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.
Highlights
Circadian clocks drive B24 h rhythms in tissue physiology
Circadian oscillations rely on a transcription–translation feedback loop driven by a core clock mechanism
A subset of clockcontrolled genes included those linked to progenitor/epithelial cell function, for example, a6-integrin, Prkce, P21 or Bcar[313–16], whose rhythmic expression was validated by qRT-PCR (Fig. 1d)
Summary
Circadian clocks drive B24 h rhythms in tissue physiology. They rely on transcriptional/ translational feedback loops driven by interacting networks of clock complexes. The mammary clock is controlled by the periductal extracellular matrix in vivo, which contributes to a dampened circadian rhythm during ageing. Cell-autonomous circadian clocks in the brain and periphery drive B24 h rhythms in fundamental biological processes that control tissue physiology, including metabolism, cell proliferation, differentiation, cell cycle and stem cell function[1,2]. Circadian oscillations rely on a transcription–translation feedback loop driven by a core clock mechanism. Our work first reveals a new function for cell-matrix interactions, which is that it regulates circadian biology. It shows that tissue stiffening suppresses the mammary circadian clock activity in vivo, which could contribute to an increased risk for breast diseases and even cancer
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