Comparative circadian transcriptome analysis reveals dampened and phase-advanced rhythms in sun-exposed human skin

Background: Daily molecular rhythms modulate skin physiology. However, the effects of chronic sun exposure on these rhythms remain unstudied. Objectives: This study aimed to identify and compare rhythmic genes and pathways in photoprotected and chronically photoexposed human skin in vivo. Methods: Twenty healthy White women, aged 51-63, with moderate-severe photoageing of the dorsal forearm were recruited. Skin biopsies (3mm) were taken from photoprotected (upper buttock) and photoexposed (dorsal forearm) skin of each individual at noon, 6PM, midnight, and 6AM, across a 24-hour cycle. Skin biopsies were analysed by RNA sequencing. Cosinor analysis identified cycling genes along with their amplitudes and peak expression phases. Nested models were used to identify genes that were differentially rhythmic between the photoprotected and photoexposed sites. Phase set and gene set analyses identified pathways enriched among rhythmic transcripts or altered between the two sites. Results: In the photoprotected buttock skin, 1546 genes (12%) met the criteria for cycling. In photoexposed forearm skin, the number was reduced to 959 (8%). As a group, transcripts that cycled in both sites had overall higher amplitude in photoprotected skin (p < 2.2e-16). Peak expression times for these transcripts showed a pronounced bimodal distribution and were clustered in the early morning and mid-afternoon. Distributions of peak times were significantly different between photoexposed and photoprotected skin (p < 0.00025), with peak times advanced in photoexposed skin. We identified 480 genes with significantly different rhythmic properties between the skin sites. Genes involved in DNA repair, MYC targets, E2F and G2M checkpoint pathways were enriched among those that showed higher amplitude oscillations in photoprotected skin. Genes involved in epithelial mesenchymal transition and apical junction pathways showed higher amplitude oscillations in photoexposed skin. Conclusions: Temporal rhythms have a marked influence on skin molecular physiology and are altered in photoaged skin. Temporally advanced cycling patterns and a reduced number of rhythmic genes in photoexposed as compared to photoprotected skin suggest that chronic UV exposure may disrupt and/or reprogram circadian output rhythms to further alter skin physiology.