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BIOLOGICAL SCIENCES / MICROBIOLOGY
Combinatorial transcriptional control of the lactose operon of Escherichia coli
*Center for Theoretical Biological Physics and Division of Biological Sciences, University of California at San Diego, La Jolla, CA 92093-0374
Edited by Carol A. Gross, University of California, San Francisco, CA, and approved January 29, 2007 (received for review August 7, 2006)
The goal of systems biology is to understand the behavior of the whole in terms of knowledge of the parts. This is hard to achieve in many cases due to the difficulty of characterizing the many constituents involved in a biological system and their complex web of interactions. The lac promoter of Escherichia coli offers the possibility of confronting "system-level" properties of transcriptional regulation with the known biochemistry of the molecular constituents and their mutual interactions. Such confrontations can reveal previously unknown constituents and interactions, as well as offer insight into how the components work together as a whole. Here we study the combinatorial control of the lac promoter by the regulators Lac repressor (LacR) and cAMP-receptor protein (CRP). A previous in vivo study [Setty Y, Mayo AE, Surette MG, Alon U (2003) Proc Natl Acad Sci USA 100:7702–7707] found gross disagreement between the observed promoter activities and the expected behavior based on the known molecular mechanisms. We repeated the study by identifying and removing several extraneous factors that significantly modulated the expression of the lac promoter. Through quantitative, systematic characterization of promoter activity for a number of key mutants and guided by the thermodynamic model of transcriptional regulation, we were able to account for the combinatorial control of the lac promoter quantitatively, in terms of a cooperative interaction between CRP and LacR-mediated DNA looping. Specifically, our analysis indicates that the sensitivity of the inducer response results from LacR-mediated DNA looping, which is significantly enhanced by CRP.
DNA looping | gene regulation | lac promoter | systems biology
The authors declare no conflict of interest.
This article is a PNAS direct submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0606717104/DC1.
However, cpdA mutants show a 2-fold overall reduction in gene expression for unknown reasons.
¶ We note that the increased in cooperativity by DNA looping was discussed recently by Vilar and Saiz (75) in the context of the lysis-lysogeny control of Phage 
. However, the mechanism of cooperativity there is the oligomerization of regulatory proteins made possible through DNA looping. In contrast here, the tetramerization of LacR is independent of DNA looping. What DNA looping enhances here is the sensitivity to IPTG rather than LacR.
To whom correspondence should be addressed at: Center for Theoretical Biological Physics, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0374. E-mail: hwa{at}ucsd.edu
© 2007 by The National Academy of Sciences of the USA
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