Specific Regulatory Motifs Predict Glucocorticoid Responsiveness of Hippocampal Gene Expression

Abstract

The glucocorticoid receptor (GR) is an ubiquitously expressed ligand-activated transcription factor that mediates effects of cortisol in relation to adaptation to stress. In the brain, GR affects the hippocampus to modulate memory processes through direct binding to glucocorticoid response elements (GREs) in the DNA. However, its effects are to a high degree cell specific, and its target genes in different cell types as well as the mechanisms conferring this specificity are largely unknown. To gain insight in hippocampal GR signaling, we characterized to which GRE GR binds in the rat hippocampus. Using a position-specific scoring matrix, we identified evolutionary-conserved putative GREs from a microarray based set of hippocampal target genes. Using chromatin immunoprecipitation, we were able to confirm GR binding to 15 out of a selection of 32 predicted sites (47%). The majority of these 15 GREs are previously undescribed and thus represent novel GREs that bind GR and therefore may be functional in the rat hippocampus. GRE nucleotide composition was not predictive for binding of GR to a GRE. A search for conserved flanking sequences that may predict GR-GRE interaction resulted in the identification of GC-box associated motifs, such as Myc-associated zinc finger protein 1, within 2 kb of GREs with GR binding in the hippocampus. This enrichment was not present around nonbinding GRE sequences nor around proven GR-binding sites from a mesenchymal stem-like cell dataset that we analyzed. GC-binding transcription factors therefore may be unique partners for DNA-bound GR and may in part explain cell-specific transcriptional regulation by glucocorticoids in the context of the hippocampus.

Astrocytes are a neural target of morphine action via glucocorticoid receptor‐dependent signaling

“…Possibly, the presence of particular GR cofactors are responsible for a cell-type specific response to GR activation (e.g., Grenier et al, 2006;see also below). Contrary to the previously described effect of GCs on other brain regions such as the hippocampus (Datson et al, 2011) or hypothalamus (Verkuyl et al, 2004;Sato et al, 2008), there are no data to date demonstrating the transcriptional effect of GR stimulation in striatal neurons. It has been reported that dexamethasone administration dose-dependently induces the death of selective subtypes of striatal neurons (enkephalin-positive neurons), as well as hippocampal and septal neurons (Haynes et al, 2001).…”

Genome-wide coexpression of steroid receptors in the mouse brain: Identifying signaling pathways and functionally coordinated regions

“…The presently modest predictive power may be improved by incorporating the effect size (i.e., the absolute expression of a gene), given the values for true positives Irs4 and Magel2. Also, the presence of conserved steroid response elements on the DNA could be a useful additional filter (38).…”

Acute stress and hippocampal histone H3 lysine 9 trimethylation, a retrotransposon silencing response

“…6E). Less is known about the expression of these genes in the peripheral tissues we examined, but binding of GR to GR-elements is highly tissue-specific (23), and although our data do not conclusively demonstrate that GR actively regulates Suv39h2 expression in the hippocampus, they do suggest that the changes in H3K9 methylation we have observed in the hippocampus may use a different mechanism than has been observed elsewhere in the brain (e.g., the accumbens, where G9a appears to be the dominant H3K9 methyltransferase) (24). It should also be added that our examination of stress-responsive brain regions and tissues was not comprehensive, so it is possible that other stress-responsive regions, such as the amygdala or paraventricular hypothalamus, could show similar changes in H3K9 methylation or transposon expression as a consequence of stress.…”