title: Acute Sleep Loss Induces Tissue-Specific Epigenetic and Transcriptional Alterations to Circadian Clock Genes in Men.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
authors.affiliation: Department of Neuroscience (J.C., S.V., J.E.B., H.B.S., C.B.), Uppsala University, 751 24 Uppsala, Sweden; Department of Molecular Medicine and Surgery (M.E.O., J.R.Z.), Karolinska Institutet, 171 77 Stockholm, Sweden; Department of Experimental Diabetology (H.V.), German Institute of Human Nutrition Potsdam-Rehbruecke, 14558 Nuthetal, Germany; and Department of Physiology, Institute of Neuroscience and Physiology (H.V., S.L.D.), The Sahlgrenska Academy at the University of Gothenburg, 411 37 Gothenburg, Sweden.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cedernaes
authors.affiliation: Department of Neuroscience (J.C., S.V., J.E.B., H.B.S., C.B.), Uppsala University, 751 24 Uppsala, Sweden; Department of Molecular Medicine and Surgery (M.E.O., J.R.Z.), Karolinska Institutet, 171 77 Stockholm, Sweden; Department of Experimental Diabetology (H.V.), German Institute of Human Nutrition Potsdam-Rehbruecke, 14558 Nuthetal, Germany; and Department of Physiology, Institute of Neuroscience and Physiology (H.V., S.L.D.), The Sahlgrenska Academy at the University of Gothenburg, 411 37 Gothenburg, Sweden.
authors.forename: Megan E
authors.initials: ME
authors.lastname: Osler
authors.affiliation: Department of Neuroscience (J.C., S.V., J.E.B., H.B.S., C.B.), Uppsala University, 751 24 Uppsala, Sweden; Department of Molecular Medicine and Surgery (M.E.O., J.R.Z.), Karolinska Institutet, 171 77 Stockholm, Sweden; Department of Experimental Diabetology (H.V.), German Institute of Human Nutrition Potsdam-Rehbruecke, 14558 Nuthetal, Germany; and Department of Physiology, Institute of Neuroscience and Physiology (H.V., S.L.D.), The Sahlgrenska Academy at the University of Gothenburg, 411 37 Gothenburg, Sweden.
authors.forename: Sarah
authors.initials: S
authors.lastname: Voisin
authors.affiliation: Department of Neuroscience (J.C., S.V., J.E.B., H.B.S., C.B.), Uppsala University, 751 24 Uppsala, Sweden; Department of Molecular Medicine and Surgery (M.E.O., J.R.Z.), Karolinska Institutet, 171 77 Stockholm, Sweden; Department of Experimental Diabetology (H.V.), German Institute of Human Nutrition Potsdam-Rehbruecke, 14558 Nuthetal, Germany; and Department of Physiology, Institute of Neuroscience and Physiology (H.V., S.L.D.), The Sahlgrenska Academy at the University of Gothenburg, 411 37 Gothenburg, Sweden.
authors.forename: Jan-Erik
authors.initials: JE
authors.lastname: Broman
authors.affiliation: Department of Neuroscience (J.C., S.V., J.E.B., H.B.S., C.B.), Uppsala University, 751 24 Uppsala, Sweden; Department of Molecular Medicine and Surgery (M.E.O., J.R.Z.), Karolinska Institutet, 171 77 Stockholm, Sweden; Department of Experimental Diabetology (H.V.), German Institute of Human Nutrition Potsdam-Rehbruecke, 14558 Nuthetal, Germany; and Department of Physiology, Institute of Neuroscience and Physiology (H.V., S.L.D.), The Sahlgrenska Academy at the University of Gothenburg, 411 37 Gothenburg, Sweden.
authors.forename: Heike
authors.initials: H
authors.lastname: Vogel
authors.affiliation: Department of Neuroscience (J.C., S.V., J.E.B., H.B.S., C.B.), Uppsala University, 751 24 Uppsala, Sweden; Department of Molecular Medicine and Surgery (M.E.O., J.R.Z.), Karolinska Institutet, 171 77 Stockholm, Sweden; Department of Experimental Diabetology (H.V.), German Institute of Human Nutrition Potsdam-Rehbruecke, 14558 Nuthetal, Germany; and Department of Physiology, Institute of Neuroscience and Physiology (H.V., S.L.D.), The Sahlgrenska Academy at the University of Gothenburg, 411 37 Gothenburg, Sweden.
authors.forename: Suzanne L
authors.initials: SL
authors.lastname: Dickson
authors.affiliation: Department of Neuroscience (J.C., S.V., J.E.B., H.B.S., C.B.), Uppsala University, 751 24 Uppsala, Sweden; Department of Molecular Medicine and Surgery (M.E.O., J.R.Z.), Karolinska Institutet, 171 77 Stockholm, Sweden; Department of Experimental Diabetology (H.V.), German Institute of Human Nutrition Potsdam-Rehbruecke, 14558 Nuthetal, Germany; and Department of Physiology, Institute of Neuroscience and Physiology (H.V., S.L.D.), The Sahlgrenska Academy at the University of Gothenburg, 411 37 Gothenburg, Sweden.
authors.forename: Juleen R
authors.initials: JR
authors.lastname: Zierath
authors.affiliation: Department of Neuroscience (J.C., S.V., J.E.B., H.B.S., C.B.), Uppsala University, 751 24 Uppsala, Sweden; Department of Molecular Medicine and Surgery (M.E.O., J.R.Z.), Karolinska Institutet, 171 77 Stockholm, Sweden; Department of Experimental Diabetology (H.V.), German Institute of Human Nutrition Potsdam-Rehbruecke, 14558 Nuthetal, Germany; and Department of Physiology, Institute of Neuroscience and Physiology (H.V., S.L.D.), The Sahlgrenska Academy at the University of Gothenburg, 411 37 Gothenburg, Sweden.
authors.forename: Helgi B
authors.initials: HB
authors.lastname: Schiöth
authors.affiliation: Department of Neuroscience (J.C., S.V., J.E.B., H.B.S., C.B.), Uppsala University, 751 24 Uppsala, Sweden; Department of Molecular Medicine and Surgery (M.E.O., J.R.Z.), Karolinska Institutet, 171 77 Stockholm, Sweden; Department of Experimental Diabetology (H.V.), German Institute of Human Nutrition Potsdam-Rehbruecke, 14558 Nuthetal, Germany; and Department of Physiology, Institute of Neuroscience and Physiology (H.V., S.L.D.), The Sahlgrenska Academy at the University of Gothenburg, 411 37 Gothenburg, Sweden.
authors.forename: Christian
authors.initials: C
authors.lastname: Benedict
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics / Q000378:metabolism; D001786:Blood Glucose; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism; D057906:Circadian Clocks / Q000235:genetics*; D002940:Circadian Rhythm / Q000235:genetics*; D018592:Cross-Over Studies; D056931:Cryptochromes / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic; D015870:Gene Expression; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism; D056950:Period Circadian Proteins / Q000235:genetics / Q000378:metabolism; D012890:Sleep / Q000235:genetics*; D012892:Sleep Deprivation / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: D056930:ARNTL Transcription Factors; D001786:Blood Glucose; C538963:CRY1 protein, human; D056931:Cryptochromes; C539022:PER1 protein, human; D056950:Period Circadian Proteins; D056926:CLOCK Proteins; D006854:Hydrocortisone