Computational modeling establishes mechanotransduction as a potent modulator of the mammalian circadian clock

Abstract

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.