Mechanical control of the mammalian circadian clock via YAP/TAZ and TEAD

Abenza, Juan F.; Rossetti, Leone; Mouelhi, Malèke; Burgués, Javier; Andreu, Ion; Kennedy, Keith; Roca‐Cusachs, Pere; Marco, Santiago; García‐Ojalvo, Jordi; Trepat, Xavier

doi:10.1101/2022.02.04.478830

Cited by 3 publications

(24 citation statements)

References 73 publications

(119 reference statements)

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“…These lower circadian power fractions indicate significantly disrupted oscillations, which manifest as weaker oscillations that are drowned out by Gaussian noise in our simulations (Figure 4B). We note that Abenza et al [15] did not observe the large increase in circadian power fraction on softer substrates that we report here; however, the average YAP/TAZ nuclear to cytosolic ratio also appears to remain elevated for cells on soft substrates in their study, perhaps indicating their cells remained in a mechanically active state not accounted for in our model.…”

Section: Model Captures Population-level Variability In Circadian Osc...contrasting

confidence: 71%

“…Several recent studies have found that local environmental cues such as substrate stiffness and cytoskeletal activity can modulate the cell circadian clock [12][13][14][15]. However, previous models of circadian compared across wild type and both mutant populations on 30 kPa substrate.…”

Section: Discussionmentioning

confidence: 98%

“…To quantify the overall disruption to circadian oscillations, we used a metric called the circadian power fraction (originally defined in [15]), which ranges from 0 (no circadian oscillations) to 1 (perfect sinu- soidal circadian oscillations). This metric corresponds to the fraction of the circadian power spectrum contained within a close window of the population-level average frequency, as detailed in Methods (Section "Calculation of the circadian power fraction").…”

Section: Model Captures Population-level Variability In Circadian Osc...mentioning

confidence: 99%

“…Next, we considered how other changes in the mechanical environment or distinct pharmacological treatments that disrupt the cytoskeleton can impact the the circadian power fraction. We tested the set of conditions examined experimentally in [15], including changes in substrate stiffness, cell density, or cell adhesion area, or treatment with cytochalasin D, latrunculin A, or blebbistatin. The assumed effects of each treatment are given in Table S3, with further details in the text of Supporting Information (Section S2).…”

Section: Nuclear Abundance Of Yap/taz and Mrtf Correlate With The Str...mentioning

confidence: 99%

“…This agrees with our findings in Figure S4, where the stability of oscillations often depends most strongly on the amount of nuclear YAP/TAZ. Additionally, if we assume that substrate stiffness only moderately affects the circadian power fraction (as observed in [15]), the correlation with MRTF nuclear abundance is no longer significant, whereas the correlation with nuclear YAP/TAZ remains significant (Figure S5).…”

Section: Nuclear Abundance Of Yap/taz and Mrtf Correlate With The Str...mentioning

confidence: 99%

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Computational modeling establishes mechanotransduction as a potent entrainment cue for the mammalian circadian clock

Francis,

Rangamani

2023

Preprint

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Mechanotransduction, which is the integration of mechanical signals from the cell’s external environment to changes in intracellular signaling, governs many cellular functions. Recent studies show that the mechanical state of the cell is also coupled to the cellular circadian clock. To investigate possible interactions between circadian rhythms and cellular mechanotransduction, we developed a computational model that integrates these two pathways. Combining previous models of mechan-otransduction and circadian clocks, we postulated that translocation of YAP/TAZ and MRTF into the nucleus leads to altered expression of circadian proteins. Simulations from our model predict that lower levels of cytoskeletal activity are associated with longer circadian oscillation periods and higher oscillation amplitudes, consistent with recent experimental observations. Furthermore, accumulation of YAP/TAZ and MRTF in the nucleus causes circadian oscillations to decay. These effects hold both at the single-cell level and within a population-level framework. Finally, we investigated the effects of mutations in YAP or lamin A, the latter of which lead to a class of diseases known as laminopathies. Oscillations in PER/CRY and BMAL1 are substantially weaker in populations of cells within silicomutations in YAP and lamin A, suggesting that defects in mechanotransduction can disrupt the circadian clock in certain disease states. However, we find that normal oscillatory behavior can be rescued by lowering substrate stiffness, indicating a possible biological compensatory mechanism. Thus our study identifies that mechanotransduction could be a potent entrainment cue for cellular clocks and this crosstalk can be leveraged to rescue the circadian clock in disease states.

