Circadian Clock Regulation in Skin

PROJECT SUMMARY/ABSTRACT
The circadian clock, an ancient, evolutionary conserved timing system required for optimal function of organs
and organismal lifespan, is active in peripheral tissues, including the skin. Clocks in peripheral organs are
coordinated by the central clock in the suprachiasmatic nucleus, but we also know that time-restricted feeding
affects circadian clocks, gene expression, and homeostasis in peripheral tissues. Although new insights are
emerging, especially from studies in metabolic organs like the liver, the interplay between feeding time, clocks,
and tissue health in epithelia is unclear. In particular, we don't know how time-restricted feeding affects the
regenerative function of epidermal stem cells and skin aging. In mice, the circadian clock coordinates progression
of the cell cycle and DNA excision repair with intermediary metabolism, as reflected in the redox state of
epidermal stem cells. Intriguingly, daytime-restricted feeding shifts the phase and decreases the amplitude of
the skin circadian clock, and it shifts the expression of the metabolism-related transcriptome without altering the
phase of the diurnal oscillations in DNA synthesis. Daytime-restricted feeding, then, disrupts the coordination
between metabolism and cell cycle progression in epidermal stem cells. Whereas these cycles in epidermal stem
cells are known to modulate the sensitivity to UVB-induced DNA damage, their role in homeostasis of epidermal
stem cells remains otherwise unknown. Here, we will investigate the idea that the clock coordinates oscillations
of metabolism-generated ROS levels with the cell cycle and the DNA repair machinery to maximize the health
and function of epidermal stem cells. Specifically, we hypothesize that this regulation minimizes metabolism-
generated ROS when most epidermal stem cells are undergoing DNA replication, the cell cycle stage most
sensitive to oxidative DNA damage. This hypothesis predicts that daytime feeding-induced circadian
misalignment in epidermal stem cells causes asynchrony between oxidative metabolism and the cell cycle,
leading to increased ROS-induced DNA mutations, epidermal stem cell dysfunction, and skin aging. To test this
hypothesis, we propose two aims. First, we will define the gene-regulatory mechanisms underlying time-
restricted feeding modulation of the circadian clock and metabolism in epidermal stem cells. Second, we will
determine how time-restricted feeding modulates epidermal stem cell function and affects the rate of age-
associated DNA mutations in epidermal stem cells. The proposal is significant because it tests a new model of
how the circadian clock coordinates the timing of intermediary metabolism and the cell cycle in epithelial stem
cells to minimize the accumulation of somatic DNA mutations, and how time-restricted feeding can enforce or
disrupt this coordination. The proposal is innovative because it pursues a new idea about the role of dietary
intervention and the circadian clock in skin aging, and it uses state of the art approaches, including duplex DNA-
sequencing, fluorescence lifetime imaging, and single cell RNA-sequencing--approaches not previously applied
to skin aging.

Grant Number: 5R01AR056439-13
NIH Institute/Center: NIH
Principal Investigator: Bogi Andersen