A population-based gene expression signature of molecular clock phase from a single epidermal sample

Gang Wu,Lauren J Francey,John B Hogenesch,Joseph D Sherrill,Marc D Ruben,John E Oblong,Kevin J Mills,David F Smith

doi:10.1186/s13073-020-00768-9

Gang Wu, Lauren J Francey + Show 6 more

Open Access

https://doi.org/10.1186/s13073-020-00768-9

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Abstract

BackgroundFor 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.MethodsWe 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 CYCLOPS-predicted phases, we used ZeitZeiger to discover potential biomarkers of clock phase.ResultsCircadian clock function was strongest in the epidermis, regardless of body site. We identified a 12-gene 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.ConclusionsThis 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).

Highlights

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 measured and generalizable across a broad population
We found that circadian clock function was strongest in the epidermis, regardless of body site
Morning-time genes were enriched for immune-related and G proteincoupled receptor (GPCR) signaling, whereas the evening was marked by genes involved in transcription, lipid and lipoprotein metabolism, and development (Additional file 1: Fig. S1C-D) (phase set enrichment analysis (PSEA) [25])

Summary

Introduction

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 measured and generalizable across a broad population. With the development of high-throughput molecular detection platforms and computational techniques, recent efforts shifted to machine learning predictions based on the transcriptome or metabolome from one or two samples of whole blood [11,12,13,14,15,16], or a specific blood cell type (e.g., CD14+ monocytes) [17] This approach can predict DLMO phase to within 3 h from a single blood sample [14, 17]. Developing and validating blood-based biomarkers of DLMO phase in the broader population remain a challenge It is not clear what the melatonin phase tells us about clock gene phase in other tissues

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Discussion

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