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Published online on June 12, 2003, 10.1073/pnas.1230759100
PNAS | June 24, 2003 | vol. 100 | no. 13 | 7702-7707


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Genetics
Detailed map of a cis-regulatory input function

Y. Setty * {dagger}, A. E. Mayo * {dagger}, M. G. Surette {ddagger}, and U. Alon * {dagger} §

Departments of *Molecular Cell Biology and {dagger}Physics of Complex Systems, The Weizmann Institute of Science, Rehovot 76100, Israel; and {ddagger}Department of Microbiology and Infectious Diseases, University of Calgary, Calgary, AB, Canada T2N 4N1

Edited by Curtis G. Callan, Jr., Princeton University, Princeton, NJ and approved April 24, 2003 (received for review February 9, 2003)

Most genes are regulated by multiple transcription factors that bind specific sites in DNA regulatory regions. These cis-regulatory regions perform a computation: the rate of transcription is a function of the active concentrations of each of the input transcription factors. Here, we used accurate gene expression measurements from living cell cultures, bearing GFP reporters, to map in detail the input function of the classic lacZYA operon of Escherichia coli, as a function of about a hundred combinations of its two inducers, cAMP and isopropyl {beta}-D-thiogalactoside (IPTG). We found an unexpectedly intricate function with four plateau levels and four thresholds. This result compares well with a mathematical model of the binding of the regulatory proteins cAMP receptor protein (CRP) and LacI to the lac regulatory region. The model is also used to demonstrate that with few mutations, the same region could encode much purer AND-like or even OR-like functions. This possibility means that the wild-type region is selected to perform an elaborate computation in setting the transcription rate. The present approach can be generally used to map the input functions of other genes.

This paper was submitted directly (Track II) to the PNAS office.

Abbreviations: CRP, cAMP receptor protein; IPTG, isopropyl {beta}-D-thiogalactoside; ONPG, o-nitrophenyl {beta}-D-galactoside.

§ To whom correspondence should be sent at the * address. E-mail: urialon{at}weizmann.ac.il.


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