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Science 315 (5819): 1716-1719

Copyright © 2007 by the American Association for the Advancement of Science

Tunability and Noise Dependence in Differentiation Dynamics

Gürol M. Süel,1 Rajan P. Kulkarni,2 Jonathan Dworkin,3 Jordi Garcia-Ojalvo,4 Michael B. Elowitz2*

Abstract: The dynamic process of differentiation depends on the architecture, quantitative parameters, and noise of underlying genetic circuits. However, it remains unclear how these elements combine to control cellular behavior. We analyzed the probabilistic and transient differentiation of Bacillus subtilis cells into the state of competence. A few key parameters independently tuned the frequency of initiation and the duration of competence episodes and allowed the circuit to access different dynamic regimes, including oscillation. Altering circuit architecture showed that the duration of competence events can be made more precise. We used an experimental method to reduce global cellular noise and showed that noise levels are correlated with frequency of differentiation events. Together, the data reveal a noise-dependent circuit that is remarkably resilient and tunable in terms of its dynamic behavior.

1 Green Center Division for Systems Biology and Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
2 Division of Biology and Department of Applied Physics, California Institute of Technology, Pasadena, CA 91125, USA.
3 Department of Microbiology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
4 Departament de Física i Enginyeria Nuclear, Universitat Politècnica de Catalunya, Colom 11, E-08222 Terrassa, Spain.

* To whom correspondence should be addressed. E-mail: melowitz{at}

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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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Mol Syst Biol 5, 294
   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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D. K. Singh, C.-J. Ku, C. Wichaidit, R. J. Steininger III, L. F. Wu, and S. J. Altschuler (2014)
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   Abstract »    Full Text »    PDF »
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V. Shahrezaei, J. F. Ollivier, and P. S. Swain (2014)
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   Abstract »    Full Text »    PDF »
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C. L. Beisel, T. S. Bayer, K. G. Hoff, and C. D. Smolke (2014)
Mol Syst Biol 4, 224
   Abstract »    Full Text »    PDF »
Functional Roles of Pulsing in Genetic Circuits.
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Science 342, 1193-1200
   Abstract »    Full Text »    PDF »
Inverse Gillespie for inferring stochastic reaction mechanisms from intermittent samples.
I. Chattopadhyay, A. Kuchina, G. M. Suel, and H. Lipson (2013)
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   Abstract »    Full Text »    PDF »
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R. Arbel-Goren, A. Tal, T. Friedlander, S. Meshner, N. Costantino, D. L. Court, and J. Stavans (2013)
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   Abstract »    Full Text »    PDF »
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L. Espinar, M. Dies, T. Cagatay, G. M. Suel, and J. Garcia-Ojalvo (2013)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »

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