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

J Clin Endocrinol Metab. 2015 Sep;100(9):E1255-61. doi: 10.1210/JC.2015-2284. Epub 2015 Jul 13.


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.

Trial registration: NCT01800253.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ARNTL Transcription Factors / genetics
  • ARNTL Transcription Factors / metabolism
  • Blood Glucose
  • CLOCK Proteins / genetics
  • CLOCK Proteins / metabolism
  • Circadian Clocks / genetics*
  • Circadian Rhythm / genetics*
  • Cross-Over Studies
  • Cryptochromes / genetics
  • Cryptochromes / metabolism
  • Epigenesis, Genetic*
  • Gene Expression
  • Humans
  • Hydrocortisone / blood
  • Male
  • Muscle, Skeletal / metabolism
  • Period Circadian Proteins / genetics
  • Period Circadian Proteins / metabolism
  • Sleep / genetics*
  • Sleep Deprivation / genetics*
  • Sleep Deprivation / metabolism
  • Young Adult


  • ARNTL Transcription Factors
  • Blood Glucose
  • CRY1 protein, human
  • Cryptochromes
  • PER1 protein, human
  • Period Circadian Proteins
  • CLOCK Proteins
  • Hydrocortisone

Associated data