Birhythmicity and Hard Excitation from Coupled Synthetic Feedback Loops

Synthetic biology opens up the possibility of creating circuits that would not survive in the natural world and studying their behaviors in living cells, expanding our notion of biology. Based on this, we analyze on a synthetic biological system the effect of coupling between two instability-generating mechanisms. The systems considered are two topologically equivalent synthetic networks. In addition to simple periodic oscillations and stable steady state, the system can exhibit a variety of new modes of dynamic behavior: coexistence between two stable periodic regimes (birhythmicity) and coexistence of a stable periodic regime with a stable steady state (hard excitation). Birhythmicity and hard excitation have been proved to exist in biochemical networks. Through bifurcation analysis on these two synthetic cellular networks, we analyze the function of network structure for the collapse and revival of birhythmicity and hard excitation with the variation of parameters. The results have illustrated that the bifurcation space can be divided into four subspaces for which the dynamical behaviors of the system are generically distinct. Our analysis corroborates the results obtained by numerical simulation of the dynamics.

[1]  K. Pye,et al.  Sustained sinusoidal oscillations of reduced pyridine nucleotide in a cell-free extract of Saccharomyces carlsbergensis. , 1966, Proceedings of the National Academy of Sciences of the United States of America.

[2]  A Goldbeter,et al.  Bursting, chaos and birhythmicity originating from self-modulation of the inositol 1,4,5-trisphosphate signal in a model for intracellular Ca2+ oscillations , 1999, Bulletin of mathematical biology.

[3]  D. A. Baxter,et al.  modeling in physiology Frequency selectivity , multistability , and oscillations emerge from models of genetic regulatory systems , 1998 .

[4]  J. Tyson,et al.  A simple model of circadian rhythms based on dimerization and proteolysis of PER and TIM. , 1999, Biophysical journal.

[5]  Nancy Kopell,et al.  Synchrony in a Population of Hysteresis-Based Genetic Oscillators , 2004, SIAM J. Appl. Math..

[6]  Sung Hoon Jung,et al.  Interlinked mutual inhibitory positive feedbacks induce robust cellular memory effects , 2007, FEBS letters.

[7]  T. Zhou,et al.  Communication-induced multistability and multirhythmicity in a synthetic multicellular system. , 2011, Physical review. E, Statistical, nonlinear, and soft matter physics.

[8]  B. Hess,et al.  Oscillatory phenomena in biochemistry. , 1971, Annual review of biochemistry.

[9]  J. Collins,et al.  Construction of a genetic toggle switch in Escherichia coli , 2000, Nature.

[10]  Markus Wieland,et al.  Engineering molecular circuits using synthetic biology in mammalian cells. , 2012, Annual review of chemical and biomolecular engineering.

[11]  Kwang-Hyun Cho,et al.  Coupled feedback loops form dynamic motifs of cellular networks. , 2008, Biophysical journal.

[12]  Jared E. Toettcher,et al.  A synthetic–natural hybrid oscillator in human cells , 2010, Proceedings of the National Academy of Sciences.

[13]  Benjamin L Turner,et al.  Supporting Online Material Materials and Methods Som Text Figs. S1 to S3 Table S1 References Robust, Tunable Biological Oscillations from Interlinked Positive and Negative Feedback Loops , 2022 .

[14]  G. Székely,et al.  Simulation of rhythmic nervous activities , 1968, Kybernetik.

[15]  A. Keller,et al.  Model genetic circuits encoding autoregulatory transcription factors. , 1995, Journal of theoretical biology.

[16]  E. Winfree,et al.  Synthetic in vitro transcriptional oscillators , 2011, Molecular systems biology.

[17]  Katherine C. Chen,et al.  Sniffers, buzzers, toggles and blinkers: dynamics of regulatory and signaling pathways in the cell. , 2003, Current opinion in cell biology.

[18]  John J. Tyson,et al.  The Dynamics of Feedback Control Circuits in Biochemical Pathways , 1978 .

[19]  M. Elowitz,et al.  A synthetic oscillatory network of transcriptional regulators , 2000, Nature.

[20]  Deb Shankar Ray,et al.  Controlling birhythmicity in a self-sustained oscillator by time-delayed feedback. , 2011, Physical review. E, Statistical, nonlinear, and soft matter physics.

[21]  A. Goldbeter,et al.  Limit Cycle Models for Circadian Rhythms Based on Transcriptional Regulation in Drosophila and Neurospora , 1999, Journal of biological rhythms.

[22]  A. Goldbeter,et al.  Chaos and birhythmicity in a model for circadian oscillations of the PER and TIM proteins in drosophila , 1999, Journal of theoretical biology.

[23]  Lars Folke Olsen,et al.  Biochemical oscillations and cellular rhythms: The molecular bases of periodic and chaotic behaviour: Albert Goldbeter. Cambridge University Press, Cambridge, 1996. $99.95 (cloth), 605 + xxiv pp , 1997 .

[24]  M. Bennett,et al.  A fast, robust, and tunable synthetic gene oscillator , 2008, Nature.

[25]  P. Hardin,et al.  Interlocked feedback loops within the Drosophila circadian oscillator. , 1999, Science.

[26]  A. Goldbeter,et al.  A Model for Circadian Rhythms in Drosophila Incorporating the Formation of a Complex between the PER and TIM Proteins , 1998, Journal of biological rhythms.

[27]  Jürgen Kurths,et al.  Multistability of synthetic genetic networks with repressive cell-to-cell communication. , 2008, Physical review. E, Statistical, nonlinear, and soft matter physics.

[28]  Alexei Zaikin,et al.  Multistability and clustering in a population of synthetic genetic oscillators via phase-repulsive cell-to-cell communication. , 2007, Physical review letters.

[29]  Liu Caixia,et al.  Coupled feedback loops form birhythmicity and inhomogeneous limit cycles of synthetic regulatory networks , 2013, Proceedings of the 32nd Chinese Control Conference.

[30]  M. Elowitz,et al.  Modeling a synthetic multicellular clock: repressilators coupled by quorum sensing. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[31]  Luonan Chen,et al.  Synchronization of genetic oscillators. , 2008, Chaos.

[32]  J. Stelling,et al.  A tunable synthetic mammalian oscillator , 2009, Nature.

[33]  Kwang-Hyun Cho,et al.  Coupled positive and negative feedback circuits form an essential building block of cellular signaling pathways. , 2007, BioEssays : news and reviews in molecular, cellular and developmental biology.

[34]  D. Thieffry,et al.  Dynamical behaviour of biological regulatory networks—I. Biological role of feedback loops and practical use of the concept of the loop-characteristic state , 1995 .

[35]  A Goldbeter,et al.  Birhythmicity, chaos, and other patterns of temporal self-organization in a multiply regulated biochemical system. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[36]  R Heinrich,et al.  Birhythmicity, trirhythmicity and chaos in bursting calcium oscillations. , 2001, Biophysical chemistry.