An integrated multi-omics analysis identifies novel regulators of circadian rhythm and sleep disruptions induced by changed photoperiod in Antarctica

Light is a dominant zeitgeber for biological clocks, and its regulatory mechanism for sleep-wake activity has been extensively studied. However, the molecular pathways through which the Antarctic unique photoperiod, i.e. polar days in summer and polar nights in winter, affects human sleep and circadian rhythm remain largely unidentified, despite previous studies have observed delayed circadian rhythm and sleep disruptions of expeditioners during polar nights. In this study, we conducted comprehensive dynamic research of the expeditioners during their residence in Antarctica for over one year. By integrating the phenotypic changes with multi-omics data, we tried to identify the novel candidate regulators and their correlation networks involved in circadian and sleep disorders under the extreme photoperiod. We found that during the austral winter, expeditioners exhibited delayed bedtime and get up time, reduced sleep efficiency, and increased sleep fragmentation. Meanwhile, serum dopamine metabolite levels significantly increased, while serotonin metabolites and antioxidants decreased. These changes were accompanied by altered expression of genes and proteins associated with neural functions, cellular activities, transcriptional regulation, and so on. Through the correlation and causal mediation analysis, we identified several potential pathways modulating human sleep-wake activity, involving genes and proteins related to neural function, glucose metabolism, and extracellular matrix homeostasis, as well as some lncRNAs. Based on the identified causal mediators, LASSO regression analysis further revealed a novel candidate gene, Shisa Family Member 8 ( SHISA8 ), as a potential key regulatory hub in this process. These findings shed light on the probable molecular mechanisms of sleep disorders in Antarctica and suggested SHISA8 as a novel candidate target for the medical intervention of sleep disorders under changed light-dark cycle.