Molecular-memory-driven phenotypic switching in a genetic toggle switch without cooperative binding.

Abstract

A genetic toggle switch would involve multistep reaction processes (e.g., complex promoter activation), creating memories between individual reaction events. Revealing the effect of this molecular memory is important for understanding intracellular processes such as cellular decision making. We propose a generalized genetic toggle switch model and use a generalized chemical master equation theory to account for the memory effect. Interestingly, we find that molecular memory can induce bimodality in this memory system although the corresponding memoryless counterpart is not bimodal. This finding implies a plausible alternative mechanism for phenotypic switching that is driven by molecular memory rather than by ultrasensitivity or cooperative binding as shown in previous studies. We also find that unbalanced memories arising from the processes by which mutually inhibiting transcription factors are produced can give rise to asymmetric bimodality without changing the positions of two peaks in the bimodal protein distribution. Given the prevalence of molecular memory in gene regulation, our findings would provide insights into cell fate decisions in growth and development.