Journal
AUTOMATICA
Volume 49, Issue 9, Pages 2581-2590Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.automatica.2013.04.020
Keywords
Gene regulatory networks; Cellular, metabolic, cardiovascular, neurosystems; Systems with time-delays; Application of nonlinear analysis and design; Large scale complex systems
Funding
- Ministry of Education, Culture, Sports, Science and Technology in Japan [19656104, 21656106, 21246067, 23-9203]
- Grants-in-Aid for Scientific Research [21656106, 21246067, 19656104] Funding Source: KAKEN
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In this paper, we propose a theoretical framework to systematically analyze the existence and the profiles of chemical oscillations in gene regulatory networks with negative cyclic feedback. In particular, we analytically derive the existence conditions and the profiles of oscillations in terms of reaction kinetic parameters and reveal dimensionless quantities that essentially characterize the oscillatory dynamics. These discoveries then allow us to provide general biological insights that are useful for the design of synthetic gene circuits and wet-lab experiments. We point out that time delays due to splicing and transport play an important role for both of the existence and the profiles of oscillations. To this end, we first show that local instability leads to oscillations in cyclic gene regulatory networks, and we derive the existence conditions based on local instability analysis. Then, we analyze the period, phase and amplitude of oscillations using multivariable harmonic balance analysis. These results are demonstrated with two existing biochemical networks, the Pentilator and a self-repression network of a Hes protein. (C) 2013 Elsevier Ltd. All rights reserved.
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