PUBLICATION
Klf9 is a key feedforward regulator of the transcriptomic response to glucocorticoid receptor activity
- Authors
- Gans, I., Hartig, E.I., Zhu, S., Tilden, A.R., Hutchins, L.N., Maki, N.J., Graber, J.H., Coffman, J.A.
- ID
- ZDB-PUB-200712-4
- Date
- 2020
- Source
- Scientific Reports 10: 11415 (Journal)
- Registered Authors
- Coffman, James A., Gans, Ian
- Keywords
- none
- Datasets
- GEO:GSE144885, GEO:GSE144884
- MeSH Terms
-
- Animals
- CRISPR-Cas Systems*
- Exons
- Frameshift Mutation*
- Gene Deletion
- Gene Expression Regulation
- Homozygote
- Humans
- Hydrocortisone/metabolism
- Inflammation
- Kruppel-Like Transcription Factors/metabolism*
- Larva
- Mutation
- RNA-Seq
- Receptors, Glucocorticoid/metabolism*
- Receptors, Mineralocorticoid/metabolism
- Signal Transduction
- Transcriptome*
- Up-Regulation
- Zebrafish/genetics
- Zebrafish Proteins/metabolism*
- PubMed
- 32651405 Full text @ Sci. Rep.
Citation
Gans, I., Hartig, E.I., Zhu, S., Tilden, A.R., Hutchins, L.N., Maki, N.J., Graber, J.H., Coffman, J.A. (2020) Klf9 is a key feedforward regulator of the transcriptomic response to glucocorticoid receptor activity. Scientific Reports. 10:11415.
Abstract
The zebrafish has recently emerged as a model system for investigating the developmental roles of glucocorticoid signaling and the mechanisms underlying glucocorticoid-induced developmental programming. To assess the role of the Glucocorticoid Receptor (GR) in such programming, we used CRISPR-Cas9 to produce a new frameshift mutation, GR369-, which eliminates all potential in-frame initiation codons upstream of the DNA binding domain. Using RNA-seq to ask how this mutation affects the larval transcriptome under both normal conditions and with chronic cortisol treatment, we find that GR mediates most of the effects of the treatment, and paradoxically, that the transcriptome of cortisol-treated larvae is more like that of larvae lacking a GR than that of larvae with a GR, suggesting that the cortisol-treated larvae develop GR resistance. The one transcriptional regulator that was both underexpressed in GR369- larvae and consistently overexpressed in cortisol-treated larvae was klf9. We therefore used CRISPR-Cas9-mediated mutation of klf9 and RNA-seq to assess Klf9-dependent gene expression in both normal and cortisol-treated larvae. Our results indicate that Klf9 contributes significantly to the transcriptomic response to chronic cortisol exposure, mediating the upregulation of proinflammatory genes that we reported previously.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping