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Multi-stable dynamics of the non-adiabatic repressilator.

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Summary

The binding rate of transcription factors (TFs) to DNA affects genetic oscillator dynamics. Slowing TF binding can create a hysteresis region where steady states and oscillations coexist in synthetic genetic circuits.

Keywords:
adiabaticbimodalitygenetic oscillatorhysteresismulti-stability

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Area of Science:

  • Synthetic biology
  • Biophysics
  • Systems biology

Background:

  • The fast binding of transcription factors (TFs) to promoters is a common assumption in synthetic genetic circuit modeling.
  • In vivo measurements suggest TF search times can be significant, questioning this assumption.

Purpose of the Study:

  • To investigate the dynamics of the repressilator genetic oscillator model considering realistic TF binding rates.
  • To analyze the impact of TF binding kinetics on the transition between steady states and oscillations.

Main Methods:

  • Deterministic mathematical modeling of the repressilator circuit.
  • Stochastic simulations to explore system dynamics and noise effects.
  • Utilized experimentally validated parameter values.

Main Results:

  • Decreased TF binding rates alter the transition dynamics, leading to a hysteresis region where steady state and oscillation coexist.
  • Hysteresis is robust across a range of parameters, but oscillations are limited by TF dimer degradation rates.
  • Stochastic simulations confirm hysteresis and reveal skewed period distributions due to attractor switching and noise-induced modulations.

Conclusions:

  • Realistic TF binding kinetics are crucial for accurately modeling synthetic genetic circuits like the repressilator.
  • The identified hysteresis phenomenon has significant implications for the design and predictability of genetic oscillators.
  • Intrinsic noise plays a key role in shaping the system's behavior, particularly outside the hysteresis region.