TY - JOUR
T1 - Multistability in the lactose utilization network of Escherichia coli
AU - Ozbudak, Ertugrul M.
AU - Thattal, Mukund
AU - Lim, Han H.
AU - Shraiman, Boris I.
AU - Van Oudenaarden, Alexander
N1 - Funding Information:
Acknowledgements We thank G. Jacobson and H. Kornberg, J. Paulsson, M. Savageau and A. Sengupta for discussions and suggestions; H. Bujard and R. Lutz for supplying the pZ vector system; and D. Boyd for help with the l-InCh technique. We thank D. Raut for his assistance with the initial lactose measurements and the construction of plasmids and strains. We also thank A. Becskei and J. Pedraza for critically reviewing the manuscript. This work was supported by NIH and DARPA grants, and an NSF-CAREER grant.
Funding Information:
Acknowledgements We thank W. Pawlowski for help with the spore nuclei count; P. Bethke for advice on nuclei microdissection; D. Baker, T. Galagher, B. King, T. Lee and T. Szaro for technical assistance; J. A. Fortin for G. intraradices; D. Douds for the DC1 isolate of Ri T-DNA-transformed carrot roots developed by G. Bécard; and D. J. Read, T. Bruns, A. Burt and the members of the Taylor laboratory for comments on the manuscript. This work was supported by the Torrey Mesa Research Institute-Syngenta Biotechnology and the National Research Initiative Competitive Grants Program (NRICGP) of the US Department of Agriculture.
PY - 2004/2/19
Y1 - 2004/2/19
N2 - Multistability, the capacity to achieve multiple internal states in response to a single set of external inputs, is the defining characteristic of a switch. Biological switches are essential for the determination of cell fate in multicellular organisms, the regulation of cell-cycle oscillations during mitosis and the maintenance of epigenetic traits in microbes. The multistability of several natural and synthetic systems has been attributed to positive feedback loops in their regulatory networks. However, feedback alone does not guarantee multistability. The phase diagram of a multistable system, a concise description of internal states as key parameters are varied, reveals the conditions required to produce a functional switch. Here we present the phase diagram of the bistable lactose utilization network of Escherichia coli. We use this phase diagram, coupled with a mathematical model of the network, to quantitatively investigate processes such as sugar uptake and transcriptional regulation in vivo. We then show how the hysteretic response of the wild-type system can be converted to an ultrasensitive graded response. The phase diagram thus serves as a sensitive probe of molecular interactions and as a powerful tool for rational network design.
AB - Multistability, the capacity to achieve multiple internal states in response to a single set of external inputs, is the defining characteristic of a switch. Biological switches are essential for the determination of cell fate in multicellular organisms, the regulation of cell-cycle oscillations during mitosis and the maintenance of epigenetic traits in microbes. The multistability of several natural and synthetic systems has been attributed to positive feedback loops in their regulatory networks. However, feedback alone does not guarantee multistability. The phase diagram of a multistable system, a concise description of internal states as key parameters are varied, reveals the conditions required to produce a functional switch. Here we present the phase diagram of the bistable lactose utilization network of Escherichia coli. We use this phase diagram, coupled with a mathematical model of the network, to quantitatively investigate processes such as sugar uptake and transcriptional regulation in vivo. We then show how the hysteretic response of the wild-type system can be converted to an ultrasensitive graded response. The phase diagram thus serves as a sensitive probe of molecular interactions and as a powerful tool for rational network design.
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U2 - 10.1038/nature02298
DO - 10.1038/nature02298
M3 - Article
C2 - 14973486
AN - SCOPUS:1442354192
SN - 0028-0836
VL - 427
SP - 737
EP - 740
JO - Nature
JF - Nature
IS - 6976
ER -