title: Cellular mechano-environment regulates the mammary circadian clock.
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.
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester M13 9PT, UK.|Wellcome Centre for Cell-Matrix Research, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Nan
authors.initials: N
authors.lastname: Yang
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester M13 9PT, UK.|Wellcome Centre for Cell-Matrix Research, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Jack
authors.initials: J
authors.lastname: Williams
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Vanja
authors.initials: V
authors.lastname: Pekovic-Vaughan
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester M13 9PT, UK.|Wellcome Centre for Cell-Matrix Research, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Pengbo
authors.initials: P
authors.lastname: Wang
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester M13 9PT, UK.|Wellcome Centre for Cell-Matrix Research, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Safiah
authors.initials: S
authors.lastname: Olabi
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors.forename: James
authors.initials: J
authors.lastname: McConnell
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Nicole
authors.initials: N
authors.lastname: Gossan
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Alun
authors.identifier: 0000-0001-7460-3216
authors.initials: A
authors.lastname: Hughes
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester M13 9PT, UK.|Wellcome Centre for Cell-Matrix Research, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Julia
authors.initials: J
authors.lastname: Cheung
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester M13 9PT, UK.|Wellcome Centre for Cell-Matrix Research, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Charles H
authors.initials: CH
authors.lastname: Streuli
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester M13 9PT, UK.|Wellcome Centre for Cell-Matrix Research, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Qing-Jun
authors.initials: QJ
authors.lastname: Meng
mesh_terms: D000375:Aging / Q000502:physiology*; D000577:Amides / Q000494:pharmacology; D000818:Animals; D001940:Breast / Q000166:cytology; D001941:Breast Diseases / Q000209:etiology; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism; D000066673:Cell Self Renewal / Q000502:physiology*; D060833:Cellular Microenvironment / Q000502:physiology; D057906:Circadian Clocks / Q000235:genetics / Q000502:physiology*; D002940:Circadian Rhythm / Q000187:drug effects / Q000502:physiology*; D004847:Epithelial Cells; D004848:Epithelium / Q000502:physiology*; D005109:Extracellular Matrix / Q000502:physiology; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D061251:Primary Cell Culture; D011725:Pyridines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D018874:Spheroids, Cellular; D046509:Tissue Culture Techniques; D016596:Vinculin / Q000502:physiology; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000577:Amides; D011725:Pyridines; D034741:RNA, Small Interfering; D016596:Vinculin; C108830:Y 27632; D056926:CLOCK Proteins; D054460:rho-Associated Kinases