Weak coupling between intracellular feedback loops explains dissociation of clock gene dynamics

Christoph Schmal; Daisuke Ono; Jihwan Myung; J Patrick Pett; Sato Honma; Ken-Ichi Honma; Hanspeter Herzel; Isao T Tokuda

doi:10.1371/journal.pcbi.1007330

Weak coupling between intracellular feedback loops explains dissociation of clock gene dynamics

PLoS Comput Biol. 2019 Sep 12;15(9):e1007330. doi: 10.1371/journal.pcbi.1007330. eCollection 2019 Sep.

Authors

Christoph Schmal^{1

2

3}, Daisuke Ono⁴, Jihwan Myung^{5

6

7

8

9}, J Patrick Pett^{2

3}, Sato Honma¹⁰, Ken-Ichi Honma¹⁰, Hanspeter Herzel^{2

3}, Isao T Tokuda¹

Affiliations

¹ Department of Mechanical Engineering, Ritsumeikan University, Kusatsu, Japan.
² Institute for Theoretical Biology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
³ Institute for Theoretical Biology, Humboldt Universität zu Berlin, Berlin, Germany.
⁴ Department of Neuroscience II, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
⁵ Laboratory of Braintime, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.
⁶ Graduate Institute of Mind, Brain, and Consciousness, Taipei Medical University, Taipei, Taiwan.
⁷ Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan.
⁸ TMU Research Center of Brain and Consciousness, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.
⁹ Computational Neuroscience Unit, Okinawa Institute of Science and Technology, Okinawa, Japan.
¹⁰ Department of Chronomedicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan.

Abstract

Circadian rhythms are generated by interlocked transcriptional-translational negative feedback loops (TTFLs), the molecular process implemented within a cell. The contributions, weighting and balancing between the multiple feedback loops remain debated. Dissociated, free-running dynamics in the expression of distinct clock genes has been described in recent experimental studies that applied various perturbations such as slice preparations, light pulses, jet-lag, and culture medium exchange. In this paper, we provide evidence that this "presumably transient" dissociation of circadian gene expression oscillations may occur at the single-cell level. Conceptual and detailed mechanistic mathematical modeling suggests that such dissociation is due to a weak interaction between multiple feedback loops present within a single cell. The dissociable loops provide insights into underlying mechanisms and general design principles of the molecular circadian clock.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Circadian Clocks / genetics*
Circadian Rhythm / genetics*
Computational Biology
Feedback
Gene Expression Regulation / genetics
Humans
Mice
Models, Genetic
Single-Cell Analysis
Suprachiasmatic Nucleus Neurons / cytology

Grants and funding

This work was supported by the Japan Society for the Promotion of Science (JSPS) through grant number PE17780 and the German Research Foundation (DFG) through grant numbers HE2168/11-1 and SCHM3362/2-1. CS acknowledges support from the Joachim Herz Stiftung. JM acknowledges supports from Taiwan Ministry of Science and Technology (MOST) Grants 107-2311-B-038-001-MY2 and 107-2410-H-038-004-MY2, Taipei Medical University Grant TMU107-AE1-B15 and International Cooperation Research Plan Subsidy (TMU decree 1020004021), Taipei Medical University-Shuang Ho Hospital Collaboration Grant 107TMU-SHH-03, and Nakayama Foundation for Human Science. ITT acknowledges financial support from the JSPS (KAKENHI Nos. 16K00343, 16H05011, 17H06313, 18H02477). DO acknowledges support from the Nakatani Foundation for Advancement of Measuring Technologies in Biomedical Engineering, the Uehara Memorial Foundation, Takeda Science Foundation, Research Foundation for Opto-Science and Technology. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.