A mixed incoherent feed-forward loop allows conditional regulation of response dynamics

Abstract

Expression of the SodA superoxide dismutase (MnSOD) in Escherichia coli is regulated by superoxide concentration through the SoxRS system and also by Fur (Ferric uptake regulator) through a mixed incoherent feed forward loop (FFL) containing the RyhB small regulatory RNA. In this work I theoretically analyze the function of this feed forward loop as part of the network controlling expression of the two cytoplasmic superoxide dismutases, SodA and SodB. I find that feed forward regulation allows faster response to superoxide stress at low intracellular iron levels compared to iron rich conditions. That is, it can conditionally modulate the response time of a superimposed transcriptional control mechanism.

Figure 1. Regulation of cytoplasmic superoxide dismutases by intracellular free iron and superoxide levels.

SodA expression is regulated by iron through an incoherent feed-forward loop (shown in red).

Figure 2. Steady state levels (solid black line) and production rate (dotted grey line) of SodA mRNA as a function of Fe-Fur level in the absence of superoxide stress.

The functional interactions in the feed-forward loop at low and high Fe-Fur levels are shown in bold.

Figure 3. Simulations of transitions from high to low (A and B) and low to high (C) iron conditions in the absence of superoxide stress.

The Fe-Fur concentration was changed at zero time from 2000 nM to 1 nM (A and B) or from 1 nM to 2000 nM (C). The solid black curves represent RyhB levels, while the solid red and green curves represent the levels of SodA and SodB mRNAs, respectively. The dashed red line represents the control system where SodA is produced constitutively. (B) Changes in the level of SodA mRNA were simulated using different sRNA production rates (α_S) and RyhB pairing rates (δ_A). The rate pairs used were chosen to obtain the same SodA mRNA levels at low and high iron conditions. The solid red curve represents simulations with the standard parameters (α_S = 280/cell gen; δ_A = 0.0019/min). The solid blue (α_S = 105/cell gen; δ_A = 0.008/min) and cyan (α_S = 70/cell gen; δ_A = 0.016/min) lines show simulations where the sRNA was produced at lower rates but formed a complex with the SodA mRNA at a higher rate. The dashed and dotted lines represent corresponding simulations when only the sRNA production rate was decreased or the complex formation rate was increased, respectively.

Figure 4. Simulations of changes in superoxide levels at low (left panels) and high (right panels) iron conditions.

The dominant regulatory interactions are indicated on the top. At zero time the maximal transcription rate of SodA (α_A) was increased 6-fold (top panels) or decreased from this induced level to the uninduced level (bottom panels). The solid black curves represent RyhB levels, while the solid red and green curves represent the levels of SodA and SodB mRNAs, respectively. The dashed red line, which overlaps with the solid red curves in panels B and C, represents the control system where SodA is produced constitutively.