ArticleProceedings of the National Academy of Sciences of the United States of America2012
Synergistic dual positive feedback loops established by molecular sequestration generate robust bimodal response.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed.
- Central Dogma Cycle and Network: A Model for Cell Memory.BioEssays : news and reviews in molecular, cellular and developmental biology · 2026Review
- Interlocked transcription factor feedback loops maintain and restore adult touch sensation.Cell reports · 2026Article
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- Chromosome 3p deletion leads to extensive genomic alterations in diverse cancers and confers synthetic lethality in uveal melanoma.bioRxiv : the preprint server for biology · 2026Article
- Article
- Sequestration of gene products by decoys enhances precision in the timing of intracellular events.Scientific reports · 2024Article
- Article
- Towards universal synthetic heterotrophy using a metabolic coordinator.Metabolic engineering · 2023Article
- Stochastic switching of delayed feedback suppresses oscillations in genetic regulatory systems.Journal of the Royal Society, Interface · 2023Article
- Spatiotemporal Patterning Enabled by Gene Regulatory Networks.ACS omega · 2023Article
- Genome-wide inference reveals that feedback regulations constrain promoter-dependent transcriptional burst kinetics.Nucleic acids research · 2023Article
- Allelic correlation is a marker of trade-offs between barriers to transmission of expression variability and signal responsiveness in genetic networks.Cell systems · 2022Article
- GAL Regulon in the YeastFrontiers in molecular biosciences · 2022Article
- Computational analysis of GAL pathway pinpoints mechanisms underlying natural variation.PLoS computational biology · 2021Article
- Variation in the modality of a yeast signaling pathway is mediated by a single regulator.eLife · 2021Article
- Decoupling transcription factor expression and activity enables dimmer switch gene regulation.Science (New York, N.Y.) · 2021Article
- Dynamical Modeling of Optogenetic Circuits in Yeast for Metabolic Engineering Applications.ACS synthetic biology · 2021Article
- Variation, Variegation and Heritable Gene Repression inFrontiers in genetics · 2021Review
- An Overview on Identification and Regulatory Mechanisms of Long Non-coding RNAs in Fungi.Frontiers in microbiology · 2021Review
- Metabolic multistability and hysteresis in a model aerobe-anaerobe microbiome community.Science advances · 2020Article
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3 authors.
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No grant is acknowledged in the PubMed record.
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.
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