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Astrocytes in the mouse suprachiasmatic nuclei respond directly to glucocorticoids feedback

ABSTRACT: The circadian timing system anticipates daily recurring changes in the environment to synchronize physiology. In mammals, the master pacemaker is the hypothalamic suprachiasmatic nuclei (SCN), which synchronizes “wake” functions by inducing the circadian release of Glucocorticoids (GCs) from the adrenal gland. GCs peak right before the active phase and set the time of peripheral clocks, however, it is still unclear whether the SCN respond to GCs feedback. While GCs influence directly the SCN during the perinatal period, the adult circuit is considered to be resistant to them, suggesting a reduction of GCs-sensitivity along development. To understand this mechanism, we followed the expression of GC receptor (GR) along mouse SCN development with single cell resolution and show that GR is up-regulated in astrocytes as the circuit matures. We provide in vivo and in vitro evidence that the adult SCN stays responsive to circulating GCs through the activation of GR in astrocytes. Astrocytes’ communication is necessary to induce the GC-dependent shift on the SCN clock. Our data provides insight into the development of the SCN and highlight a new role of astrocytes as time-keepers in the adult. This finding might shed light on how the circadian system adapts to jetlag or shift work.

ORGANISM(S): Mus musculus

PROVIDER: GSE240803 | GEO | 2024/04/10

REPOSITORIES: GEO

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Project description:Glucocorticoids (GCs) are among the most effective and frequently prescribed anti-inflammatory drugs in dermatology. The effects of GCs are mediated by the glucocorticoid receptor (GR), a well-known transcription factor (TF). Despite the well-studied therapeutic and adverse effects of GCs, the molecular signature of GC/GR in human skin is largely unknown. Here, we present a bioinformatics analysis of the human skin transcriptome induced by the glucocorticoid clobetasol propionate (CBP). Full thickness arm skin biopsies were obtained from a cohort of 17 healthy volunteers balanced in sex and race (African-American and Caucasian) 24 hrs after single CBP topical application. Non-treated skin from the same volunteers served as control. Analyses of differentially expressed genes (DEGs) and gene set enrichments (GSE) from RNASeq reflected anti-inflammatory, metabolic and atrophogenic effects of GCs in skin. More than 40% of all DEGs were non-coding RNAs, including long non-coding RNAs (lncRNAs) suggesting that GR effects in skin may extend towards regulation at the post-transcriptional level. Furthermore, we observed sexual and racial dimorphism in the CBP response including a shift towards IFNg/IFNa and IL6/JAK/STAT3 signaling in female skin; and an overall larger response to CBP (increased number of DEGs and increased induction of some GR-target genes) in African-American skin. Weighted gene co-expression network analysis (WGCNA) unveiled a regulatory network comprising 41 TFs, with network hub TFs enriched for direct GR targets and ~ 260 of their target genes that were enriched for the majority of altered functional pathways of the entire CBP transcriptome. Interestingly, ~ 80% of these TFs involved in the regulation of circadian clock, metabolism, and development have been associated with skin aging supporting at the molecular level the known similarities between skin chronically treated with GCs and aged skin. Overall, these findings indicate that GR acts as a master regulator of gene expression in skin via multiple mechanisms including regulation of expression of noncoding RNAs and multiple core TFs

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Astrocytes in the mouse suprachiasmatic nuclei respond directly to glucocorticoids feedback

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