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Role of DNA binding sites and slow unbinding kinetics in titration-based oscillators.

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Date
2015-12
Authors
Karapetyan, Sargis
Buchler, Nicolas E
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Abstract
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.
Type
Journal article
Subject
Binding Sites
Circadian Clocks
DNA
Kinetics
Models, Genetic
Stochastic Processes
Permalink
https://hdl.handle.net/10161/11506
Published Version (Please cite this version)
10.1103/PhysRevE.92.062712
Publication Info
Karapetyan, Sargis; & Buchler, Nicolas E (2015). Role of DNA binding sites and slow unbinding kinetics in titration-based oscillators. Phys Rev E Stat Nonlin Soft Matter Phys, 92(6). pp. 062712. 10.1103/PhysRevE.92.062712. Retrieved from https://hdl.handle.net/10161/11506.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
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Scholars@Duke

Buchler

Nicolas Buchler

Assistant Professor of Biology
Our lab is interested in the systems biology and evolution of epigenetic switches (bistability) and clocks (oscillators) in gene regulatory networks, two functions that are essential for patterning, cell proliferation, and differentiation in biological systems. We also study biochemical oscillators such as the cell cycle, metabolic rhythms, and circadian clocks, which co-exist in the same cells and interact with one another through shared resources.
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