Brain-keratinocyte communication suffices for epidermal daily homeostasis

In mammals, an integrated network of molecular oscillators drives daily rhythms of tissue-specific homeostatic processes. This network is required for maintaining health and can be compromised by physiological aging, disease, and lifestyle choices. However, critical elements and properties of this network, such as key signaling nodes, the mechanisms of communication, and how physiological coherence is maintained, remain undefined. To dissect this system, we constructed a minimal clock network comprising only two nodes: the peripheral epidermal clock and the central brain clock. We observe that communication between the brain and epidermal clock is sufficient for wild-type core clock activity and specific homeostatic processes in the epidermis, yet full daily physiology requires input from other clock nodes. Moreover, our results show that the epidermal clock selectively suppresses or interprets systemic signals to ensure coherence of specific homeostatic processes, such as the cell cycle, identifying a previously-unrecognized gatekeeper role for this peripheral clock. This novel approach for dissecting a tissue's daily physiology reveals the specific rhythmic processes controlled by secondary tissues and niche components, opening the possibility of identifying the sources of age-related circadian disruption and potentially developing therapeutic interventions. ### Competing Interest Statement SAB is a co-founder and scientific advisor of ONA Therapeutics.