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 mechano-chemical microenvironment. Whereas the mechanisms by which biochemical signalling controls the circadian clock at the single cell level are increasingly well understood, mechanisms underlying regulation by mechanical cues 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 clock gene Rev-erb. We observe that Rev-erb 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.