Co-existing feedback loops generate tissue-specific circadian rhythms

Pett, J. Patrick; Kondoff, Matthew; Bordyugov, Grigory; Kramer, Achim; Herzel, Hanspeter

doi:10.26508/lsa.201800078

Cited by 61 publications

(68 citation statements)

References 64 publications

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“…This emphasizes the biological relevance of our bifurcation analyses [41]. A recent study by Pett et al [45] suggested that different interlocked feedback loops might coexist and generate tissue-specific circadian rhythms. Taken together, the findings of potential tissue-specific clocks with the conditions under which nonlinear phenomena occur might contribute to the further understanding of organismic circadian desynchronization.…”

Section: Discussionsupporting

confidence: 53%

“…These clock proteins interact with each other by different positive and negative feedback loops, including the BMAL1-REVERB loop in addition to the wellknown PER-CRY loop [25,[41][42][43]. Interestingly, several studies have pointed to the fact that the relevance of specific loops in rhythm generation might be tissue-dependent [44][45][46]. The growing pool of identified regulators for circadian oscillations and their corresponding feedback loops stress the fundamental importance of synergistic loops, that seem to confer robustness to the clock [35].…”

Section: Introductionmentioning

confidence: 99%

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Nonlinear phenomena in models of the circadian clock

Soest

Olmo

Schmal

et al. 2020

J. R. Soc. Interface.

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The mammalian circadian clock is well-known to be important for our sleep–wake cycles, as well as other daily rhythms such as temperature regulation, hormone release or feeding–fasting cycles. Under normal conditions, these daily cyclic events follow 24 h limit cycle oscillations, but under some circumstances, more complex nonlinear phenomena, such as the emergence of chaos, or the splitting of physiological dynamics into oscillations with two different periods, can be observed. These nonlinear events have been described at the organismic and tissue level, but whether they occur at the cellular level is still unknown. Our results show that period-doubling, chaos and splitting appear in different models of the mammalian circadian clock with interlocked feedback loops and in the absence of external forcing. We find that changes in the degradation of clock genes and proteins greatly alter the dynamics of the system and can induce complex nonlinear events. Our findings highlight the role of degradation rates in determining the oscillatory behaviour of clock components, and can contribute to the understanding of molecular mechanisms of circadian dysregulation.

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Section: Discussionsupporting

confidence: 53%

Section: Introductionmentioning

confidence: 99%

Nonlinear phenomena in models of the circadian clock

Soest

Olmo

Schmal

et al. 2020

J. R. Soc. Interface.

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“…For example, in mammals, clock cells located in the suprachiasmatic nucleus (SCN) drive rhythms in peripheral tissues across the body via neural and humoral signals [1,14]. Peripheral tissues have the same clock network as in the SCN [15,16], although the relative importance of each circuit component may vary between tissues [17]. In plants, studies of synchronization [5,[18][19][20][21][22][23], grafting experiments [22], and the use of tissue-specific promoters [10] suggest that cell-cell communication is also important for coherent rhythms.…”

Section: Introductionmentioning

confidence: 99%

Coordinated circadian timing through the integration of local inputs in Arabidopsis thaliana

