Final Report Summary - STEMCLOCK (Spatiotemporal regulation of epidermal stem cells by circadian rhythms: impact on homeostasis and aging) Our understanding of the molecular mechanisms underlying the function of adult stem cells during homeostasis and ageing is still poor. Work from our lab has shown that adult stem cells are spatiotemporally regulated by circadian rhythms, and that perturbation of this mechanism leads to premature tissue ageing and alters the predisposition to develop tumors (Janich et al, Nature 2011; Janich et al Curr Opin Cell BIol 2014). During the course of this ERC starting grant we have obtained data showing an essential role for circadian rhythms in regulating the temporal segregation of epidermal stem cell function during homeostasis (Janich et al, Cell Stem Cell 2013). In addition, and unexpectedly, we have found that aged mice remain behaviorally circadian, and that their epidermal and muscle stem cells retain a robustly rhythmic core circadian machinery. However, the oscillating transcriptome is extensively reprogrammed in aged stem cells, switching from genes involved in homeostasis to those involved in tissue-specific stresses, such as DNA damage or inefficient autophagy. Importantly, deletion of circadian clock components did not reproduce the hallmarks of this reprogramming, underscoring that rewiring, rather than arrhythmia, is associated with physiological aging. While age-associated rewiring of the oscillatory diurnal transcriptome is not recapitulated by a high-fat diet in young adult mice, it is significantly prevented by long-term caloric restriction in aged mice. Thus, stem cells rewire their diurnal timed functions to adapt to metabolic cues and to tissue-specific age-related traits (Solanas et al., Cell 2017). Furthermore, we have seen that reprogramming of the circadian transcriptome also occurs in the liver of aged mice. These age-dependent changes occur in a highly tissue-specific manner, as demonstrated by comparing circadian gene expression in the liver versus epidermal and skeletal muscle stem cells. Moreover, de novo oscillating genes under CR show an enrichment in SIRT1 targets in the liver. This is accompanied by distinct circadian hepatic signatures in NAD+ -related metabolites and cyclic global protein acetylation. Strikingly, this oscillation in acetylation is absent in old mice while CR robustly rescues global protein acetylation. Our findings indicate that the clock operates at the crossroad between protein acetylation, liver metabolism, and aging (Sato et al., Cell 2017).
