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Synergistic dual positive feedback loops established by molecular sequestration generate robust bimodal response.

Abstract：

:Feedback loops are ubiquitous features of biological networks and can produce significant phenotypic heterogeneity, including a bimodal distribution of gene expression across an isogenic cell population. In this work, a combination of experiments and computational modeling was used to explore the roles of multiple feedback loops in the bimodal, switch-like response of the Saccharomyces cerevisiae galactose regulatory network. Here, we show that bistability underlies the observed bimodality, as opposed to stochastic effects, and that two unique positive feedback loops established by Gal1p and Gal3p, which both regulate network activity by molecular sequestration of Gal80p, induce this bimodality. Indeed, systematically scanning through different single and multiple feedback loop knockouts, we demonstrate that there is always a concentration regime that preserves the system's bimodality, except for the double deletion of GAL1 and the GAL3 feedback loop, which exhibits a graded response for all conditions tested. The constitutive production rates of Gal1p and Gal3p operate as bifurcation parameters because variations in these rates can also abolish the system's bimodal response. Our model indicates that this second loss of bistability ensues from the inactivation of the remaining feedback loop by the overexpressed regulatory component. More broadly, we show that the sequestration binding affinity is a critical parameter that can tune the range of conditions for bistability in a circuit with positive feedback established by molecular sequestration. In this system, two positive feedback loops can significantly enhance the region of bistability and the dynamic response time.

journal_name

Proc Natl Acad Sci U S A

journal_title

Proceedings of the National Academy of Sciences of the United States of America

authors

Venturelli OS,El-Samad H,Murray RM

doi

10.1073/pnas.1211902109

subject

Has Abstract

pub_date

2012-11-27 00:00:00

pages

E3324-33

issue

eissn

0027-8424

issn

1091-6490

pii

1211902109

journal_volume

109

pub_type

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Synergistic dual positive feedback loops established by molecular sequestration generate robust bimodal response.