Regulatory activity revealed by dynamic correlations in gene expression noise

• Published in: Nature genetics Vol. 40; no. 12; pp. 1493 - 1498
• Main Authors: Elowitz, Michael B, Dunlop, Mary J, Cox, Robert Sidney, Levine, Joseph H, Murray, Richard M
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.12.2008; Nature Publishing Group
• Subjects: Agriculture; Animal Genetics and Genomics; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell cycle; Cellular proteins; Circuits; E coli; Escherichia coli; Escherichia coli - cytology; Escherichia coli - genetics; Escherichia coli - metabolism; Fluorescence; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Expression Regulation, Bacterial; Gene Function; Genetic regulation; Genetics of eukaryotes. Biological and molecular evolution; Human Genetics; letter; Models, Genetic; Noise; Physiological aspects; United States; Gene expression; Correlation
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng.281

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. 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.