Speed, Sensitivity, and Bistability in Auto-activating Signaling Circuits

Abstract

Cells employ a myriad of signaling circuits to detect environmental signals and drive specific gene expression responses. A common motif in these circuits is inducible auto-activation: a transcription factor that activates its own transcription upon activation by a ligand or by post-transcriptional modification. Examples range from the two-component signaling systems in bacteria and plants to the genetic circuits of animal viruses such as HIV. We here present a theoretical study of such circuits, based on analytical calculations, numerical computations, and simulation. Our results reveal several surprising characteristics. They show that auto-activation can drastically enhance the sensitivity of the circuit's response to input signals: even without molecular cooperativity, an ultra-sensitive threshold response can be obtained. However, the increased sensitivity comes at a cost: auto-activation tends to severely slow down the speed of induction, a stochastic effect that was strongly underestimated by earlier deterministic models. This slow-induction effect again requires no molecular cooperativity and is intimately related to the bimodality recently observed in non-cooperative auto-activation circuits. These phenomena pose strong constraints on the use of auto-activation in signaling networks. To achieve both a high sensitivity and a rapid induction, an inducible auto-activation circuit is predicted to acquire low cooperativity and low fold-induction. Examples from Escherichia coli's two-component signaling systems support these predictions.

Coupling between feedback loops in autoregulatory networks affects bistability range, open-loop gain and switching times

“…These effects result in large variability in the switching times of bistable networks. A recent study showed that, at large effective fold changes, the switching times for an autoregulatory network computed using a stochastic model deviates strongly from the deterministic network, and a significant slowdown is predicted [43]. Thus, it would be interesting to explore the effects of the features of feedback architecture studied here in a stochastic framework especially with regards to switching times.…”

Evolutionary Tuning of Protein Expression Levels of a Positively Autoregulated Two-Component System

“…In E. coli , nearly half of the 30 RR transcription factors auto-activate expression of operons encoding themselves [4]. Genetic mechanisms and regulatory features of this feedback control have been explored [4]–[8] but the potential fitness benefit of TCS autoregulation in environmental adaptation are less examined experimentally.…”

“…In E. coli , nearly half of the 30 RR transcription factors auto-activate expression of operons encoding themselves [4]. Genetic mechanisms and regulatory features of this feedback control have been explored [4]–[8] but the potential fitness benefit of TCS autoregulation in environmental adaptation are less examined experimentally. Positive feedback can lead to an ultra-sensitive switch-like response, an increase of regulatory capacity, a delay of response time, and promotion of a bistable system that can yield all-or-none output [4], [5], [9].…”

“…Genetic mechanisms and regulatory features of this feedback control have been explored [4]–[8] but the potential fitness benefit of TCS autoregulation in environmental adaptation are less examined experimentally. Positive feedback can lead to an ultra-sensitive switch-like response, an increase of regulatory capacity, a delay of response time, and promotion of a bistable system that can yield all-or-none output [4], [5], [9]. The ability to switch between two discrete “ON” and “OFF” states or to defer responses after multiple cell division cycles could be beneficial to some differentiation and developmental processes [10]–[12].…”

Measurement of bistability in a multidimensional parameter space

“…For a single feedback loop to be bistable, its reactions must generate a non-linear switch-like sigmoidal response, termed ultrasensitive response even in the absence of feedback regulation [9][10][11] . In the absence of ultrasensitive reactions, the feedback loop is strictly monostable, and the expression converges to a single steady-state level.…”