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Regulatory activity revealed by dynamic correlations in gene expression noise

Dunlop, Mary J. and Cox, Robert Sidney, III and Levine, Joseph H. and Murray, Richard M. and Elowitz, Michael B. (2008) Regulatory activity revealed by dynamic correlations in gene expression noise. Nature Genetics, 40 (12). pp. 1493-1498. ISSN 1061-4036. PMCID PMC2829635. doi:10.1038/ng.281.

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Gene regulatory interactions are context dependent, active in some cellular states but not in others. Stochastic fluctuations, or 'noise', in gene expression propagate through active, but not inactive, regulatory links^(1,2). Thus, correlations in gene expression noise could provide a noninvasive means to probe the activity states of regulatory links. However, global, 'extrinsic', noise sources generate correlations even without direct regulatory links. Here we show that single-cell time-lapse microscopy, by revealing time lags due to regulation, can discriminate between active regulatory connections and extrinsic noise. We demonstrate this principle mathematically, using stochastic modeling, and experimentally, using simple synthetic gene circuits. We then use this approach to analyze dynamic noise correlations in the galactose metabolism genes of Escherichia coli. We find that the CRP-GalS-GalE feed-forward loop is inactive in standard conditions but can become active in a GalR mutant. These results show how noise can help analyze the context dependence of regulatory interactions in endogenous gene circuits.

Item Type:Article
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URLURL TypeDescription ReadCube access CentralArticle
Murray, Richard M.0000-0002-5785-7481
Elowitz, Michael B.0000-0002-1221-0967
Additional Information:© 2008 Nature Publishing Group. Received 9 June; accepted 23 September; published online 23 November 2008. We thank M. Fontes, F. Tan, L. Cai, E. Franco, and all members of the Elowitz and Murray groups for their feedback and suggestions. H. Garcia provided advice on the chromosomal integration and gene knockout experiments. We thank J. Garcia-Ojalvo, U. Alon, R. Kishony, N. Rosenfeld and B. Shraiman for discussions. M.J.D. and R.M.M. are supported by the Institute for Collaborative Biotechnologies through grant DAAD19-03-D-0004 from the US Army Research Office. M.J.D. was additionally supported by a Department of Energy Computational Science Graduate Fellowship. This research was supported by US National Institutes of Health grants R01GM079771, P50 GM068763, National Science Foundation CAREER Award 0644463 and the Packard Foundation.
Funding AgencyGrant Number
Army Research Office (ARO)DAAD19-03-D-0004
Department of Energy (DOE)UNSPECIFIED
NIHP50 GM068763
David and Lucile Packard FoundationUNSPECIFIED
Subject Keywords:incoherent feedforward loop; Escherichia-coli; Bacillius-subtilis; consequences; construction; networks; pathway; system; time; cell
Issue or Number:12
PubMed Central ID:PMC2829635
Record Number:CaltechAUTHORS:DUNng08
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:13444
Deposited By: Tony Diaz
Deposited On:14 Apr 2009 18:43
Last Modified:08 Nov 2021 22:37

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