Glucocorticoid receptor regulates protein chaperone, circadian clock and affective disorder genes in the zebrafish brain

Helen Eachus, Lara Oberski, Jack Paveley, Irina Bacila, John Paul Ashton, Umberto Esposito, Fayaz Seifuddin, Mehdi Pirooznia, Eran Elhaik, Marysia Placzek, Nils P. Krone, Vincent T. Cunliffe*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Glucocorticoid resistance is commonly observed in depression, and has been linked to reduced expression and/or function of the glucocorticoid receptor (NR3C1 in human, hereafter referred to as GR). Previous studies have shown that GR-mutant zebrafish exhibit behavioural abnormalities that are indicative of an affective disorder, suggesting that GR plays a role in brain function. We compared the brain methylomes and brain transcriptomes of adult wild-type and GR-mutant zebrafish, and identified 249 differentially methylated regions (DMRs) that are regulated by GR. These include a cluster of CpG sites within the first intron of fkbp5, the gene encoding the glucocorticoid-inducible heat shock protein co-chaperone Fkbp5. RNA-sequencing analysis revealed that genes associated with chaperone-mediated protein folding, the regulation of circadian rhythm and the regulation of metabolism are particularly sensitive to loss of GR function. In addition, we identified subsets of genes exhibiting GR-regulated transcription that are known to regulate behaviour, and are linked to unipolar depression and anxiety. Taken together, our results identify key biological processes and novel molecular mechanisms through which the GR is likely to mediate responses to stress in the adult zebrafish brain, and they provide further support for the zebrafish GR mutant as a model for the study of affective disorders.

Original languageEnglish
Article numberdmm050141
JournalDMM Disease Models and Mechanisms
Issue number9
Publication statusPublished - 30 Sept 2023


  • DNA methylation
  • Glucocorticoid
  • Nervous system
  • Transcriptome


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  • First person - Helen Eachus

    Eachus, H., Sept 2023, In: DMM Disease Models and Mechanisms. 16, 9, 2 p., dmm050452.

    Research output: Contribution to journalLetter, comment/opinion or interview

    Open Access

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