Genomic glucocorticoid action in embryonic mouse neural stem cells

Antenatal administration of synthetic glucocorticoids (sGC) ameliorates infant complications of premature delivery by mimicking the endogenous surge of cortisol that peaks during late gestation (ACOG committee opnion, 2002; Liggins and Howie, 1972). However, potential adverse neurodevelopmental consequences of antenatal sGC exposure include short-term cortical architectural changes in mice, sheep, and non-human primates, and long-term behavioral or cognitive impairments in humans (Antonow-Schlorke et al., 2009; Cheong et al., 2017; Franca et al., 2016; Tijsseling et al., 2012; Tsiarli et al., 2017; Uno et al., 1990; Damsted et al., 2011). Mouse models of sGC administration revealed that a single dose of the glucocorticoid receptor (GR) agonist Dexamethasone (Dex) at embryonic day E14.5 altered neural stem and progenitor cell (NSPC) proliferation and differentiation in vivo, while in-vitro experiments with primary embryonic NSPCs demonstrated robust and sex-specific changes in gene expression following acute Dex treatment (Tsiarli et al., 2017; Frahm et al., 2018).

Cerebral cortical development represents a dynamic period of chromatin remodeling that directs neurogenesis and other cell fate decisions, with subpopulations of cells within neuronal or glial lineages expressing distinct global chromatin signatures (Forrest et al., 2017; Trevino et al., 2020). This is a flexible epigenetic process guided by specialized enzymatic complexes and transcription factors (Forrest et al., 2017; Trevino et al., 2020; Larrigan et al., 2021; Markenscoff-Papadimitriou et al., 2020). Furthermore, gene-regulatory enhancer regions upon which transcription factors act are often located far from their target promoters, highlighting the need for genome wide assessment of chromatin architecture to fully understand how developmental programming of gene expression is established and/or maintained (Kempfer and Pombo, 2020).

Transcriptional regulation by GCs is driven by GR, which associates directly or indirectly with DNA to activate or repress target genes (Weikum et al., 2017). Both chromatin accessibility and histone modifications play a major role in determining de-novo genomic GR occupancy (John et al., 2011; McDowell et al., 2018; Podobinska et al., 2017). However, some GR binding sites occur in less permissive chromatin or genomic sites lacking distinct histone modifications (John et al., 2011; Johnson et al., 1987, 2018). Importantly, cell type-enriched co-factors or coregulators create unique GR occupancy patterns in different cell types by enhancing the receptor's ability to associate directly with specific DNA sequences (i.e., glucocorticoid response elements or GREs), or recruiting GR indirectly to genomic sites occupied by other transcription factors (Oakley and Cidlowski, 2013; Sacta et al., 2016).

While antenatal exposure to sGC reprograms the neurodevelopmental trajectories in the fetal forebrain, the molecular signatures that direct basal and hormone-induced genomic GR action in NSPCs have not previously been elucidated. In this study we characterized the chromatin landscape and GR cistrome of embryonic mouse NSPCs to determine whether robust acute sGC-induced alterations in gene expression are accompanied by changes in chromatin accessibility and GR distribution at regulatory genomic sites that control NSPC fate.

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