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Science 307 (5717): 1962-1965

Copyright © 2005 by the American Association for the Advancement of Science

Gene Regulation at the Single-Cell Level

Nitzan Rosenfeld,1* Jonathan W. Young,3 Uri Alon,1 Peter S. Swain,2* Michael B. Elowitz3{dagger}

Abstract: The quantitative relation between transcription factor concentrations and the rate of protein production from downstream genes is central to the function of genetic networks. Here we show that this relation, which we call the gene regulation function (GRF), fluctuates dynamically in individual living cells, thereby limiting the accuracy with which transcriptional genetic circuits can transfer signals. Using fluorescent reporter genes and fusion proteins, we characterized the bacteriophage lambda promoter PR in Escherichia coli. A novel technique based on binomial errors in protein partitioning enabled calibration of in vivo biochemical parameters in molecular units. We found that protein production rates fluctuate over a time scale of about one cell cycle, while intrinsic noise decays rapidly. Thus, biochemical parameters, noise, and slowly varying cellular states together determine the effective single-cell GRF. These results can form a basis for quantitative modeling of natural gene circuits and for design of synthetic ones.

1 Departments of Molecular Cell Biology and Physics of Complex Systems, Weizmann Institute of Science, Rehovot, 76100, Israel.
2 Centre for Non-linear Dynamics, Department of Physiology, McGill University, 3655 Promenade Sir William Osler, Montréal, Québec, Canada, H3G 1Y6.
3 Division of Biology and Department of Applied Physics, Caltech, Pasadena, CA 91125, USA.

* These authors contributed equally to this work

{dagger} To whom correspondence should be addressed. E-mail: melowitz{at}caltech.edu

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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 »
Delay-induced stochastic oscillations in gene regulation.
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   Abstract »    Full Text »    PDF »
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J. M. Raser and E. K. O'Shea (2005)
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   Abstract »    Full Text »    PDF »
Physical limits to biochemical signaling.
W. Bialek and S. Setayeshgar (2005)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
MOLECULAR BIOLOGY: Signal Processing in Single Cells.
F. J. Isaacs, W. J. Blake, and J. J. Collins (2005)
Science 307, 1886-1888
   Abstract »    Full Text »    PDF »

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