Acute Sleep Loss Induces Tissue-Specific Epigenetic and Transcriptional Alterations to Circadian Clock Genes in Men

TLDR

Shift workers have a higher risk of metabolic disorders, partly because clock genes regulate peripheral metabolic processes such as glucose oxidation. This study examined the epigenetic and transcriptional effects of a single night of total sleep deprivation on core circadian clock genes in peripheral tissues of healthy men. In a randomized crossover trial, 15 healthy men underwent a sleep and a wakefulness session, after which serum cortisol, skeletal muscle and subcutaneous adipose tissue biopsies were taken for DNA methylation and gene expression of core clock genes, and plasma glucose was measured before and two hours after an oral glucose load. Acute sleep deprivation increased CRY1 promoter methylation and PER1 enhancer methylation in adipose tissue, decreased BMAL1 and CRY1 expression in skeletal muscle, lowered serum cortisol, and raised postprandial glucose, indicating that a single night of wakefulness can alter core circadian clock genes in metabolic tissues and may underlie shift‑work–related metabolic dysfunction.

Abstract

Context: Shift workers are at increased risk of metabolic morbidities. Clock genes are known to regulate metabolic processes in peripheral tissues, eg, glucose oxidation. Objective: This study aimed to investigate how clock genes are affected at the epigenetic and transcriptional level in peripheral human tissues following acute total sleep deprivation (TSD), mimicking shift work with extended wakefulness. Intervention: In a randomized, two-period, two-condition, crossover clinical study, 15 healthy men underwent two experimental sessions: x sleep (2230–0700 h) and overnight wakefulness. On the subsequent morning, serum cortisol was measured, followed by skeletal muscle and subcutaneous adipose tissue biopsies for DNA methylation and gene expression analyses of core clock genes (BMAL1, CLOCK, CRY1, PER1). Finally, baseline and 2-h post-oral glucose load plasma glucose concentrations were determined. Main Outcome Measures: In adipose tissue, acute sleep deprivation vs sleep increased methylation in the promoter of CRY1 (+4%; P = .026) and in two promoter-interacting enhancer regions of PER1 (+15%; P = .036; +9%; P = .026). In skeletal muscle, TSD vs sleep decreased gene expression of BMAL1 (−18%; P = .033) and CRY1 (−22%; P = .047). Concentrations of serum cortisol, which can reset peripheral tissue clocks, were decreased (2449 ± 932 vs 3178 ± 723 nmol/L; P = .039), whereas postprandial plasma glucose concentrations were elevated after TSD (7.77 ± 1.63 vs 6.59 ± 1.32 mmol/L; P = .011). Conclusions: Our findings demonstrate that a single night of wakefulness can alter the epigenetic and transcriptional profile of core circadian clock genes in key metabolic tissues. Tissue-specific clock alterations could explain why shift work may disrupt metabolic integrity as observed herein.