Sleep-wake cycles are disrupted by diseases that result in cytoplasmic crowding

Montague-Cardoso, Karli

doi:10.1038/s42003-020-01445-8

Cited by 4 publications

(4 citation statements)

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“…For the TTFL to generate robust circadian rhythms, precise nucleus entry of the PER complex is critical [7][8][9][10] . However, the distribution of the PER complex arrival time at the perinuclear region is highly heterogeneous due to various noise sources.…”

Section: Discussionmentioning

confidence: 99%

“…The cytoplasm in which 𝑅 ! diffuses can become overcrowded due to various reasons, such as increased fat deposition, hindering the cytoplasmic trafficking [8][9][10] . This leads to noisier cytoplasmic trafficking of PER molecules, and thus they arrive at the perinucleus in a wider time window.…”

Section: Bistable Phosphorylation Of Per Allows Sharp Transcriptional...mentioning

confidence: 99%

“…The mammalian circadian (~24h) clock is a self-sustained endogenous oscillator that relies on a transcriptional-translational negative feedback loop (TTFL), where the activator complex, BMAL1:CLOCK, promotes the transcription of Per1/2 and Cry1/2 genes, and the PER:CRY complex inhibits BMAL1:CLOCK to close the loop [1][2][3][4][5][6] . In the TTFL, precise transcriptional repression (i.e., transcription being repressed at the right time of the day) of BMAL1:CLOCK by the PER complex is essential to generate circadian rhythms [7][8][9][10] .…”

Section: Introductionmentioning

confidence: 99%

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Spatially coordinated collective phosphorylation filters spatiotemporal noises for precise circadian timekeeping

Chae

Kim

Lee

et al. 2022

Preprint

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The mammalian circadian (~24h) clock is based on a self-sustaining transcriptional-translational negative feedback loop (TTFL) centered around the PERIOD protein (PER), which is translated in the cytoplasm and then enters the nucleus to repress its own transcription at the right time of day. How such precise nucleus entry, critical for generating circadian rhythms, occurs is mysterious because thousands of PER molecules transit through crowded cytoplasm and arrive at the perinucleus across several hours. Here, we investigate this by developing a mathematical model that effectively describes the complex spatiotemporal dynamics of PER as a single random time delay. We find that the spatially coordinated bistable phosphoswitch of PER, which triggers the phosphorylation of accumulated PER at the perinucleus, can lead to the synchronous and precise nuclear entry of PER, and thus to precise transcriptional repression despite the heterogenous PER arrival times at the perinucleus. In particular, even when cell crowdedness, cell size, and transcriptional activator level change, and thus PER arrival times at the perinucleus are greatly perturbed, the bistable phosphoswitch allows the TTFL to maintain robust circadian rhythms. These results provide fundamental insight into how the circadian clock compensates for spatiotemporal noise from various intracellular sources.

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Section: Discussionmentioning

confidence: 99%

Section: Bistable Phosphorylation Of Per Allows Sharp Transcriptional...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Spatially coordinated collective phosphorylation filters spatiotemporal noises for precise circadian timekeeping

Chae

Kim

Lee

et al. 2022

Preprint

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“…For instance, generating strong circadian rhythms requires PERIOD proteins to enter the nucleus to inhibit their own production at a precise time of day [15][16][17]. The distributed delay that results from the stochasticity associated with protein generation and travel weakens the circadian rhythm [15,18,19]. Consequently, biological filtering mechanisms to mitigate the heterogeneous nuclear entry time have been investigated [15,16].…”

Section: Introductionmentioning

confidence: 99%

Noisy delay denoises biochemical oscillators

Song

Campbell

Shiau

et al. 2023

Preprint

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Genetic oscillations are generated by delayed transcriptional negative feedback loops, wherein repressor proteins inhibit their own synthesis after a temporal production delay. This delay is distributed because it arises from a sequence of noisy processes, including transcription, translation, folding, and translocation. Because the delay determines repression timing and, therefore oscillation period, it has been commonly believed that delay noise weakens oscillatory dynamics. Here, we demonstrate that noisy delay can surprisingly denoise genetic oscillators. Moderate delay noise unexpectedly sharpens oscillation peaks and improves temporal peak reliability without impacting period. We show that this denoising phenomenon occurs in a variety of well-studied genetic oscillators, and we use queueing theory to uncover the universal mechanisms that produce it.

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