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

Glucocorticoid resistance is commonly observed in depression and has been linked to reduced expression and/or function of the Glucocorticoid Receptor (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 wild-type and GR mutant adult zebrafish. 249 GR-regulated Differentially Methylated Regions (DMRs) were identified, including a cluster of CpGs within the first intron of the glucocorticoid-inducible, heat shock protein co-chaperone gene fkbp5. RNA-seq analysis revealed that genes associated with chaperone-mediated protein folding, regulation of circadian rhythm and regulation of metabolism were particularly sensitive to loss of GR function. In addition, subsets of genes exhibiting GR-regulated transcription were identified 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 likely mediates responses to stress in the adult zebrafish brain, and they provide further support for the GR mutant as a model for the study of affective disorders.