Intracellular noise level determines ratio control strategy confined by speed-accuracy tradeoff

Robust and precise ratio control of heterogeneous phenotypes within an isogenic population is essential in the development and differentiation. 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 homogenous 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 timeframe. 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 tradeoff and limitations on both ratio control strategies, which guides the selection of strategy alternatives.