Title: Noise Can Induce Steady-State Bimodality in Positive Feedback Loops Without Cooperativity
Abstract: Positive feedback is a common network motif in gene regulatory networks that is widely recognized to lead to bistability and, as a consequence, to hysteresis and switch-like responses. A non-linear, cooperative promoter response provides the necessary ingredient to generate bistability in deterministic descriptions of positive feedback. Using a synthetic system, we show experimentally that positive feedback is capable of inducing a bimodal, switch-like response with non-cooperative feedback, even when the underlying deterministic dynamics do not admit bistability. In accordance with theoretical models, the bimodal response requires the promoter within the feedback loop to be noisy, with infrequent, large bursts of expression. In addition, the transcription factor (TF) involved in the feedback loop has to be short-lived. Using a stochastic model and experimentally measured in vivo parameters of the promoter response in the absence of feedback, we can quantitatively describe the feedback response. We also find that multiple TF binding sites in a promoter can be important for the bimodal response not because of molecular cooperativity in TF binding, but because of increased noise in the promoter. Because many promoters possess multiple binding sites and many TFs are unstable, positive feedback loops in many gene regulatory networks may exhibit bimodal responses, but not necessarily because of deterministic bistability as is commonly thought.