSED (Context-specific Logic-bASed Signaling nEtwork Development), to revise a large-scale signaling model based on context-specific data and identify main reactions and new crosstalks regulating context-specific response. CLASSED involves four sequential stages with an automated validation module as a core which builds a logic-based ODE model from the interaction graph and outputs the model validation percent. The context-specific model is developed by estimation of default parameters, classified qualitative validation, hybrid Morris-Sobol global sensitivity analysis, and discovery of missing context-dependent crosstalks. Applying this pipeline to our prior-knowledge hypertrophy network with context-specific data revealed key signaling reactions which distinctly regulate cell response to isoproterenol, phenylephrine, angiotensin II and stretch. Furthermore, with CLASSED we developed a context-specific model of β-adrenergic cardiac hypertrophy. The model predicted new crosstalks between calcium/calmodulin-dependent pathways and upstream signaling of Ras in the ISO-specific context. Experiments in cardiomyocytes validated the model's predictions on the role of CaMKII-Gβγ and CaN-Gβγ interactions in mediating hypertrophic signals in ISO-specific context and revealed a difference in the phosphorylation magnitude and translocation of ERK1/2 between cardiac myocytes and fibroblasts. CLASSED is a systematic approach for developing context-specific large-scale signaling networks, yielding insights into new-found crosstalks in β-adrenergic cardiac hypertrophy. |
| doi_str_mv | 10.1371/journal.pcbi.1008490 |
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Although numerous studies have investigated hypertrophic signaling pathways, less is known about hypertrophy signaling as a whole network and how this network acts in a context-dependent manner. Here, we developed a systematic approach, CLASSED (Context-specific Logic-bASed Signaling nEtwork Development), to revise a large-scale signaling model based on context-specific data and identify main reactions and new crosstalks regulating context-specific response. CLASSED involves four sequential stages with an automated validation module as a core which builds a logic-based ODE model from the interaction graph and outputs the model validation percent. The context-specific model is developed by estimation of default parameters, classified qualitative validation, hybrid Morris-Sobol global sensitivity analysis, and discovery of missing context-dependent crosstalks. Applying this pipeline to our prior-knowledge hypertrophy network with context-specific data revealed key signaling reactions which distinctly regulate cell response to isoproterenol, phenylephrine, angiotensin II and stretch. Furthermore, with CLASSED we developed a context-specific model of β-adrenergic cardiac hypertrophy. The model predicted new crosstalks between calcium/calmodulin-dependent pathways and upstream signaling of Ras in the ISO-specific context. Experiments in cardiomyocytes validated the model's predictions on the role of CaMKII-Gβγ and CaN-Gβγ interactions in mediating hypertrophic signals in ISO-specific context and revealed a difference in the phosphorylation magnitude and translocation of ERK1/2 between cardiac myocytes and fibroblasts. CLASSED is a systematic approach for developing context-specific large-scale signaling networks, yielding insights into new-found crosstalks in β-adrenergic cardiac hypertrophy.</description><identifier>ISSN: 1553-7358</identifier><identifier>ISSN: 1553-734X</identifier><identifier>EISSN: 1553-7358</identifier><identifier>DOI: 10.1371/journal.pcbi.1008490</identifier><identifier>PMID: 33338038</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animals ; Automation ; Biology and Life Sciences ; Boolean algebra ; Cardiomegaly - metabolism ; Cardiomyocytes ; Cells, Cultured ; Computer and Information Sciences ; Computer Simulation ; Context ; Crosstalk ; Forkhead protein ; Gene deletion ; Gene expression ; Heart ; Hypertrophy ; Knowledge ; Laboratory animals ; Medicine and Health Sciences ; Modelling ; Myocytes ; Myocytes, Cardiac - cytology ; Myocytes, Cardiac - metabolism ; Ordinary differential equations ; Phosphorylation ; Rats ; Rats, Sprague-Dawley ; Receptors, Adrenergic, beta - metabolism ; Sensitivity analysis ; Signal Transduction ; Signaling</subject><ispartof>PLoS computational biology, 2020-12, Vol.16 (12), p.e1008490-e1008490</ispartof><rights>2020 Khalilimeybodi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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Although numerous studies have investigated hypertrophic signaling pathways, less is known about hypertrophy signaling as a whole network and how this network acts in a context-dependent manner. Here, we developed a systematic approach, CLASSED (Context-specific Logic-bASed Signaling nEtwork Development), to revise a large-scale signaling model based on context-specific data and identify main reactions and new crosstalks regulating context-specific response. CLASSED involves four sequential stages with an automated validation module as a core which builds a logic-based ODE model from the interaction graph and outputs the model validation percent. The context-specific model is developed by estimation of default parameters, classified qualitative validation, hybrid Morris-Sobol global sensitivity analysis, and discovery of missing context-dependent crosstalks. Applying this pipeline to our prior-knowledge hypertrophy network with context-specific data revealed key signaling reactions which distinctly regulate cell response to isoproterenol, phenylephrine, angiotensin II and stretch. Furthermore, with CLASSED we developed a context-specific model of β-adrenergic cardiac hypertrophy. The model predicted new crosstalks between calcium/calmodulin-dependent pathways and upstream signaling of Ras in the ISO-specific context. Experiments in cardiomyocytes validated the model's predictions on the role of CaMKII-Gβγ and CaN-Gβγ interactions in mediating hypertrophic signals in ISO-specific context and revealed a difference in the phosphorylation magnitude and translocation of ERK1/2 between cardiac myocytes and fibroblasts. 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Although numerous studies have investigated hypertrophic signaling pathways, less is known about hypertrophy signaling as a whole network and how this network acts in a context-dependent manner. Here, we developed a systematic approach, CLASSED (Context-specific Logic-bASed Signaling nEtwork Development), to revise a large-scale signaling model based on context-specific data and identify main reactions and new crosstalks regulating context-specific response. CLASSED involves four sequential stages with an automated validation module as a core which builds a logic-based ODE model from the interaction graph and outputs the model validation percent. The context-specific model is developed by estimation of default parameters, classified qualitative validation, hybrid Morris-Sobol global sensitivity analysis, and discovery of missing context-dependent crosstalks. Applying this pipeline to our prior-knowledge hypertrophy network with context-specific data revealed key signaling reactions which distinctly regulate cell response to isoproterenol, phenylephrine, angiotensin II and stretch. Furthermore, with CLASSED we developed a context-specific model of β-adrenergic cardiac hypertrophy. The model predicted new crosstalks between calcium/calmodulin-dependent pathways and upstream signaling of Ras in the ISO-specific context. Experiments in cardiomyocytes validated the model's predictions on the role of CaMKII-Gβγ and CaN-Gβγ interactions in mediating hypertrophic signals in ISO-specific context and revealed a difference in the phosphorylation magnitude and translocation of ERK1/2 between cardiac myocytes and fibroblasts. 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| subjects | Animals Automation Biology and Life Sciences Boolean algebra Cardiomegaly - metabolism Cardiomyocytes Cells, Cultured Computer and Information Sciences Computer Simulation Context Crosstalk Forkhead protein Gene deletion Gene expression Heart Hypertrophy Knowledge Laboratory animals Medicine and Health Sciences Modelling Myocytes Myocytes, Cardiac - cytology Myocytes, Cardiac - metabolism Ordinary differential equations Phosphorylation Rats Rats, Sprague-Dawley Receptors, Adrenergic, beta - metabolism Sensitivity analysis Signal Transduction Signaling |
| title | Context-specific network modeling identifies new crosstalk in β-adrenergic cardiac hypertrophy |
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