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Acute Sleep Loss Induces Tissue-Specific Epigenetic and Transcriptional Alterations to Circadian Clock Genes in Men
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.ORCID iD: 0000-0002-9052-8372
Karolinska Inst, Dept Mol Med & Surg, S-17177 Stockholm, Sweden..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
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2015 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 100, no 9, E1255-E1261 p.Article in journal (Refereed) Published
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Text
Abstract [en]

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 (8MAL1, CLOCK, CRYT, PERT). 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 PERT (+15%; P =.036; +9%; P =.026). In skeletal muscle, TSD vs sleep decreased gene expression of BMALT (-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.

Place, publisher, year, edition, pages
2015. Vol. 100, no 9, E1255-E1261 p.
National Category
Endocrinology and Diabetes
Identifiers
URN: urn:nbn:se:uu:diva-269283DOI: 10.1210/jc.2015-2284ISI: 000364867800024PubMedID: 26168277OAI: oai:DiVA.org:uu-269283DiVA: diva2:882640
Funder
The Swedish Brain FoundationAFA InsuranceNovo NordiskSwedish Society of MedicineMagnus Bergvall FoundationSwedish Research Council
Available from: 2015-12-15 Created: 2015-12-15 Last updated: 2017-12-01Bibliographically approved
In thesis
1. Bioinformatic and Biostatistic Analysis of Epigenetic Data from Humans and Mice in the Context of Obesity and its Complications
Open this publication in new window or tab >>Bioinformatic and Biostatistic Analysis of Epigenetic Data from Humans and Mice in the Context of Obesity and its Complications
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Worldwide obesity has more than doubled since 1980 and at least 2.8 million people die each year as a result of being overweight or obese. An elevated body weight is the result of the interplay between susceptibility gene variants and an obesogenic environment, and recent evidence shows that epigenetic processes are likely involved. The growing availability of high-throughput technologies has made it possible to assess quickly the entire epigenome of large samples at a relatively low cost. As a result, vast amounts of data have been generated and researchers are now confronted to both bioinformatic and biostatistic challenges to make sense of such data in the context of obesity and its complications. In this doctoral thesis, we explored associations between the human blood methylome and obesity-associated gene variants as well as dietary fat quality and quantity. We used well described preprocessing techniques and statistical methods, along with publicly available data from consortiums and other research groups, as well as tools for pathway enrichment and chromatin state inference. We found associations between obesityassociated SNPs and methylation levels at proximal promoters and enhancers, and some of these associations were replicated in multiple tissues. We also found that contrary to dietary fat quantity, dietary fat quality associates with methylation levels in the promoter of genes involved in metabolic pathways. Then, using a gene-targeted approach, we looked at the impact of an acute environmental stress (sleep loss) on the methylation and transcription levels of circadian clock genes in skeletal muscle and adipose tissue of healthy men. We found that a single night of wakefulness can alter the epigenetic and transcriptional profile of core circadian clock genes in a tissue-specific manner. Finally, we looked at the effects of chronic maternal obesity and subsequent weight loss on the transcription of epigenetic machinery genes in the fetus and placenta of mice. We found that the transcription of epigenetic machinery genes is highly sensitive to maternal weight trajectories, and particularly those of the histone acetylation pathway. Overall, this thesis demonstrated that genetics, obesogenic environment stimuli and maternal programming impact epigenetic marks at genomic locations relevant in the pathogenesis of obesity.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 143 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1245
Keyword
obesity, genetics, epigenetics, DNA methylation, sleep, developmental origins of health and disease, single nucleotide polymorphism, genome-wide association study
National Category
Medical Genetics Nutrition and Dietetics Genetics
Identifiers
urn:nbn:se:uu:diva-300751 (URN)978-91-554-9655-5 (ISBN)
Public defence
2016-09-22, C8:301, BMC, Husargatan 3, Uppsala, 13:00 (English)
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Available from: 2016-08-31 Created: 2016-08-12 Last updated: 2016-09-21

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Cedernaes, JonathanVoisin, SarahBroman, Jan-ErikSchioth, Helgi B.Benedict, Christian

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