Genomic glucocorticoid action in embryonic mouse neural stem cells

Area of Science:

• Neuroscience
• Developmental Biology
• Genomics

Background:

• Prenatal exposure to synthetic glucocorticoids (sGCs) can disrupt fetal brain development.
• Previous research indicates sexually dimorphic transcriptomic changes in neural stem and progenitor cells (NSPCs) following sGC exposure.

Purpose of the Study:

• To investigate the relationship between gene regulation, chromatin structure, and genomic glucocorticoid receptor (GR) action in NSPCs.
• To identify novel regulatory mechanisms underlying neurodevelopmental changes induced by sGCs.

Main Methods:

• Utilized a mouse model of sGC administration.
• Performed multiplexed genome-wide assays: RNA-seq, ATAC-seq, ChIP-seq, and microarray gene expression.
• Analyzed data to understand GR binding and its impact on chromatin accessibility and gene expression in NSPCs.

Main Results:

• The genomic glucocorticoid receptor (GR) preferentially binds to accessible chromatin regions to regulate gene programming and cell fate.
• Identified SOX2 as a transcription factor influencing the genomic response of GR target genes to sGCs (dexamethasone).
• Demonstrated sexually dimorphic effects on NSPC transcriptomes.

Conclusions:

• GR binding to accessible chromatin is a key mechanism in mediating the effects of sGCs on NSPC gene expression.
• SOX2 plays a role in modulating the cellular response to sGCs during critical developmental periods.
• Findings provide insights into the molecular basis of sGC-induced neurodevelopmental alterations.