A population-based gene expression signature of molecular clock phase from a single epidermal sample
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RESEARCH
Open Access
A population-based gene expression signature of molecular clock phase from a single epidermal sample Gang Wu1, Marc D. Ruben1, Lauren J. Francey1, David F. Smith2,3, Joseph D. Sherrill4, John E. Oblong4, Kevin J. Mills4 and John B. Hogenesch1*
Abstract Background: For circadian medicine to influence health, such as when to take a drug or undergo a procedure, a biomarker of molecular clock phase is required––one that is easily measured and generalizable across a broad population. It is not clear that any circadian biomarker yet satisfies these criteria. Methods: We analyzed 24-h molecular rhythms in human dermis and epidermis at three distinct body sites, leveraging both longitudinal (n = 20) and population (n = 154) data. We applied cyclic ordering by periodic structure (CYCLOPS) to order the population samples where biopsy time was not recorded. With CYCLOPSpredicted phases, we used ZeitZeiger to discover potential biomarkers of clock phase. Results: Circadian clock function was strongest in the epidermis, regardless of body site. We identified a 12gene expression signature that reported molecular clock phase to within 3 h (mean error = 2.5 h) from a single sample of epidermis––the skin’s most superficial layer. This set performed well across body sites, ages, sexes, and detection platforms. Conclusions: This research shows that the clock in epidermis is more robust than dermis regardless of body site. To encourage ongoing validation of this putative biomarker in diverse populations, diseases, and experimental designs, we developed SkinPhaser––a user-friendly app to test biomarker performance in datasets (https://github.com/gangwug/SkinPhaser). Keywords: Skin, Dermis, Epidermis, Circadian medicine, Population rhythm, Circadian biomarkers
Background In the last 50 years, dozens of clinical studies showed that dosing time-of-day can impact the efficacy and safety of many different types of medical treatments [1, 2]. We know from multi-tissue studies in mice [3] and humans [4] that thousands of rhythmically expressed genes encode known drug targets. Circadian medicine * Correspondence: [email protected] 1 Divisions of Human Genetics and Immunobiology, Center for Circadian Medicine, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, 240 Albert Sabin Way, Cincinnati, OH 45229, USA Full list of author information is available at the end of the article
aims to incorporate this knowledge to improve treatment outcomes. This requires a reliable measure of a patient’s molecular clock phase as wall time does not necessarily equate to clock gene phase. Accumulating evidence shows interpersonal variation in the timing of physiology and behavior due to genetics, age, sex, and lifestyle [5–8]. Robust markers of the molecular clock phase are therefore in high demand. Previous research focused on dim-light melatoninonset (DLMO) as a marker of suprachiasmatic nucleus (SCN) phase [9, 10]. However, DLMO is inconvenient, costly, difficult to standardize, and thus rarely used
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