High Cooperativity in Negative Feedback can Amplify Noisy Gene Expression
Burst-like synthesis of protein is a significant source of cell-to-cell variability in protein levels. Negative feedback is a common example of a regulatory mechanism by which such stochasticity can be controlled. Here we consider a specific kind of negative feedback, which makes bursts smaller in t...
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| Published in: | Bulletin of mathematical biology Vol. 80; no. 7; pp. 1871 - 1899 |
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| Main Authors: | , , |
| Format: | Journal Article |
| Language: | English |
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01.07.2018
Springer Nature B.V |
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| ISSN: | 0092-8240, 1522-9602, 1522-9602 |
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| Abstract | Burst-like synthesis of protein is a significant source of cell-to-cell variability in protein levels. Negative feedback is a common example of a regulatory mechanism by which such stochasticity can be controlled. Here we consider a specific kind of negative feedback, which makes bursts smaller in the excess of protein. Increasing the strength of the feedback may lead to dramatically different outcomes depending on a key parameter, the noise load, which is defined as the squared coefficient of variation the protein exhibits in the absence of feedback. Combining stochastic simulation with asymptotic analysis, we identify a critical value of noise load: for noise loads smaller than critical, the coefficient of variation remains bounded with increasing feedback strength; contrastingly, if the noise load is larger than critical, the coefficient of variation diverges to infinity in the limit of ever greater feedback strengths. Interestingly, feedbacks with lower cooperativities have higher critical noise loads, suggesting that they can be preferable for controlling noisy proteins. |
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| AbstractList | Burst-like synthesis of protein is a significant source of cell-to-cell variability in protein levels. Negative feedback is a common example of a regulatory mechanism by which such stochasticity can be controlled. Here we consider a specific kind of negative feedback, which makes bursts smaller in the excess of protein. Increasing the strength of the feedback may lead to dramatically different outcomes depending on a key parameter, the noise load, which is defined as the squared coefficient of variation the protein exhibits in the absence of feedback. Combining stochastic simulation with asymptotic analysis, we identify a critical value of noise load: for noise loads smaller than critical, the coefficient of variation remains bounded with increasing feedback strength; contrastingly, if the noise load is larger than critical, the coefficient of variation diverges to infinity in the limit of ever greater feedback strengths. Interestingly, feedbacks with lower cooperativities have higher critical noise loads, suggesting that they can be preferable for controlling noisy proteins.Burst-like synthesis of protein is a significant source of cell-to-cell variability in protein levels. Negative feedback is a common example of a regulatory mechanism by which such stochasticity can be controlled. Here we consider a specific kind of negative feedback, which makes bursts smaller in the excess of protein. Increasing the strength of the feedback may lead to dramatically different outcomes depending on a key parameter, the noise load, which is defined as the squared coefficient of variation the protein exhibits in the absence of feedback. Combining stochastic simulation with asymptotic analysis, we identify a critical value of noise load: for noise loads smaller than critical, the coefficient of variation remains bounded with increasing feedback strength; contrastingly, if the noise load is larger than critical, the coefficient of variation diverges to infinity in the limit of ever greater feedback strengths. Interestingly, feedbacks with lower cooperativities have higher critical noise loads, suggesting that they can be preferable for controlling noisy proteins. Burst-like synthesis of protein is a significant source of cell-to-cell variability in protein levels. Negative feedback is a common example of a regulatory mechanism by which such stochasticity can be controlled. Here we consider a specific kind of negative feedback, which makes bursts smaller in the excess of protein. Increasing the strength of the feedback may lead to dramatically different outcomes depending on a key parameter, the noise load, which is defined as the squared coefficient of variation the protein exhibits in the absence of feedback. Combining stochastic simulation with asymptotic analysis, we identify a critical value of noise load: for noise loads smaller than critical, the coefficient of variation remains bounded with increasing feedback strength; contrastingly, if the noise load is larger than critical, the coefficient of variation diverges to infinity in the limit of ever greater feedback strengths. Interestingly, feedbacks with lower cooperativities have higher critical noise loads, suggesting that they can be preferable for controlling noisy proteins. |
| Author | Singh, Abhyudai Bokes, Pavol Lin, Yen Ting |
| Author_xml | – sequence: 1 givenname: Pavol orcidid: 0000-0002-8414-6933 surname: Bokes fullname: Bokes, Pavol email: pavol.bokes@fmph.uniba.sk organization: Department of Applied Mathematics and Statistics, Comenius University – sequence: 2 givenname: Yen Ting surname: Lin fullname: Lin, Yen Ting organization: Theoretical Division and Center for Nonlinear Studies, Los Alamos National Laboratory, Statistical Physics and Complex System Group, School of Physics and Astronomy, The University of Manchester – sequence: 3 givenname: Abhyudai surname: Singh fullname: Singh, Abhyudai organization: Department of Electrical and Computer Engineering, University of Delaware |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/29696600$$D View this record in MEDLINE/PubMed |
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| CitedBy_id | crossref_primary_10_1007_s00285_020_01512_y crossref_primary_10_1007_s00285_021_01549_7 crossref_primary_10_1007_s00285_018_1277_z crossref_primary_10_1088_1742_5468_ac2edb crossref_primary_10_1007_s00294_018_0879_8 crossref_primary_10_1109_TCBB_2019_2938502 crossref_primary_10_3390_math10132169 |
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| Keywords | Asymptotic expansions Negative feedback 60K40 Stochastic gene expression Delayed production 41A60 Protein bursting 92C40 |
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| Snippet | Burst-like synthesis of protein is a significant source of cell-to-cell variability in protein levels. Negative feedback is a common example of a regulatory... |
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| SubjectTerms | Algorithms Animals Bursting strength Cell Biology Coefficient of variation Computer Simulation Feedback Feedback, Physiological Gene Expression Humans Life Sciences Load Markov Chains Mathematical and Computational Biology Mathematical Concepts Mathematics Mathematics and Statistics Models, Genetic Negative feedback Original Article Protein biosynthesis Protein Biosynthesis - genetics Proteins Regulatory mechanisms (biology) Single-Cell Analysis Stochastic Processes Stochasticity Variation |
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| Title | High Cooperativity in Negative Feedback can Amplify Noisy Gene Expression |
| URI | https://link.springer.com/article/10.1007/s11538-018-0438-y https://www.ncbi.nlm.nih.gov/pubmed/29696600 https://www.proquest.com/docview/2030543030 https://www.proquest.com/docview/2031420870 |
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