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Simplified mechanistic models of gene regulation for analysis and design.

Hancock EJ, Stan GB, Arpino JA, Papachristodoulou A - J R Soc Interface (2015)

Bottom Line: However, conventional simplified models typically have outputs that are not directly measurable and are based on assumptions that do not often hold under experimental conditions.The proposed approach is based on assumptions that hold generally and include typical cases in systems and synthetic biology where conventional models do not hold.We also apply the methodology to propose simplified models of gene regulation in the presence of multiple protein binding sites, providing both biological insights and an illustration of the generality of the methodology.

View Article: PubMed Central - PubMed

Affiliation: Department of Engineering Science, University of Oxford, Oxford OX1 3PJ, UK.

ABSTRACT
Simplified mechanistic models of gene regulation are fundamental to systems biology and essential for synthetic biology. However, conventional simplified models typically have outputs that are not directly measurable and are based on assumptions that do not often hold under experimental conditions. To resolve these issues, we propose a 'model reduction' methodology and simplified kinetic models of total mRNA and total protein concentration, which link measurements, models and biochemical mechanisms. The proposed approach is based on assumptions that hold generally and include typical cases in systems and synthetic biology where conventional models do not hold. We use novel assumptions regarding the 'speed of reactions', which are required for the methodology to be consistent with experimental data. We also apply the methodology to propose simplified models of gene regulation in the presence of multiple protein binding sites, providing both biological insights and an illustration of the generality of the methodology. Lastly, we show that modelling total protein concentration allows us to address key questions on gene regulation, such as efficiency, burden, competition and modularity.

No MeSH data available.


Prototypical genetic network modules. The prototypical input–output system (a) with total DNA (), mRNA  and protein () is shown. Dimerization of monomeric input transcription factor (TF) () and output TF () has been considered as well as operator-binding and lumped transcription, translation and degradation. The input–output ‘module’ acts as a building block for modelling larger networks. For the case of multiple operators (b), the system also includes the total additional TF binding sites () and the total protein concentration also includes the TF bound to the second operator. In (b), the additional regulatory element is part of a second promoter, but the models and methodology are also applicable when additional elements regulate expression of the same gene. (Online version in colour.)
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RSIF20150312F1: Prototypical genetic network modules. The prototypical input–output system (a) with total DNA (), mRNA and protein () is shown. Dimerization of monomeric input transcription factor (TF) () and output TF () has been considered as well as operator-binding and lumped transcription, translation and degradation. The input–output ‘module’ acts as a building block for modelling larger networks. For the case of multiple operators (b), the system also includes the total additional TF binding sites () and the total protein concentration also includes the TF bound to the second operator. In (b), the additional regulatory element is part of a second promoter, but the models and methodology are also applicable when additional elements regulate expression of the same gene. (Online version in colour.)

Mentions: To illustrate our framework, we use the simple prototypical gene regulatory network shown in figure 1a in which a dimeric TF represses the expression of a second dimeric TF. This case is used to introduce the gene expression models and model reduction methodology, noting that the same methodology and simplified model structure can be used more generally. This generality is demonstrated in the electronic supplementary material and subsequent models. The regulating protein is treated as an input, and the expressed protein as an output. This input–output ‘module’ acts as a building block for larger gene regulatory network models. The prototypical case with added gene regulatory elements (figure 1b) is also considered both owing to its importance and to illustrate that the methodology can be used more generally.Figure 1.


Simplified mechanistic models of gene regulation for analysis and design.

Hancock EJ, Stan GB, Arpino JA, Papachristodoulou A - J R Soc Interface (2015)

Prototypical genetic network modules. The prototypical input–output system (a) with total DNA (), mRNA  and protein () is shown. Dimerization of monomeric input transcription factor (TF) () and output TF () has been considered as well as operator-binding and lumped transcription, translation and degradation. The input–output ‘module’ acts as a building block for modelling larger networks. For the case of multiple operators (b), the system also includes the total additional TF binding sites () and the total protein concentration also includes the TF bound to the second operator. In (b), the additional regulatory element is part of a second promoter, but the models and methodology are also applicable when additional elements regulate expression of the same gene. (Online version in colour.)
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4528597&req=5

RSIF20150312F1: Prototypical genetic network modules. The prototypical input–output system (a) with total DNA (), mRNA and protein () is shown. Dimerization of monomeric input transcription factor (TF) () and output TF () has been considered as well as operator-binding and lumped transcription, translation and degradation. The input–output ‘module’ acts as a building block for modelling larger networks. For the case of multiple operators (b), the system also includes the total additional TF binding sites () and the total protein concentration also includes the TF bound to the second operator. In (b), the additional regulatory element is part of a second promoter, but the models and methodology are also applicable when additional elements regulate expression of the same gene. (Online version in colour.)
Mentions: To illustrate our framework, we use the simple prototypical gene regulatory network shown in figure 1a in which a dimeric TF represses the expression of a second dimeric TF. This case is used to introduce the gene expression models and model reduction methodology, noting that the same methodology and simplified model structure can be used more generally. This generality is demonstrated in the electronic supplementary material and subsequent models. The regulating protein is treated as an input, and the expressed protein as an output. This input–output ‘module’ acts as a building block for larger gene regulatory network models. The prototypical case with added gene regulatory elements (figure 1b) is also considered both owing to its importance and to illustrate that the methodology can be used more generally.Figure 1.

Bottom Line: However, conventional simplified models typically have outputs that are not directly measurable and are based on assumptions that do not often hold under experimental conditions.The proposed approach is based on assumptions that hold generally and include typical cases in systems and synthetic biology where conventional models do not hold.We also apply the methodology to propose simplified models of gene regulation in the presence of multiple protein binding sites, providing both biological insights and an illustration of the generality of the methodology.

View Article: PubMed Central - PubMed

Affiliation: Department of Engineering Science, University of Oxford, Oxford OX1 3PJ, UK.

ABSTRACT
Simplified mechanistic models of gene regulation are fundamental to systems biology and essential for synthetic biology. However, conventional simplified models typically have outputs that are not directly measurable and are based on assumptions that do not often hold under experimental conditions. To resolve these issues, we propose a 'model reduction' methodology and simplified kinetic models of total mRNA and total protein concentration, which link measurements, models and biochemical mechanisms. The proposed approach is based on assumptions that hold generally and include typical cases in systems and synthetic biology where conventional models do not hold. We use novel assumptions regarding the 'speed of reactions', which are required for the methodology to be consistent with experimental data. We also apply the methodology to propose simplified models of gene regulation in the presence of multiple protein binding sites, providing both biological insights and an illustration of the generality of the methodology. Lastly, we show that modelling total protein concentration allows us to address key questions on gene regulation, such as efficiency, burden, competition and modularity.

No MeSH data available.