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Computational study on ratio-sensing in yeast galactose utilization pathway

Metabolic networks undergo gene expression regulation in response to external nutrient signals. In microbes, the synthesis of enzymes that are used to transport and catabolize less preferred carbon sources is repressed in the presence of a preferred carbon source. For most microbes, glucose is a pre...

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Autores principales: Hong, Jiayin, Hua, Bo, Springer, Michael, Tang, Chao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744065/
https://www.ncbi.nlm.nih.gov/pubmed/33275601
http://dx.doi.org/10.1371/journal.pcbi.1007960
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author Hong, Jiayin
Hua, Bo
Springer, Michael
Tang, Chao
author_facet Hong, Jiayin
Hua, Bo
Springer, Michael
Tang, Chao
author_sort Hong, Jiayin
collection PubMed
description Metabolic networks undergo gene expression regulation in response to external nutrient signals. In microbes, the synthesis of enzymes that are used to transport and catabolize less preferred carbon sources is repressed in the presence of a preferred carbon source. For most microbes, glucose is a preferred carbon source, and it has long been believed that as long as glucose is present in the environment, the expression of genes related to the metabolism of alternative carbon sources is shut down, due to catabolite repression. However, recent studies have shown that the induction of the galactose (GAL) metabolic network does not solely depend on the exhaustion of glucose. Instead, the GAL genes respond to the external concentration ratio of galactose to glucose, a phenomenon of unknown mechanism that we termed ratio-sensing. Using mathematical modeling, we found that ratio-sensing is a general phenomenon that can arise from competition between two carbon sources for shared transporters, between transcription factors for binding to communal regulatory sequences of the target genes, or a combination of the aforementioned two levels of competition. We analyzed how the parameters describing the competitive interaction influenced ratio-sensing behaviors in each scenario and found that the concatenation of both layers of signal integration could expand the dynamical range of ratio-sensing. Finally, we investigated the influence of circuit topology on ratio-sensing and found that incorporating negative auto-regulation and/or coherent feedforward loop motifs to the basic signal integration unit could tune the sensitivity of the response to the external nutrient signals. Our study not only deepened our understanding of how ratio-sensing is achieved in yeast GAL metabolic regulation, but also elucidated design principles for ratio-sensing signal processing that can be used in other biological settings, such as being introduced into circuit designs for synthetic biology applications.
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spelling pubmed-77440652020-12-31 Computational study on ratio-sensing in yeast galactose utilization pathway Hong, Jiayin Hua, Bo Springer, Michael Tang, Chao PLoS Comput Biol Research Article Metabolic networks undergo gene expression regulation in response to external nutrient signals. In microbes, the synthesis of enzymes that are used to transport and catabolize less preferred carbon sources is repressed in the presence of a preferred carbon source. For most microbes, glucose is a preferred carbon source, and it has long been believed that as long as glucose is present in the environment, the expression of genes related to the metabolism of alternative carbon sources is shut down, due to catabolite repression. However, recent studies have shown that the induction of the galactose (GAL) metabolic network does not solely depend on the exhaustion of glucose. Instead, the GAL genes respond to the external concentration ratio of galactose to glucose, a phenomenon of unknown mechanism that we termed ratio-sensing. Using mathematical modeling, we found that ratio-sensing is a general phenomenon that can arise from competition between two carbon sources for shared transporters, between transcription factors for binding to communal regulatory sequences of the target genes, or a combination of the aforementioned two levels of competition. We analyzed how the parameters describing the competitive interaction influenced ratio-sensing behaviors in each scenario and found that the concatenation of both layers of signal integration could expand the dynamical range of ratio-sensing. Finally, we investigated the influence of circuit topology on ratio-sensing and found that incorporating negative auto-regulation and/or coherent feedforward loop motifs to the basic signal integration unit could tune the sensitivity of the response to the external nutrient signals. Our study not only deepened our understanding of how ratio-sensing is achieved in yeast GAL metabolic regulation, but also elucidated design principles for ratio-sensing signal processing that can be used in other biological settings, such as being introduced into circuit designs for synthetic biology applications. Public Library of Science 2020-12-04 /pmc/articles/PMC7744065/ /pubmed/33275601 http://dx.doi.org/10.1371/journal.pcbi.1007960 Text en © 2020 Hong et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Hong, Jiayin
Hua, Bo
Springer, Michael
Tang, Chao
Computational study on ratio-sensing in yeast galactose utilization pathway
title Computational study on ratio-sensing in yeast galactose utilization pathway
title_full Computational study on ratio-sensing in yeast galactose utilization pathway
title_fullStr Computational study on ratio-sensing in yeast galactose utilization pathway
title_full_unstemmed Computational study on ratio-sensing in yeast galactose utilization pathway
title_short Computational study on ratio-sensing in yeast galactose utilization pathway
title_sort computational study on ratio-sensing in yeast galactose utilization pathway
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744065/
https://www.ncbi.nlm.nih.gov/pubmed/33275601
http://dx.doi.org/10.1371/journal.pcbi.1007960
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