Autonomous circadian clocks exist in nearly every mammalian cell type. These cellular clocks are subjected to a multilayered regulation sensitive to the mechanochemical cell microenvironment. Whereas the biochemical signaling that controls the cellular circadian clock is increasingly well understood, mechanisms underlying regulation by mechanical cues are largely unknown. Here we show that the fibroblast circadian clock is mechanically regulated through YAP/TAZ nuclear levels. 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-erbα. We observe that Rev-erbα circadian oscillations are disrupted with YAP/TAZ nuclear translocation. By targeted mutations and overexpression of YAP/TAZ, we show that this mechanobiological regulation, which also impacts core components of the clock such as Bmal1 and Cry1, depends on the binding of YAP/TAZ to the transcriptional effector TEAD. This mechanism could explain the impairment of circadian rhythms observed when YAP/TAZ activity is upregulated, as in cancer and aging.
Mechanical control of the mammalian circadian clock via YAP/TAZ and TEAD
Disclosures: K. Kennedy reported grants from Agencia de Gestión de Ayudas Universitarias y de Investigación outside the submitted work. J. García-Ojalvo reported grants from Ministerio de Ciencia e Innovación, Spain, and grants from Institució Catalana de Recerca i Estudis Avançats outside the submitted work. No other disclosures were reported.
- Award Id(s): SGR-2017-01602,BP-B 00105
- Award Id(s): PGC2018-099645-B-I00,BFU2016-79916-P,PID2019-110298GB-I00,PID2021-127311NB-I00
- Award Id(s): Adv-883739
- Award Id(s): 201903-30-31-32
- Award Id(s): H2020-FETPROACT-01-2016-731957,MECHADIAN - IF/750557
- Award Id(s): LCF/PR/HR20/52400004
Juan F. Abenza, Leone Rossetti, Malèke Mouelhi, Javier Burgués, Ion Andreu, Keith Kennedy, Pere Roca-Cusachs, Santiago Marco, Jordi García-Ojalvo, Xavier Trepat; Mechanical control of the mammalian circadian clock via YAP/TAZ and TEAD. J Cell Biol 4 September 2023; 222 (9): e202209120. doi: https://doi.org/10.1083/jcb.202209120
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