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bioRxiv · 10.1101/2023.10.09.561563

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

Francis, E. A.·Rangamani, P.
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Abstract

Mechanotransduction, which is the integration of mechanical signals from the cells external environment to changes in intracellular signaling, governs many cellular functions. Recent studies have shown 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 have developed a computational model that integrates the two pathways. We postulated that the translocation of the transcriptional regulators 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 circadian proteins are substantially weaker in populations of cells with in silico mutations in YAP or lamin A, suggesting that defects in mechanotransduction can disrupt the circadian clock in certain disease states. However, by reducing substrate stiffness, we were able to restore normal oscillatory behavior, suggesting a possible compensatory mechanism. Thus our study identifies that mechanotransduction could be a potent modulatory cue for cellular clocks and this crosstalk can be leveraged to rescue the circadian clock in disease states.

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Francis, E. A., Rangamani, P.. 2023-10-10. Computational modeling establishes mechanotransduction as a potent entrainment cue for the mammalian circadian clock. https://doi.org/10.1101/2023.10.09.561563

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