Browsing by Author "Karapetyan, Sargis"

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    Design Principles and Coupling of Biological Oscillators
    (2015) Karapetyan, Sargis

    One of the main challenges that biological oscillators face at the cellular level is maintaining coherence in the presence of molecular noise. Mechanisms of noise resistance have been proposed, however the findings are sometimes contradictory and not universal. Another challenge faced by biological oscillators is the proper timing of cellular events and effective distribution of cellular resources when there is more than one oscillator in the same cell. Biological oscillators are often coupled, however, the mechanisms and extent of these couplings are poorly understood. In this thesis, I describe three separate yet interconnected projects in an attempt to understand these biophysical phenomena.

    I show that slow DNA unbinding rates are important in titration-based oscillators and can mitigate molecular noise. Multiple DNA binding sites can also increase the coherence of the oscillations through protected states, where the DNA binding/unbinding between these states has little effect on gene expression. I then show that experimental titration-based oscillator in budding yeast is innately coupled to the cell cycle. The oscillator and the cell cycle show 1:1 and 2:1 phase locking similar to what has been observed in natural systems. Finally, by studying the relationship between the circadian redox rhythm and genetic circadian clock in plants I show how perturbation of one of the coupled oscillators can be transformed into a reinforcement signal for the other one via a balanced network architecture.

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    Role of DNA binding sites and slow unbinding kinetics in titration-based oscillators.
    (Phys Rev E Stat Nonlin Soft Matter Phys, 2015-12) Karapetyan, Sargis; Buchler, Nicolas E
    Genetic oscillators, such as circadian clocks, are constantly perturbed by molecular noise arising from the small number of molecules involved in gene regulation. One of the strongest sources of stochasticity is the binary noise that arises from the binding of a regulatory protein to a promoter in the chromosomal DNA. In this study, we focus on two minimal oscillators based on activator titration and repressor titration to understand the key parameters that are important for oscillations and for overcoming binary noise. We show that the rate of unbinding from the DNA, despite traditionally being considered a fast parameter, needs to be slow to broaden the space of oscillatory solutions. The addition of multiple, independent DNA binding sites further expands the oscillatory parameter space for the repressor-titration oscillator and lengthens the period of both oscillators. This effect is a combination of increased effective delay of the unbinding kinetics due to multiple binding sites and increased promoter ultrasensitivity that is specific for repression. We then use stochastic simulation to show that multiple binding sites increase the coherence of oscillations by mitigating the binary noise. Slow values of DNA unbinding rate are also effective in alleviating molecular noise due to the increased distance from the bifurcation point. Our work demonstrates how the number of DNA binding sites and slow unbinding kinetics, which are often omitted in biophysical models of gene circuits, can have a significant impact on the temporal and stochastic dynamics of genetic oscillators.