de Zeeuw, J. | bioRxiv Science

bioRxiv2025

Hair test reveals plasticity of human chronotype

Circadian clocks govern daily physiological and behavioral processes and are crucial for health, yet disruptions can lead to various diseases. Chronotype, the state of circadian timing, varies between individuals and is reflected in behaviors such as sleep-wake patterns, cognitive performance, and physical activity. This interindividual variability is influenced by both genetic factors and environmental cues, but the relative contributions of each remain unclear, particularly in terms of plasticity - how much chronotype can shift in response to lifestyle and environmental factors. The gold standard for chronotype assessment, dim-light melatonin onset (DLMO), is invasive and impractical for large-scale studies, while blood-based molecular biomarker tests, which estimate internal time, show promise but are limited by practicality. Here, we introduce HairTime, a novel assay that estimates chronotype from a single hair sample collected at one point during the day. HairTime was developed and evaluated in two studies: a training study and a validation study, where it demonstrated a strong ability to predict chronotype, with DLMO as the comparison. This non-invasive method is suitable for large-scale, longitudinal studies and clinical practice. We assessed HairTime using over 4,000 samples, observing a normal distribution of chronotype across the population, with its estimation associating with age, sex, and notably, work schedules. The association with work schedules reveals the plasticity of chronotype, as workdays circadian timing earlier, highlighting that societal factors can influence and modify an individuals internal rhythm. Additionally, we explore the concept of circadian amplitude, finding that lower amplitude rhythms in hair follicle cells are linked to reduced chronotype prediction accuracy. Our results highlight that both intrinsic circadian mechanisms and external factors, such as lifestyle and work schedules, shape chronotype. HairTime offers an innovative tool for understanding circadian rhythms, facilitating personalized chronotherapy to improve health outcomes by aligning treatments with an individuals biological rhythms.

systems biology↗

bioRxiv2022

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

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 circadian gene expression in two skin layers, epidermis and dermis, in a cohort of young, healthy adults, who maintained natural, regular sleep schedules. 10% of the expressed genes showed rhythms at the population level, of which only a third differed between the two layers. Broadly, expression magnitudes of circadian genes were consistent across subjects in each layer. Amplitude and phases of circadian gene expression, however, 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 the their variability across subjects. We used this data to identify 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 to realize the potential of circadian medicine as well as a novel methodology to quantify sources of variability in human circadian rhythms.

bioinformatics↗