title: The circadian molecular clock creates epidermal stem cell heterogeneity.
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.
authors.affiliation: Center for Genomic Regulation and UPF, 08003 Barcelona, Spain.
authors.forename: Peggy
authors.initials: P
authors.lastname: Janich
authors.forename: Gloria
authors.initials: G
authors.lastname: Pascual
authors.forename: Anna
authors.initials: A
authors.lastname: Merlos-Suárez
authors.forename: Eduard
authors.initials: E
authors.lastname: Batlle
authors.forename: Jürgen
authors.initials: J
authors.lastname: Ripperger
authors.forename: Urs
authors.initials: U
authors.lastname: Albrecht
authors.forename: Hai-Ying M
authors.initials: HY
authors.lastname: Cheng
authors.forename: Karl
authors.initials: K
authors.lastname: Obrietan
authors.forename: Luciano
authors.initials: L
authors.lastname: Di Croce
authors.forename: Salvador Aznar
authors.initials: SA
authors.lastname: Benitah
mesh_terms: D056930:ARNTL Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology; D002448:Cell Adhesion / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics; D002478:Cells, Cultured; D016922:Cellular Senescence; D057906:Circadian Clocks / Q000235:genetics / Q000502:physiology*; D002940:Circadian Rhythm / Q000235:genetics / Q000502:physiology*; D003463:Cues; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D018859:Hair Follicle / Q000166:cytology*; D006706:Homeostasis / Q000235:genetics / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012878:Skin Neoplasms / Q000235:genetics / Q000473:pathology; D055153:Stem Cell Niche; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000235:genetics
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D016212:Transforming Growth Factor beta
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