%0 Journal Article %1 SiegalGaskins2011Emergence %A Siegal-Gaskins, Dan %A Mejia-Guerra, Maria K. %A Smith, Gregory D. %A Grotewold, Erich %D 2011 %I Public Library of Science %J PLoS Comput Biol %K design-principles emergence switch %N 5 %P e1002039+ %R 10.1371/journal.pcbi.1002039 %T Emergence of Switch-Like Behavior in a Large Family of Simple Biochemical Networks %U http://dx.doi.org/10.1371/journal.pcbi.1002039 %V 7 %X Bistability plays a central role in the gene regulatory networks (GRNs) controlling many essential biological functions, including cellular differentiation and cell cycle control. However, establishing the network topologies that can exhibit bistability remains a challenge, in part due to the exceedingly large variety of GRNs that exist for even a small number of components. We begin to address this problem by employing chemical reaction network theory in a comprehensive in silico survey to determine the capacity for bistability of more than 40,000 simple networks that can be formed by two transcription factor-coding genes and their associated proteins (assuming only the most elementary biochemical processes). We find that there exist reaction rate constants leading to bistability in \~90\% of these GRN models, including several circuits that do not contain any of the TF cooperativity commonly associated with bistable systems, and the majority of which could only be identified as bistable through an original subnetwork-based analysis. A topological sorting of the two-gene family of networks based on the presence or absence of biochemical reactions reveals eleven minimal bistable networks (i.e., bistable networks that do not contain within them a smaller bistable subnetwork). The large number of previously unknown bistable network topologies suggests that the capacity for switch-like behavior in GRNs arises with relative ease and is not easily lost through network evolution. To highlight the relevance of the systematic application of CRNT to bistable network identification in real biological systems, we integrated publicly available protein-protein interaction, protein-DNA interaction, and gene expression data from Saccharomyces cerevisiae, and identified several GRNs predicted to behave in a bistable fashion. Switch-like behavior is found across a wide range of biological systems, and as a result there is significant interest in identifying the various ways in which biochemical reactions can be combined to yield a switch-like response. In this work we use a set of mathematical tools from chemical reaction network theory that provide information about the steady-states of a reaction network irrespective of the values of network rate constants, to conduct a large computational study of a family of model networks consisting of only two protein-coding genes. We find that a large majority of these networks (\~90\%) have (for some set of parameters) the mathematical property known as bistability and can behave in a switch-like manner. Interestingly, the capacity for switch-like behavior is often maintained as networks increase in size through the introduction of new reactions. We then demonstrate using published yeast data how theoretical parameter-free surveys such as this one can be used to discover possible switch-like circuits in real biological systems. Our results highlight the potential usefulness of parameter-free modeling for the characterization of complex networks and to the study of network evolution, and are suggestive of a role for it in the development of novel synthetic biological switches.

@article{SiegalGaskins2011Emergence, abstract = {Bistability plays a central role in the gene regulatory networks ({GRNs}) controlling many essential biological functions, including cellular differentiation and cell cycle control. However, establishing the network topologies that can exhibit bistability remains a challenge, in part due to the exceedingly large variety of {GRNs} that exist for even a small number of components. We begin to address this problem by employing chemical reaction network theory in a comprehensive in silico survey to determine the capacity for bistability of more than 40,000 simple networks that can be formed by two transcription factor-coding genes and their associated proteins (assuming only the most elementary biochemical processes). We find that there exist reaction rate constants leading to bistability in \~{}90\% of these {GRN} models, including several circuits that do not contain any of the {TF} cooperativity commonly associated with bistable systems, and the majority of which could only be identified as bistable through an original subnetwork-based analysis. A topological sorting of the two-gene family of networks based on the presence or absence of biochemical reactions reveals eleven minimal bistable networks (i.e., bistable networks that do not contain within them a smaller bistable subnetwork). The large number of previously unknown bistable network topologies suggests that the capacity for switch-like behavior in {GRNs} arises with relative ease and is not easily lost through network evolution. To highlight the relevance of the systematic application of {CRNT} to bistable network identification in real biological systems, we integrated publicly available protein-protein interaction, {protein-DNA} interaction, and gene expression data from Saccharomyces cerevisiae, and identified several {GRNs} predicted to behave in a bistable fashion. Switch-like behavior is found across a wide range of biological systems, and as a result there is significant interest in identifying the various ways in which biochemical reactions can be combined to yield a switch-like response. In this work we use a set of mathematical tools from chemical reaction network theory that provide information about the steady-states of a reaction network irrespective of the values of network rate constants, to conduct a large computational study of a family of model networks consisting of only two protein-coding genes. We find that a large majority of these networks (\~{}90\%) have (for some set of parameters) the mathematical property known as bistability and can behave in a switch-like manner. Interestingly, the capacity for switch-like behavior is often maintained as networks increase in size through the introduction of new reactions. We then demonstrate using published yeast data how theoretical parameter-free surveys such as this one can be used to discover possible switch-like circuits in real biological systems. Our results highlight the potential usefulness of parameter-free modeling for the characterization of complex networks and to the study of network evolution, and are suggestive of a role for it in the development of novel synthetic biological switches.}, added-at = {2018-12-02T16:09:07.000+0100}, author = {Siegal-Gaskins, Dan and Mejia-Guerra, Maria K. and Smith, Gregory D. and Grotewold, Erich}, biburl = {https://www.bibsonomy.org/bibtex/2b5a0f3b5b05a1b7f495561a8541b2a92/karthikraman}, citeulike-article-id = {9291641}, citeulike-linkout-0 = {http://dx.doi.org/10.1371/journal.pcbi.1002039}, day = 12, doi = {10.1371/journal.pcbi.1002039}, interhash = {337d26a525711abcaa5aa0356416840f}, intrahash = {b5a0f3b5b05a1b7f495561a8541b2a92}, journal = {PLoS Comput Biol}, keywords = {design-principles emergence switch}, month = may, number = 5, pages = {e1002039+}, posted-at = {2011-05-31 05:31:13}, priority = {2}, publisher = {Public Library of Science}, timestamp = {2018-12-02T16:09:07.000+0100}, title = {Emergence of {Switch-Like} Behavior in a Large Family of Simple Biochemical Networks}, url = {http://dx.doi.org/10.1371/journal.pcbi.1002039}, volume = 7, year = 2011 }