The Glucocorticoid Receptor regulates behaviour, DNA methylation and gene transcription in the adult zebrafish brain

The Glucocorticoid Receptor (GR) is a transcriptional regulator which co-ordinates behavioural, metabolic and immune responses to stressors. Previous studies have shown that wild-type and grs357 mutant zebrafish exhibit a range of behavioural differences, implying possible roles for GR function in the brain. As part of a study to elucidate the mechanisms underlying the behaviours that are regulated by GR, we compared the brain transcriptomes of wild-type and grs357 mutant adults. RNA-seq analysis identified 19 Biological Process and 4 Molecular Function Gene Ontology (GO) terms that were particularly sensitive to loss of GR function. Foremost among the Biological Process terms linked to GR function are Chaperone-mediated Protein Folding, Regulation of Circadian Rhythm and Regulation of Primary Metabolic Process, each of which is accompanied by several other closely related GO terms. In addition, the Biological Process GO term Behavior was significantly associated with 32 genes exhibiting GR-regulated gene transcription. The Molecular Function terms most closely linked to GR function are Heat Shock Protein Binding, Protein Serine/Threonine Kinase Activity, Transcription Regulator Activity and Unfolded Protein Binding. Taken together, our results identify key biological processes and novel molecular mechanisms through which the GR likely regulates responses to stress in the zebrafish adult brain. Overall design: To determine the molecular function of GR in the adult brain, we compared the brain transcriptomes of adult grs357 mutant zebrafish brains versus wild-type age matched sibling brains through RNA sequencing analysis.