A bottom-up approach to gene regulation

Nicholas J. Guido, Xiao Wang, David Adalsteinsson, David McMillen, Jeff Hasty, Charles R. Cantor, Timothy C. Elston and J. J. Collins ()
Additional contact information
Nicholas J. Guido: Boston University
Xiao Wang: Department of Statistics and Operations Research
David Adalsteinsson: Department of Mathematics
David McMillen: University of Toronto at Mississauga
Jeff Hasty: University of California
Charles R. Cantor: Boston University
Timothy C. Elston: University of North Carolina
J. J. Collins: Boston University

Nature, 2006, vol. 439, issue 7078, 856-860

Abstract: Abstract The ability to construct synthetic gene networks enables experimental investigations of deliberately simplified systems that can be compared to qualitative and quantitative models1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23. If simple, well-characterized modules can be coupled together into more complex networks with behaviour that can be predicted from that of the individual components, we may begin to build an understanding of cellular regulatory processes from the ‘bottom up’. Here we have engineered a promoter to allow simultaneous repression and activation of gene expression in Escherichia coli. We studied its behaviour in synthetic gene networks under increasingly complex conditions: unregulated, repressed, activated, and simultaneously repressed and activated. We develop a stochastic model that quantitatively captures the means and distributions of the expression from the engineered promoter of this modular system, and show that the model can be extended and used to accurately predict the in vivo behaviour of the network when it is expanded to include positive feedback. The model also reveals the counterintuitive prediction that noise in protein expression levels can increase upon arrest of cell growth and division, which we confirm experimentally. This work shows that the properties of regulatory subsystems can be used to predict the behaviour of larger, more complex regulatory networks, and that this bottom-up approach can provide insights into gene regulation.

Date: 2006
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DOI: 10.1038/nature04473

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