Article | Published:

The circadian molecular clock creates epidermal stem cell heterogeneity

Nature volume 480, pages 209214 (08 December 2011) | Download Citation

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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.

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Change history

  • 07 December 2011

    Author H.-Y.M.C. was added.

Accessions

Primary accessions

Gene Expression Omnibus

Data deposits

Microarray data can be retrieved from the Gene Expression Omnibus under accession number GSE27079.

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Acknowledgements

We thank the AICR (Association for International Cancer Research), the Spanish Ministry of Health (FIS) and AGAUR (Agència de Gestió d'Ajuts Universitaris i de Recerca; Government of Cataluña) for financial support. P.J. is the recipient of an AGAUR PhD Fellowship, and G.P. of a FIS fellowship. We thank D. McMahon (Vanderbilt University) for providing us with the Per1–GFP mice; E. Wagner (CNIO) for the K5-SOS mice; B. Kübler, the FACS and Genomics units of the IRB (Institute de Recerca Biomedica), the CRG (Center for Genomic Regulation) core facilities and the Animal Unit (Juan Martin Caballero) for technical support.

Author information

Affiliations

  1. Center for Genomic Regulation and UPF, 08003 Barcelona, Spain

    • Peggy Janich
    • , Gloria Pascual
    • , Luciano Di Croce
    •  & Salvador Aznar Benitah
  2. Institute for Research in Biomedicine, 08028 Barcelona, Spain

    • Anna Merlos-Suárez
    •  & Eduard Batlle
  3. Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain

    • Eduard Batlle
    • , Luciano Di Croce
    •  & Salvador Aznar Benitah
  4. University of Fribourg, 1700 Fribourg, Switzerland

    • Jürgen Ripperger
    •  & Urs Albrecht
  5. Department of Biology, University of Toronto Mississauga, 3359 Mississauga Road N., Mississauga, Ontario L5L 1C6, Canada

    • Hai-Ying M. Cheng
  6. Ohio State University, Columbus, Ohio 43210, USA

    • Karl Obrietan

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Contributions

P.J. performed the experiments, and P.J. and S.A.B. analysed the results and wrote the manuscript. G.P. performed the analysis of K5-SOS mice, and A.M. and E.B. assisted P.J. in the initial FACS sorts. L.D.C. helped us with the initial ChIP experiments. K.O. provided the Per1–venus mice and H.-Y.M.C. generated the Per1–venus mice. J.R. and U.A. provided the Per1/Per2dKO mice.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Salvador Aznar Benitah.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains Supplementary Figures 1-17 with legends and Supplementary Tables 2, 4 and 5 (see separate files for Supplementary Tables 1 and 3).

Excel files

  1. 1.

    Supplementary Table 1

    This table contains affymetrix microarray data comparing Venusbright and Venusdim bulge cells of P19 Per1-Venus mice.

  2. 2.

    Supplementary Table 3

    This table contains affymetrix microarray data comparing basal epidermal cells of 10 months old Bmal1WT and Bmal1KO mice.

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DOI

https://doi.org/10.1038/nature10649

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