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Section: Model Captures Population-level Variability In Circadian Osc...contrasting

confidence: 71%

Section: Discussionmentioning

confidence: 98%

Section: Model Captures Population-level Variability In Circadian Osc...mentioning

confidence: 99%

Section: Nuclear Abundance Of Yap/taz and Mrtf Correlate With The Str...mentioning

confidence: 99%

Section: Nuclear Abundance Of Yap/taz and Mrtf Correlate With The Str...mentioning

confidence: 99%

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Computational modeling establishes mechanotransduction as a potent entrainment cue for the mammalian circadian clock

Francis,

Rangamani

2023

Preprint

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Parametric modeling of mechanical effects on circadian oscillators

Kennedy

Abenza

Rossetti

et al. 2023

Preprint

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Circadian rhythms are archetypical examples of nonlinear oscillations. While these oscillations are usually attributed to circuits of biochemical interactions among clock genes and proteins, recent experimental studies reveal that they are also affected by the cell's mechanical environment. Here we extend a standard biochemical model of circadian rhythmicity to include mechanical effects in a parametric manner. Using experimental observations to constrain the model, we suggest specific ways in which the mechanical signal might affect the clock. Additionally, a bifurcation analysis of the system predicts that these mechanical signals need to be within an optimal range for circadian oscillations to occur.

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Measuring integrin force loading rates using a two-step DNA tension sensor

Combs,

Foote,

Ogasawara

et al. 2024

Preprint

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Cells apply forces to extracellular matrix (ECM) ligands through transmembrane integrin receptors: an interaction which is intimately involved in cell motility, wound healing, cancer invasion and metastasis. These small (pN) forces exerted by cells have been studied by molecular tension fluorescence microscopy (MTFM), which utilizes a force-induced conformational change of a probe to detect mechanical events. MTFM has revealed the force magnitude for integrins receptors in a variety of cell models including primary cells. However, force dynamics and specifically the force loading rate (LR) have important implications in receptor signaling and adhesion formation and remain poorly characterized. Here, we develop a LR probe which is comprised of an engineered DNA structures that undergoes two mechanical transitions at distinct force thresholds: a low force threshold at 4.7 pN corresponding to hairpin unfolding and a high force threshold at 56 pN triggered through duplex shearing. These transitions yield distinct fluorescence signatures observed through single-molecule fluorescence microscopy in live-cells. Automated analysis of tens of thousands of events from 8 cells showed that the bond lifetime of integrins that engage their ligands and transmit a force >4.7 pN decays exponentially with a [tau] of 45.6 sec. A small subset of these events (<10%) mature in magnitude to >56pN with a median loading rate of 1.3 pNs-1 with these mechanical ramp events localizing at the periphery of the cell-substrate junction. Importantly, the LR probe design is modular and can be adapted to measure force ramp rates for a broad range of mechanoreceptors and cell models, thus aiding in the study of mechanotransduction.

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Mechanical control of the mammalian circadian clock via YAP/TAZ and TEAD

Cited by 3 publications

References 73 publications

Computational modeling establishes mechanotransduction as a potent entrainment cue for the mammalian circadian clock

Computational modeling establishes mechanotransduction as a potent entrainment cue for the mammalian circadian clock

Parametric modeling of mechanical effects on circadian oscillators

Measuring integrin force loading rates using a two-step DNA tension sensor

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