Cellular mechano-environment regulates the mammary circadian clock

Nan Yang, Jack Williams, Vanja Pekovic-Vaughan, Pengbo Wang, Safiah Olabi, James McConnell, Nicole Gossan, Alun Hughes, Julia Cheung, Charles H. Streuli () and Qing-Jun Meng ()
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Nan Yang: Faculty of Biology, Medicine and Health, University of Manchester
Jack Williams: Faculty of Biology, Medicine and Health, University of Manchester
Vanja Pekovic-Vaughan: Faculty of Biology, Medicine and Health, University of Manchester
Pengbo Wang: Faculty of Biology, Medicine and Health, University of Manchester
Safiah Olabi: Faculty of Biology, Medicine and Health, University of Manchester
James McConnell: Faculty of Biology, Medicine and Health, University of Manchester
Nicole Gossan: Faculty of Biology, Medicine and Health, University of Manchester
Alun Hughes: Faculty of Biology, Medicine and Health, University of Manchester
Julia Cheung: Faculty of Biology, Medicine and Health, University of Manchester
Charles H. Streuli: Faculty of Biology, Medicine and Health, University of Manchester
Qing-Jun Meng: Faculty of Biology, Medicine and Health, University of Manchester

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: Abstract Circadian clocks drive ∼24 h rhythms in tissue physiology. They rely on transcriptional/translational feedback loops driven by interacting networks of clock complexes. However, little is known about how cell-intrinsic circadian clocks sense and respond to their microenvironment. Here, we reveal that the breast epithelial clock is regulated by the mechano-chemical stiffness of the cellular microenvironment in primary cell culture. Moreover, the mammary clock is controlled by the periductal extracellular matrix in vivo, which contributes to a dampened circadian rhythm during ageing. Mechanistically, the tension sensing cell-matrix adhesion molecule, vinculin, and the Rho/ROCK pathway, which transduces signals provided by extracellular stiffness into cells, regulate the activity of the core circadian clock complex. We also show that genetic perturbation, or age-associated disruption of self-sustained clocks, compromises the self-renewal capacity of mammary epithelia. Thus, circadian clocks are mechano-sensitive, providing a potential mechanism to explain how ageing influences their amplitude and function.

Date: 2017
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DOI: 10.1038/ncomms14287

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