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

Eachus, Helen ; Oberski, Lara ; Paveley, Jack ; Bacila, Irina ; Ashton, John Paul ; Esposito, Umberto ; Seifuddin, Fayaz ; Pirooznia, Mehdi ; Elhaik, Eran LU orcid and Placzek, Marysia , et al. (2023) In DMM Disease Models and Mechanisms 16(9).
Abstract

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... (More)

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.

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publishing date
type
Contribution to journal
publication status
published
subject
keywords
DNA methylation, Glucocorticoid, Nervous system, Transcriptome
in
DMM Disease Models and Mechanisms
volume
16
issue
9
article number
dmm050141
publisher
The Company of Biologists Ltd
external identifiers
  • pmid:37525888
  • scopus:85174080096
ISSN
1754-8403
DOI
10.1242/dmm.050141
language
English
LU publication?
no
additional info
Publisher Copyright: © 2023 Published by The Company of Biologists Ltd.
id
d9aebeda-dc9d-4e79-bf61-04b7d075e20d
date added to LUP
2024-09-09 15:19:01
date last changed
2024-09-16 17:23:06
@article{d9aebeda-dc9d-4e79-bf61-04b7d075e20d,
  abstract     = {{<p>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.</p>}},
  author       = {{Eachus, Helen and Oberski, Lara and Paveley, Jack and Bacila, Irina and Ashton, John Paul and Esposito, Umberto and Seifuddin, Fayaz and Pirooznia, Mehdi and Elhaik, Eran and Placzek, Marysia and Krone, Nils P. and Cunliffe, Vincent T.}},
  issn         = {{1754-8403}},
  keywords     = {{DNA methylation; Glucocorticoid; Nervous system; Transcriptome}},
  language     = {{eng}},
  number       = {{9}},
  publisher    = {{The Company of Biologists Ltd}},
  series       = {{DMM Disease Models and Mechanisms}},
  title        = {{Glucocorticoid receptor regulates protein chaperone, circadian clock and affective disorder genes in the zebrafish brain}},
  url          = {{http://dx.doi.org/10.1242/dmm.050141}},
  doi          = {{10.1242/dmm.050141}},
  volume       = {{16}},
  year         = {{2023}},
}