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The circadian molecular clock creates epidermal stem cell heterogeneity

Author

Listed:
  • Peggy Janich

    (Center for Genomic Regulation and UPF)

  • Gloria Pascual

    (Center for Genomic Regulation and UPF)

  • Anna Merlos-Suárez

    (Institute for Research in Biomedicine)

  • Eduard Batlle

    (Institute for Research in Biomedicine
    Institució Catalana de Recerca i Estudis Avançats (ICREA))

  • Jürgen Ripperger

    (University of Fribourg)

  • Urs Albrecht

    (University of Fribourg)

  • Hai-Ying M. Cheng

    (University of Toronto Mississauga, 3359 Mississauga Road N., Mississauga, Ontario L5L 1C6, Canada)

  • Karl Obrietan

    (Ohio State University)

  • Luciano Di Croce

    (Center for Genomic Regulation and UPF
    Institució Catalana de Recerca i Estudis Avançats (ICREA))

  • Salvador Aznar Benitah

    (Center for Genomic Regulation and UPF
    Institució Catalana de Recerca i Estudis Avançats (ICREA))

Abstract

Murine epidermal stem cells undergo alternate cycles of dormancy and activation, fuelling tissue renewal. However, only a subset of stem cells becomes active during each round of morphogenesis, indicating that stem cells coexist in heterogeneous responsive states. Using a circadian-clock reporter-mouse model, here we show that the dormant hair-follicle stem cell niche contains coexisting populations of cells at opposite phases of the clock, which are differentially predisposed to respond to homeostatic cues. The core clock protein Bmal1 modulates the expression of stem cell regulatory genes in an oscillatory manner, to create populations that are either predisposed, or less prone, to activation. Disrupting this clock equilibrium, through deletion of Bmal1 (also known as Arntl) or Per1/2, resulted in a progressive accumulation or depletion of dormant stem cells, respectively. Stem cell arrhythmia also led to premature epidermal ageing, and a reduction in the development of squamous tumours. Our results indicate that the circadian clock fine-tunes the temporal behaviour of epidermal stem cells, and that its perturbation affects homeostasis and the predisposition to tumorigenesis.

Suggested Citation

  • Peggy Janich & Gloria Pascual & Anna Merlos-Suárez & Eduard Batlle & Jürgen Ripperger & Urs Albrecht & Hai-Ying M. Cheng & Karl Obrietan & Luciano Di Croce & Salvador Aznar Benitah, 2011. "The circadian molecular clock creates epidermal stem cell heterogeneity," Nature, Nature, vol. 480(7376), pages 209-214, December.
    • Handle: RePEc:nat:nature:v:480:y:2011:i:7376:d:10.1038_nature10649
    DOI: 10.1038/nature10649
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    Cited by:

    1. Xue Zhang & Shishir M. Pant & Cecily C. Ritch & Hsin-Yao Tang & Hongguang Shao & Harsh Dweep & Yao-Yu Gong & Rebekah Brooks & Patricia Brafford & Adam J. Wolpaw & Yool Lee & Ashani Weeraratna & Amita , 2024. "Cell state dependent effects of Bmal1 on melanoma immunity and tumorigenicity," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

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