title: Ultrasensitivity and noise propagation in a synthetic transcriptional cascade.
abstract: 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.
authors.affiliation: Departments of Electrical Engineering and Molecular Biology, Princeton University, J-319, E-Quad, Princeton, NJ 08544, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Hooshangi
authors.forename: Stephan
authors.initials: S
authors.lastname: Thiberge
authors.forename: Ron
authors.initials: R
authors.lastname: Weiss
mesh_terms: D001426:Bacterial Proteins / Q000235:genetics; D015964:Gene Expression Regulation, Bacterial; D008164:Luminescent Proteins / Q000235:genetics; D013269:Stochastic Processes; D014158:Transcription, Genetic
chemical_list: D001426:Bacterial Proteins; D008164:Luminescent Proteins; C054562:yellow fluorescent protein, Bacteria
references.citation: Biophys J. 2000 Dec;79(6):2801-17
references.pmid: 11106590
references.citation: Science. 2001 Jun 15;292(5524):2080-3
references.pmid: 11408658
references.citation: Science. 2002 Mar 1;295(5560):1669-78
references.pmid: 11872831
references.citation: Nat Genet. 2002 May;31(1):69-73
references.pmid: 11967532
references.citation: Nat Genet. 2002 May;31(1):64-8
references.pmid: 11967538
references.citation: Biophys J. 2002 Jun;82(6):2943-50
references.pmid: 12023217
references.citation: Science. 2002 Aug 16;297(5584):1183-6
references.pmid: 12183631
references.citation: Science. 2002 Oct 25;298(5594):799-804
references.pmid: 12399584
references.citation: Nature. 2003 Apr 10;422(6932):633-7
references.pmid: 12687005
references.citation: Cell. 2003 May 30;113(5):597-607
references.pmid: 12787501
references.citation: J Mol Biol. 2003 Jun 13;329(4):645-54
references.pmid: 12787666
references.citation: Proc Natl Acad Sci U S A. 2003 Jun 24;100(13):7714-9
references.pmid: 12808135
references.citation: Science. 2003 Sep 26;301(5641):1874-7
references.pmid: 14512618
references.citation: Nat Genet. 2004 May;36(5):486-91
references.pmid: 15107854
references.citation: Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6355-60
references.pmid: 15096621
references.citation: Biophys J. 2004 Oct;87(4):2195-202
references.pmid: 15454422
references.citation: Nature. 1974 Dec 13;252(5484):546-9
references.pmid: 4431516
references.citation: Proc Natl Acad Sci U S A. 1977 Jul;74(7):2761-5
references.pmid: 268625
references.citation: Proc Natl Acad Sci U S A. 1977 Jul;74(7):2766-70
references.pmid: 19739
references.citation: Antimicrob Agents Chemother. 1984 Aug;26(2):263-5
references.pmid: 6486766
references.citation: Nature. 2000 Jan 20;403(6767):335-8
references.pmid: 10659856
references.citation: Nature. 2000 Jan 20;403(6767):339-42
references.pmid: 10659857
references.citation: Nat Struct Biol. 2000 Mar;7(3):215-9
references.pmid: 10700280
references.citation: Nature. 2000 Jun 1;405(6786):590-3
references.pmid: 10850721
references.citation: Science. 1989 Nov 3;246(4930):629-34
references.pmid: 2683079
references.citation: Science. 1994 Apr 15;264(5157):418-20
references.pmid: 8153629
references.citation: Proc Natl Acad Sci U S A. 1996 Jan 23;93(2):566-70
references.pmid: 8570596
references.citation: Trends Biochem Sci. 1996 Dec;21(12):460-6
references.pmid: 9009826
references.citation: Proc Natl Acad Sci U S A. 1997 Feb 4;94(3):814-9
references.pmid: 9023339
references.citation: Nucleic Acids Res. 1997 Mar 15;25(6):1203-10
references.pmid: 9092630
references.citation: Development. 1997 May;124(10):1851-64
references.pmid: 9169833
references.citation: Science. 1998 May 8;280(5365):895-8
references.pmid: 9572732
references.citation: Genetics. 1998 Aug;149(4):1633-48
references.pmid: 9691025
references.citation: Science. 1998 Oct 23;282(5389):699-705
references.pmid: 9784122
references.citation: Microbiol Mol Biol Rev. 1998 Dec;62(4):1264-300
references.pmid: 9841672
references.citation: Trends Genet. 1999 Feb;15(2):65-9
references.pmid: 10098409