Role of DNA binding sites and slow unbinding kinetics in titration-based oscillators.
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 articlePermalink
https://hdl.handle.net/10161/11506Published Version (Please cite this version)
10.1103/PhysRevE.92.062712Publication 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.
Collections
More Info
Show full item recordScholars@Duke
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.

Articles written by Duke faculty are made available through the campus open access policy. For more information see: Duke Open Access Policy
Rights for Collection: Scholarly Articles
Works are deposited here by their authors, and represent their research and opinions, not that of Duke University. Some materials and descriptions may include offensive content. More info