Coupling protocol of interlocked feedback oscillators in circadian clocks

Rashid, Md. Mamunur; Kurata, Hiroyuki

doi:10.1098/rsif.2020.0287

Cited by 5 publications

(3 citation statements)

References 60 publications

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“…However, such repression mechanisms have not yet been incorporated into the mathematical models [54][55][56][57]. Similarly, the recent discoveries of multiple repression mechanisms underlying biological oscillators such as the circadian clock [14][15][16][17] and the NF-kB oscillator [12,13] have not been fully incorporated even in recent mathematical models [24,[58][59][60][61][62][63]. In particular, the majority of the mathematical models for various systems have used the simple Michaelis-Menten-or Hill-type functions to describe the transcriptional repression regardless of its underlying repression mechanisms, which can distort the dynamics of the system [21,43].…”

Section: Discussionmentioning

confidence: 99%

Combined multiple transcriptional repression mechanisms generate ultrasensitivity and oscillations

Jeong

Kim

2022

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Transcriptional repression can occur via various mechanisms, such as blocking, sequestration and displacement. For instance, the repressors can hold the activators to prevent binding with DNA or can bind to the DNA-bound activators to block their transcriptional activity. Although the transcription can be completely suppressed with a single mechanism, multiple repression mechanisms are used together to inhibit transcriptional activators in many systems, such as circadian clocks and NF-κB oscillators. This raises the question of what advantages arise if seemingly redundant repression mechanisms are combined. Here, by deriving equations describing the multiple repression mechanisms, we find that their combination can synergistically generate a sharply ultrasensitive transcription response and thus strong oscillations. This rationalizes why the multiple repression mechanisms are used together in various biological oscillators. The critical role of such combined transcriptional repression for strong oscillations is further supported by our analysis of formerly identified mutations disrupting the transcriptional repression of the mammalian circadian clock. The hitherto unrecognized source of the ultrasensitivity, the combined transcriptional repressions, can lead to robust synthetic oscillators with a previously unachievable simple design.

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Section: Discussionmentioning

confidence: 99%

Combined multiple transcriptional repression mechanisms generate ultrasensitivity and oscillations

Jeong

Kim

2022

Interface Focus.

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“…However, such repression mechanisms have not yet been incorporated into the mathematical models [53][54][55][56]. Similarly, the recent discoveries of multiple repression mechanisms underlying biological oscillators such as the circadian clock [14][15][16][17] and the NF-𝜅B oscillator [12,13] have not been fully incorporated even in recent mathematical models [24,[57][58][59][60][61][62].…”

Section: Discussionmentioning

confidence: 99%

Combined multiple transcriptional repression mechanisms generate ultrasensitivity and oscillations

Jeong

Kim

2022

Preprint

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Transcriptional repression can occur via various mechanisms, such as blocking, sequestration, and displacement. For instance, the repressors can hold the activators to prevent binding with DNA or can bind to the DNA-bound activators to block their transcriptional activity. Although the transcription can be completely suppressed with a single mechanism, multiple repression mechanisms are utilized together to inhibit transcriptional activators in many systems, such as circadian clocks and NF-κB oscillators. This raises the question of what advantages arise if seemingly redundant repression mechanisms are combined. Here, by deriving equations describing the multiple repression mechanisms, we find that their combination can synergistically generate a sharply ultrasensitive transcription response and thus strong oscillations. This rationalizes why the multiple repression mechanisms are used together in various biological oscillators. The critical role of such combined transcriptional repression for strong oscillations is further supported by our analysis of formerly identified mutations disrupting the transcriptional repression of the mammalian circadian clock. The hitherto unrecognized source of the ultrasensitivity, the combined transcriptional repressions, can lead to robust synthetic oscillators with a previously unachievable simple design.

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“…Now, we turn our focus on the effect of the intercellular coupling time delay. Time delay can have an interesting effects on the coupled oscillations Kim et al (2010); Joshi et al (2020); Rashid and Kurata (2020); Amdaoud et al (2007). It also plays a critical role in synchronization between the coupled feedback oscillators Smolen et al (2001).…”

Section: Effect Of Intercellular Time Delaymentioning

confidence: 99%

Stochastic comparison of synchronization in activator- and repressor-based coupled gene oscillators

Dey

Abms

Singh

et al. 2021

Preprint

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Inside living cells, proteins or mRNA can show oscillations even without a periodic driving force. Such genetic oscillations are precise timekeepers for cell-cycle regulations, pattern formation during embryonic development in higher animals, and daily cycle maintenance in most organisms. The synchronization between oscillations in adjacent cells happens via intercellular coupling, which is essential for periodic segmentation formation in vertebrates and other biological processes. While molecular mechanisms of generating sustained oscillations are quite well understood, how do simple intercellular coupling produces robust synchronizations are still poorly understood? To address this question, we investigate two models of coupled gene oscillators - activator-based coupled oscillators (ACO) and repressor-based coupled oscillators (RCO) models. In our study, a single autonomous oscillator (that operates in a single cell) is based on a negative feedback, which is delayed by intracellular dynamics of an intermediate species. For the ACO model (RCO), the repressor protein of one cell activates (represses) the production of another protein in the neighbouring cell after a intercellular time delay. We investigate the coupled models in the presence of intrinsic noise due to the inherent stochasticity of the biochemical reactions. We analyze the collective oscillations from stochastic trajectories in the presence and absence of explicit coupling delay and make careful comparison between two models. Our results show no clear synchronizations in the ACO model when the coupling time delay is zero. However, a non-zero coupling delay can lead to anti-phase synchronizations in ACO. Interestingly, the RCO model shows robust in-phase synchronizations in the presence and absence of the coupling time delay. Our results suggest that the naturally occurring intercellular couplings might be based on repression rather than activation where in-phase synchronization is crucial.

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Coupling protocol of interlocked feedback oscillators in circadian clocks

Cited by 5 publications

References 60 publications

Combined multiple transcriptional repression mechanisms generate ultrasensitivity and oscillations

Combined multiple transcriptional repression mechanisms generate ultrasensitivity and oscillations

Combined multiple transcriptional repression mechanisms generate ultrasensitivity and oscillations

Stochastic comparison of synchronization in activator- and repressor-based coupled gene oscillators

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