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Biophys J. 2010 Apr 7;98(7):1247-56. doi: 10.1016/j.bpj.2009.11.046.

Predicting gene-regulation functions: lessons from temperate bacteriophages.

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Research Group Genome Organization & Function, Deutsches Krebsforschungszentrum and BioQuant, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.


Gene-regulation functions (GRF) provide a unique characteristic of a cis-regulatory module (CRM), relating the concentrations of transcription factors (input) to the promoter activities (output). The challenge is to predict GRFs from the sequence. Here we systematically consider the lysogeny-lysis CRMs of different temperate bacteriophages such as the Lactobacillus casei phage A2, Escherichia coli phages lambda, and 186 and Lactococcal phage TP901-1. This study allowed explaining a recent experimental puzzle on the role of Cro protein in the lambda switch. Several general conclusions have been drawn: 1), long-range interactions, multilayer assembly and DNA looping may lead to complex GRFs that cannot be described by linear functions of binding site occupancies; 2), in general, GRFs cannot be described by the Boolean logic, whereas a three-state non-Boolean logic suffices for the studied examples; 3), studied CRMs of the intact phages seemed to have a similar GRF topology (the number of plateaus and peaks corresponding to different expression regimes); we hypothesize that functionally equivalent CRMs might have topologically equivalent GRFs for a larger class of genetic systems; and 4) within a given GRF class, a set of mechanistic-to-mathematical transformations has been identified, which allows shaping the GRF before carrying out a system-level analysis.

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