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Combinatorial Gene Regulation Using Auto-Regulation
Figure 2
Conditional auto-activation.
In some simulation results, auto-activation occurs only in the presence of another transcription factor (TF). We call this conditional auto-activation. The figure presents two examples. Fig. A: The promoter of an AND gate using conditional auto-activation and, for comparison, one using hetero-cooperative activation. Both designs emerged in the simulations. In the first case, the regulated gene tf3 codes for a transcription factor TF3 that binds to its own cis-regulatory region. However, from its binding site, TF3 can activate transcription only indirectly, by facilitating the binding of TF1 and TF2 to their binding sites. As a result, the auto-activation depends on the presence of TF1 and TF2 (
and 
). Fig. B shows plots of the expression level of tf3 (fold-change 
vs. the concentrations 
and 
of TF1 and TF2) resulting from the cis-regulatory regions in Fig. A. The red dots show the values of 
that were used to evaluate the fitness of the gate (see Methods). Fig. C and D show the same mechanism in a simplified model inspired by the simulation results. Plot D compares the response functions corresponding to three activation systems depicted in C. In all cases, a single TF activates the expression of a gene tf3 coding for another transcription factor, TF3. The first two scenarios constitute conventional activation systems with one or two binding sites. In the third scenario, one binding site is replaced by an operator for TF3, which introduces a positive feedback loop depending on the presence TF1. The binding affinities of all sites are optimized using the fitness function described in the main text. The response of the conditional auto-activation system is clearly sharper/more sensitive than the one using a single activation site. Cooperative auto-activation by two sites, however, leads to a slightly sharper response. The results suggest that conditional auto-activation is an alternative design principle that can be used to sharpen responses.
doi: https://doi.org/10.1371/journal.pcbi.1000813.g002