et al. 2019

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Individual plant cells have a genetic circuit, the circadian clock, that times key processes to the day-night cycle. These clocks are aligned to the day-night cycle by multiple environmental signals that vary across the plant. How does the plant integrate clock rhythms, both within and between organs, to ensure coordinated timing? To address this question, we examined the clock at the sub-tissue level across Arabidopsis thaliana seedlings under multiple environmental conditions and genetic backgrounds. Our results show that the clock runs at different speeds (periods) in each organ, which causes the clock to peak at different times across the plant in both constant environmental conditions and light-dark (LD) cycles. Closer examination reveals that spatial waves of clock gene expression propagate both within and between organs. Using a combination of modeling and experiment, we reveal that these spatial waves are the result of the period differences between organs and local coupling, rather than long-distance signaling. With further experiments we show that the endogenous period differences, and thus the spatial waves, can be generated by the organ specificity of inputs into the clock. We demonstrate this by modulating periods using light and metabolic signals, as well as with genetic perturbations. Our results reveal that plant clocks can be set locally by organ-specific inputs but coordinated globally via spatial waves of clock gene expression.PLOS Biology | https://doi.org/10.days at near-cellular resolution (Materials and methods). This reporter line was chosen because of its strong expression level and its similar spatial expression to other clock components [5].In order to observe the endogenous component of the rhythms, we first imaged seedlings under LL, having previously grown them under LD cycles (LD-to-LL; Fig 2A and Materials and methods). Under the LD-to-LL condition we observed phase differences of GI::LUC expression between organs ( Fig 2B and 2C). The cotyledon and hypocotyl peaked before the root, but the tip of the root peaked before the middle region of the root (Fig 2C, S1 Fig, and S1 Video). Furthermore, we observed a decrease in coherence between regions over time, with a range between the earliest and latest peaking region of 4.92 ± 3.79 h (mean ± standard deviation) in the first and 18.36 ± 5.67 h in the final oscillation. This is due to the emergence of period differences between all regions ( Fig 2D). The cotyledon maintained a mean period of 23.82 ± 0.60 h, whereas the hypocotyl and root ran at 25.41 ± 0.91 h and 28.04 ± 0.86 h, respectively. However, the root tip ran slightly faster than the middle of the root, with a mean period of 26.90 ± 0.45 h, demonstrating the presence of endogenous period differences across all regions. We verified that our results were not specific to the GI::LUC reporter, as we observed similar differences in periods and phases across the plant using luciferase reporters for promoter activity of the core clock genes PSEUDO-RESPONSE REGULATOR 9 (PRR9) [31], TI...

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“…Such a Goodwin model was motivated by self-inhibition of the Period and Cryptochrome genes and the Bmal1-Rev-erba loop. However, in contrast to previous models [15,22,52,53], we did not fit the models to specific expression data. This implies that our models, while not quantitative in detail, can nevertheless be applicable in a wider context including in organisms other than mammals.…”

Section: Modeling Can Be Applied On Different Levelsmentioning

confidence: 96%

Amplitude effects allow short jetlags and large seasonal phase shifts in minimal clock models

Ananthasubramaniam

Schmal

Herzel

2019

Preprint

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Mathematical models of varying complexity have helped shed light on different aspects of circadian clock function. In this work, we question whether minimal clock models (Goodwin models) are sufficient to reproduce essential phenotypes of the clock: a small phase response curve (PRC), fast jetlag and seasonal phase shifts. Instead of building a single best model, we take an approach where we study the properties of a set of models satisfying certain constraints; here a PRC to a one-hour pulse of three hours and clock periods between 22h and 26h. Surprisingly, almost all these randomly parameterized models showed a phase shift of about four hours between long and short days and jetlag durations of three to seven days in advance and delay. Moreover, intrinsic clock period influenced jetlag duration and entrainment amplitude and phase. Fast jetlag was realized in this model by means of a novel amplitude effect: the association between clock amplitude and clock period termed 'twist'. This twist allows amplitude changes to speed up and slow down clocks enabling faster shifts. These findings were robust to the addition of additional positive feedback to the model. In summary, the known design principles of rhythm generation -negative feedback, long delay and switch-like inhibition (we review these in detail) -are sufficient to reproduce the essential clock phenotypes. Furthermore, amplitudes play a role in determining clock properties and must be always considered, although they are difficult to measure.

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Co-existing feedback loops generate tissue-specific circadian rhythms

Abstract: The analysis of tissue-specific data-based models of the gene regulatory network of the mammalian circadian clock reveals organ-specific synergies of feedback loops.

Cited by 61 publications

References 64 publications

Nonlinear phenomena in models of the circadian clock

Nonlinear phenomena in models of the circadian clock

Coordinated circadian timing through the integration of local inputs in Arabidopsis thaliana

Amplitude effects allow short jetlags and large seasonal phase shifts in minimal clock models

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