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PLoS Genet. 2016 Dec 12;12(12):e1006512. doi: 10.1371/journal.pgen.1006512. eCollection 2016 Dec.

Extensive Regulation of Diurnal Transcription and Metabolism by Glucocorticoids.

Author information

1
Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Hermann-von-Helmholtz-Platz 1, Eggenstein-Leopoldshafen, Germany.
2
Nestlé Institute of Health Sciences SA, EPFL Innovation Park, Bâtiment H, Lausanne, Switzerland.
3
Centre for Endocrinology, Diabetes and Metabolism, University of Birmingham, Birmingham, United Kingdom.
4
Institute for Organic Chemistry, Karlsruhe Institute of Technology, Hermann-von-Helmholtz-Platz 1, Eggenstein-Leopoldshafen, Germany.
5
Institute for Biological Interfaces 4 -Magnetic Resonance, Karlsruhe Institute of Technology, Hermann-von-Helmholtz-Platz 1, Eggenstein-Leopoldshafen, Germany.
6
Faculty of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
7
Plateforme Biopuces et séquençage, IGBMC, 1 rue Laurent Fries, Parc d'Innovation, Illkirch, France.
8
Centre for Organismal Studies (COS), University of Heidelberg, Heidelberg, Germany.
9
Academic Unit of Child Health, Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom.

Abstract

Altered daily patterns of hormone action are suspected to contribute to metabolic disease. It is poorly understood how the adrenal glucocorticoid hormones contribute to the coordination of daily global patterns of transcription and metabolism. Here, we examined diurnal metabolite and transcriptome patterns in a zebrafish glucocorticoid deficiency model by RNA-Seq, NMR spectroscopy and liquid chromatography-based methods. We observed dysregulation of metabolic pathways including glutaminolysis, the citrate and urea cycles and glyoxylate detoxification. Constant, non-rhythmic glucocorticoid treatment rescued many of these changes, with some notable exceptions among the amino acid related pathways. Surprisingly, the non-rhythmic glucocorticoid treatment rescued almost half of the entire dysregulated diurnal transcriptome patterns. A combination of E-box and glucocorticoid response elements is enriched in the rescued genes. This simple enhancer element combination is sufficient to drive rhythmic circadian reporter gene expression under non-rhythmic glucocorticoid exposure, revealing a permissive function for the hormones in glucocorticoid-dependent circadian transcription. Our work highlights metabolic pathways potentially contributing to morbidity in patients with glucocorticoid deficiency, even under glucocorticoid replacement therapy. Moreover, we provide mechanistic insight into the interaction between the circadian clock and glucocorticoids in the transcriptional regulation of metabolism.

PMID:
27941970
PMCID:
PMC5191836
DOI:
10.1371/journal.pgen.1006512
[Indexed for MEDLINE]
Free PMC Article

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