Ultrasensitivity and Noise Propagation in a Synthetic Transcriptional Cascade

The precise nature of information flow through a biological network, which is governed by factors such as response sensitivities and noise propagation, greatly affects the operation of biological systems. Quantitative analysis of these properties is often difficult in naturally occurring systems but...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 102; no. 10; pp. 3581 - 3586
Main Authors Hooshangi, Sara, Thiberge, Stephan, Weiss, Ron, Cantor, Charles R.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 08.03.2005
National Acad Sciences
Subjects
Bacteria
Bacterial Proteins - genetics
Biological Sciences
Cellular biology
Delay circuits
Dimers
Fluorescence
Gene expression
Gene Expression Regulation, Bacterial
Genes
Kinetics
Low noise
Luminescent Proteins - genetics
Mathematical models
Molecules
Plasmids
Repression
Signal noise
Signal transduction
Stochastic Processes
Transcription, Genetic
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Summary:The precise nature of information flow through a biological network, which is governed by factors such as response sensitivities and noise propagation, greatly affects the operation of biological systems. Quantitative analysis of these properties is often difficult in naturally occurring systems but can be greatly facilitated by studying simple synthetic networks. Here, we report the construction of synthetic transcriptional cascades comprising one, two, and three repression stages. These model systems enable us to analyze sensitivity and noise propagation as a function of network complexity. We demonstrate experimentally steady-state switching behavior that becomes sharper with longer cascades. The regulatory mechanisms that confer this ultrasensitive response both attenuate and amplify phenotypical variations depending on the system's input conditions. Although noise attenuation allows the cascade to act as a low-pass filter by rejecting short-lived perturbations in input conditions, noise amplification results in loss of synchrony among a cell population. The experimental results demonstrating the above network properties correlate well with simulations of a simple mathematical model of the system.
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To whom correspondence should be addressed. E-mail: rweiss@princeton.edu.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: aTc, anhydrotetracycline; CV, coefficient of variation; EYFP, enhanced yellow fluorescent protein.
Edited by Charles R. Cantor, Sequenom, Inc., San Diego, CA
Author contributions: S.H., S.T., and R.W. designed research; S.H. and R.W. performed research; S.H., S.T., and R.W. analyzed data; and S.H., S.T., and R.W. wrote the paper.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0408507102