Inter-layer and inter-subject variability of diurnal gene expression in human skin

Abstract

The skin is the largest human organ with a circadian clock that regulates its function. Although circadian rhythms in specific functions are known, rhythms in the proximal clock output, gene expression, in human skin have not been thoroughly explored. This work reports 24 h gene expression rhythms in two skin layers, epidermis and dermis, in a cohort of young, healthy adults, who maintained natural, regular sleep-wake schedules. 10% of the expressed genes showed such diurnal rhythms at the population level, of which only a third differed between the two layers. Amplitude and phases of diurnal gene expression varied more across subjects than layers, with amplitude being more variable than phases. Expression amplitudes in the epidermis were larger and more subject-variable, while they were smaller and more consistent in the dermis. Core clock gene expression was similar across layers at the population-level, but were heterogeneous in their variability across subjects. We also identified small sets of biomarkers for internal clock phase in each layer, which consisted of layer-specific non-core clock genes. This work provides a valuable resource to advance our understanding of human skin and presents a novel methodology to quantify sources of variability in human circadian rhythms.

Data integration and analysis for circadian medicine

“…Omics data are also a great source to mine for new clock components 14 and biomarkers for different clock parameters, such as the circadian phase. [15][16][17] Circadian tissue cultured in vitro have also been shown to retain the circadian properties of the human donor. 18 Thus, time series recordings from cell/tissue cultures transfected with a clock gene/protein reporter are another source of circadian molecular data.…”

“…Since studies in humans are often longitudinal, measurements from each subject are correlated, unlike (typical) samples from model organisms. As one solution, cosinor analysis can be made to account for correlations using linear mixed models 16 . Rhythms can be averaged across study subjects to reduce the impact of noise and assess a population rhythm if the study cohort is sufficiently homogenous.…”

“…This depends critically on the circadian variation exceeding the inter-individual variation, which has been shown to be the case in human skin. 16 In fact, such single tissue biopsies are available in many public databases, such as The Cancer Genome Atlas, or are part of tissue banks. Of course, accurate time labels for these samples are still needed to construct a population-level time series.…”

“…As one solution, cosinor analysis can be made to account for correlations using linear mixed models. 16 Rhythms can be averaged across study subjects to reduce the impact of noise and assess a population rhythm if the study cohort is sufficiently homogenous. In circadian studies, this homogeneity extends to the ability to align the internal time of subjects by correcting the sampling times to characterize the underlying common circadian rhythm.…”

“…In circadian studies, this homogeneity extends to the ability to align the internal time of subjects by correcting the sampling times to characterize the underlying common circadian rhythm. 16 This often requires a complete chronobiological profile of the subjects. When the subjects under study are highly heterogeneous and chronobiological profiling is infeasible, circadian rhythms can be analyzed at the individual level using amplitude as the metric.…”