Cellular mechano-environment regulates the mammary circadian clock

Nat Commun. 2017 Jan 30;8:14287. doi: 10.1038/ncomms14287.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / physiology*
  • Amides / pharmacology
  • Animals
  • Breast / cytology
  • Breast Diseases / etiology
  • CLOCK Proteins / genetics
  • CLOCK Proteins / metabolism
  • Cell Self Renewal / physiology*
  • Cellular Microenvironment / physiology
  • Circadian Clocks / genetics
  • Circadian Clocks / physiology*
  • Circadian Rhythm / drug effects
  • Circadian Rhythm / physiology*
  • Epithelial Cells
  • Epithelium / physiology*
  • Extracellular Matrix / physiology
  • Female
  • HEK293 Cells
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Primary Cell Culture
  • Pyridines / pharmacology
  • RNA, Small Interfering / metabolism
  • Signal Transduction / physiology
  • Spheroids, Cellular
  • Tissue Culture Techniques
  • Vinculin / physiology
  • rho-Associated Kinases / antagonists & inhibitors
  • rho-Associated Kinases / metabolism

Substances

  • Amides
  • Pyridines
  • RNA, Small Interfering
  • Vinculin
  • Y 27632
  • CLOCK Proteins
  • rho-Associated Kinases