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Abstract The inference of gene regulatory networks (GRNs) from high-throughput data constitutes a fundamental and challenging task in systems biology. Boolean networks are a popular modeling framework to understand the dynamic nature of GRNs. In the absence of reliable methods to infer the regulatory logic of Boolean GRN models, researchers frequently assume threshold logic as a default. Using the largest repository of published expert-curated Boolean GRN models as best proxy of reality, we systematically compare the ability of two popular threshold formalisms, the Ising and the 01 formalism, to truthfully recover biological functions and biological system dynamics. While Ising rules match fewer biological functions exactly than 01 rules, they yield a better average agreement. In general, more complex regulatory logic proves harder to be represented by either threshold formalism. Informed by these results and a meta-analysis of regulatory logic, we propose modified versions for both formalisms, which provide a better function-level and dynamic agreement with biological GRN models than the usual threshold formalisms. For small biological GRN models with low connectivity, corresponding threshold networks exhibit similar dynamics. However, they generally fail to recover the dynamics of large networks or highly connected networks. In conclusion, this study provides new insights into an important question in computational systems biology: how truthfully do Boolean threshold networks capture the dynamics of GRNs?
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Assessing biological network dynamics: comparing numerical simulations with analytical decomposition of parameter space
Abstract Mathematical modeling of the emergent dynamics of gene regulatory networks (GRN) faces a double challenge of (a) dependence of model dynamics on parameters, and (b) lack of reliable experimentally determined parameters. In this paper we compare two complementary approaches for describing GRN dynamics across unknown parameters: (1) parameter sampling and resulting ensemble statistics used by RACIPE (RAndom CIrcuit PErturbation), and (2) use of rigorous analysis of combinatorial approximation of the ODE models by DSGRN (Dynamic Signatures Generated by Regulatory Networks). We find a very good agreement between RACIPE simulation and DSGRN predictions for four different 2- and 3-node networks typically observed in cellular decision making. This observation is remarkable since the DSGRN approach assumes that the Hill coefficients of the models are very high while RACIPE assumes the values in the range 1-6. Thus DSGRN parameter domains, explicitly defined by inequalities between systems parameters, are highly predictive of ODE model dynamics within a biologically reasonable range of parameters.
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- Award ID(s):
- 1839299
- PAR ID:
- 10428698
- Publisher / Repository:
- Nature Publishing Group
- Date Published:
- Journal Name:
- npj Systems Biology and Applications
- Volume:
- 9
- Issue:
- 1
- ISSN:
- 2056-7189
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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