Mechanical control of the mammalian circadian clock via YAP/TAZ and TEAD
Year: 2023
Type: article
Abstract: 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.
Source: The Journal of Cell Biology
Language: English
Subfield: Endocrine and Autonomic Systems
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Funders: Fundació la Marató de TV3, “la Caixa” Foundation, Centres de Recerca de Catalunya, European Commission, Yonsei University, Generalitat de Catalunya, Ministerio de Economía y Competitividad, Institució Catalana de Recerca i Estudis Avançats, Ministerio de Ciencia e Innovación, Université de Genève, Institute for Bioengineering of Catalonia, Horizon 2020 Framework Programme, Agència de Gestió d'Ajuts Universitaris i de Recerca, H2020 European Research Council, HORIZON EUROPE Marie Sklodowska-Curie Actions
Awards: G1111604172, G1159234760, G1650125035, G1781902864, G1822579751, G215709278, G2576392025, G3349351141, G3453205160, G3690828678, G3834906971, G3941244505, G4039856780, G4769775006, G490073602, G4937468798, Mechanical control of biological function, G5175525644, G5264237701, G5569441440, Mechanobiology of the cellular circadian clock, G5984434282, G7061641793, G7425137858, G7494299514, G7867645178, G8351427924, G8811904117, G8935248985, G918993045
OpenAlex ID: W4382344396