Intracellular Noise Level Determines Ratio Control Strategy Confined by Speed–Accuracy Trade-off

Abstract

Robust and precise ratio control of heterogeneous phenotypes within an isogenic population is an essential task, especially in the development and differentiation of a large number of cells such as bacteria, sensory receptors, and blood cells. However, the mechanisms of such ratio control are poorly understood. Here, we employ experimental and mathematical techniques to understand the combined effects of signal induction and gene expression stochasticity on phenotypic multimodality. We identify two strategies to control phenotypic ratios from an initially homogeneous population, suitable roughly to high-noise and low-noise intracellular environments, and we show that both can be used to generate precise fractional differentiation. In noisy gene expression contexts, such as those found in bacteria, induction within the circuit's bistable region is enough to cause noise-induced bimodality within a feasible time frame. However, in less noisy contexts, such as tightly controlled eukaryotic systems, spontaneous state transitions are rare and hence bimodality needs to be induced with a controlled pulse of induction that falls outside the bistable region. Finally, we show that noise levels, system response time, and ratio tuning accuracy impose trade-offs and limitations on both ratio control strategies, which guide the selection of strategy alternatives.

Topology-Dependent Interference of Circuit Function by Growth Feedback

“…In Fig. 4I, the hysteresis curves from conditioned medium (green curve) and the fresh medium (red curve) both showed the irreversibility of the toggle switch, consistent with the previous works 28,36,37 . Thus, the toggle switch is refractory to memory loss from the growth-mediated feedback.…”

“…Measurement of the self-activated circuit was performed in E. coli K-12 MG1655DlacIDaraCBAD as described in 13 . Measurement of the Toggle switch was performed with E. coli K-12 MG1655DlacI as described in 36 . Cells were grown in 5ml or 15ml tubes with 220 rotations per minutes at 37 °C in Luria-Bertani broth (LB broth) with 100µg/ml chloramphenicol or 50 µg/ml kanamycin.…”

“…The operons constituting the self-activation circuits were constructed monocistronically. The plasmid of toggle switch was kindly provided by Dr. James Collins as described in 36,37 .…”

“…The following equations were used the toggle switch circuit without growth feedback, 36,37 . The nullclines in Fig.…”

Winner-Takes-All Resource Competition Redirects Cascading Cell Fate Transitions

“…3B). It is noted that the activation speed of the bistable switch elevates while the dose of its inducer increases 3,23 . Thus, under low dose of C6, M1 is activated so fast that M2 is repressed from activation.…”