Dissection of the contribution of regulation mode to the properties of feedforward and feedback gene regulatory motifs

Abstract

We present a framework enabling dissection of the effects of motif structure (feedback or feedforward), nature of the controller (mRNA or protein), and regulation mode (transcriptional, post-transcriptional or translational) on the response to a step change in the input. We have used a common model framework for gene expression where both motif structures have an activating input and repressing regulator, with the same set of parameters to enable comparison of the responses. We studied the global sensitivity of the system properties such as steady-state gain, overshoot, peak time, and peak duration, to parameters. We find that, in all motifs, overshoot correlated negatively whereas peak duration varied concavely, with peak time. Differences in other system properties were found to be mainly dependent on the the nature of the regulator, than the motif structure. Protein mediated motifs showed a higher degree of adaptation; feedforward motifs exhibited perfect adaptation. RNA mediated motifs had a mild regulatory effect; they also exhibited lower peaking tendency and mean overshoot. Protein mediated feedforward motifs showed higher overshoot and lower peak time compared to corresponding feedback motifs.

Properties of compostite feedback-feedforward pulse generating motifs

“…This study reveals that the AND-gated motifs exhibit "feedforward-like" properties (based on the metrics) whereas the OR-gated motifs exhibit "feedbacklike" properties. This study also reveals that in these composite motifs the pulse dynamics follows a previously observed pattern with feedback and feedforward loopsthe overshoot correlates negatively with peak time and the peak duration correlates concavely with peak time [10] . This suggests that this property may be a universal feature of these pulse-generating motifs.…”

“…It is apparent that most of the cases which showed saturation and non-monotonicity, were hypersensitive at low values of input. Considering our previous observations with uncoupled feedback and feedforward motifs [10] , it appears that the steady state properties of ANDn motifs have a more "feedforward-like" nature whereas those of ORn motifs have more of a "feedback-like" nature.…”

“…3, Equations 1-5). These metrics are defined in our previous work [10] ; I shall provide a brief description of these motifs, here.…”

“…the output steady state level after the step change is same as the initial level, while the transient levels are different. However, a simple feedback loop which does not have a perfect integral feedback does not lead to perfect adaptation ( [10] ). Under certain conditions, the incoherent feedforward motif can also exhibit fold change detection, a phenomenon in which both the dynamics and the steady state of the output, are only dependent on the fold difference between the input levels [8,11] .…”