1
Systems, Synthetic, and Physical Biology Graduate Program, Rice University, Houston, TX 77005, USA
2
Department of Bioengineering, Rice University, Houston, Texas 77005, USA
3
Department of Chemical & Biomolecular Engineering, Rice University, Houston, Texas 77005, USA
4
Department of BioSciences, Rice University, Houston, Texas 77005, USA
*
Authors to whom correspondence should be addressed.
Received: 12 Nov 2022
Accepted: 27 Feb 2023
Published: 13 Mar 2023
Abstract
Many essential
functions in biological systems, including cell cycle progression and circadian
rhythm regulation, are governed by the periodic behaviors of specific
molecules. These periodic behaviors arise from the precise arrangement of
components in biomolecular networks that generate oscillatory output signals.
The dynamic properties of individual components of these networks, such as
maturation delays and degradation rates, often play a key role in determining
the network's oscillatory behavior. In this study, we explored the
post-translational modulation of network components as a means to generate
genetic circuits with oscillatory behaviors and perturb the oscillation
features. Specifically, we used the NanoDeg platform—A bifunctional molecule
consisting of a target-specific nanobody and a degron tag—to control the
degradation rates of the circuit’s components and predicted the effect of
NanoDeg-mediated post-translational depletion of a key circuit component on the
behavior of a series of proto-oscillating network topologies. We modeled the
behavior of two main classes of oscillators, namely relaxation oscillator
topologies (the activator-repressor and the Goodwin oscillator) and ring
oscillator topologies (repressilators). We identified two main mechanisms by
which non-oscillating networks could be induced to oscillate through
post-translational modulation of network components: an increase in the
separation of timescales of network components and mitigation of the leaky
expression of network components. These results are in agreement with previous
findings describing the effect of timescale separation and mitigation of leaky
expression on oscillatory behaviors. This work thus validates the use of tools
to control protein degradation rates as a strategy to modulate existing
oscillatory signals and construct oscillatory networks. In addition, this study
provides the design rules to implement such an approach based on the control of
protein degradation rates using the NanoDeg platform, which does not require
genetic manipulation of the network components and can be adapted to virtually
any cellular protein. This work also establishes a framework to explore the use
of tools for post-translational perturbations of biomolecular networks and
generates desired behaviors of the network output.
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© 2023 by the authors; licensee SCIEPublish, SCISCAN co. Ltd. This article is an open access article distributed under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
