Extensive Regulation of Diurnal Transcription and Metabolism by Glucocorticoids

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

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.

MeSH terms

  • Animals
  • CLOCK Proteins / biosynthesis*
  • CLOCK Proteins / genetics
  • Circadian Clocks / genetics*
  • Circadian Rhythm / genetics
  • Citric Acid / metabolism
  • E-Box Elements / genetics*
  • Gene Expression Regulation
  • Glucocorticoids / biosynthesis
  • Glucocorticoids / deficiency
  • Glucocorticoids / genetics*
  • High-Throughput Nucleotide Sequencing
  • Hormones / genetics
  • Hormones / metabolism
  • Humans
  • Magnetic Resonance Spectroscopy
  • Metabolic Networks and Pathways / genetics*
  • Transcription, Genetic
  • Transcriptome / genetics
  • Urea / metabolism
  • Zebrafish

Substances

  • Glucocorticoids
  • Hormones
  • Citric Acid
  • Urea
  • CLOCK Proteins

Grant support

We acknowledge funding by the Studienstiftung des Deutschen Volkes (to MW), by the Marie Curie Intra-European Fellowships For Career Development (FP7-PEOPLE-2013-IEF) (PIEF-GA-2013-625827) (to MW), and by the Deutsche Forschungsgemeinschaft (DFG grants DI913/4-1 to TD and ZUK 49/2 to GP and RH), by the Excellence Initiative (“Anschubmittel” to BL and TD; and the CellNetworks Excellence Cluster EcTop6 to TD), and by the Helmholtz Programme BioInterfaces (BIF, to BL and TD). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.