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

Abstract

Circadian rhythms are a key survival mechanism that dictates biological activity according to the day-night cycle. In animals, cell-autonomous circadian clocks can be found in nearly every cell type and are subjected to multi-layered regulation. Although these peripheral clocks are remotely controlled by the master clock in the brain, they are also sensitive to their immediate physical microenvironment through mechanisms that are still unknown. Here we show that the circadian clock in fibroblasts is regulated mechanically through YAP/TAZ and TEAD. We use high-throughput analysis of single-cell circadian rhythms and apply controlled mechanical, biochemical, and genetic perturbations to study the expression of the core clock gene Rev-erbα. We observe that Rev-erbα circadian oscillations are disrupted concomitantly with the translocation of YAP/TAZ to the nucleus. By targeted mutations and tuning expression levels of YAP we identify TEAD as the transcriptional effector of this mechanosensitive regulatory pathway. Our findings establish a mechanism that links cell mechanobiology and the circadian clock, which could contribute to explain the circadian impairment observed in cancer and ageing, where the regulation of the mechanical environment and YAP/TAZ is lost.

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

“…However, unlike in [15], we do observe a significant correlation between MRTF nuclear to cytosolic ratio and circadian power fraction. This difference appears to come down to the assumed effect of substrate stiffness on the circadian power fraction; our model predicts a larger increase in power fraction for cells on soft substrates than that observed in [15].…”

“…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.…”

“…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.…”

“…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).…”

“…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).…”