Abstract
SummaryGlucocorticoids act by binding to the glucocorticoid receptor (GR), which binds to specific motifs within enhancers of target genes to activate transcription. Previous studies have suggested that GRs can promote interactions between gene promoters and distal elements within target loci. In contrast, we demonstrate here that glucocorticoid addition to mouse bone-marrow-derived macrophages produces very rapid chromatin unfolding detectable by fluorescence in situ hybridization (FISH) at loci associated with GR binding. Rapid chromatin decompaction was generally not dependent on transcription at those loci that are known to be inducible in both mouse and human macrophages and was sustained for up to 5 days following ligand removal. Chromatin decompaction was not dependent upon persistent GR binding, which decayed fully after 24 hr. We suggest that sustained large-scale chromatin reorganization forms an important part of the response to glucocorticoid and might contribute to glucocorticoid sensitivity and resistance.
Highlights
Glucocorticoids (GCs) are clinically important metabolic hormones with powerful anti-inflammatory effects
In the case of macrophages, glucocorticoid receptor (GR) binding is strongly associated with binding sites for the macrophage lineage transcription factor (TF) PU.1 (Jubb et al, 2016; Oh et al, 2017), and further binding sites become available upon inflammatory activation, associated with AP1 and RelA binding (Oh et al, 2017)
GC Induces Rapid GR Binding at Enhancers at the Fkbp5 Locus We have previously generated genome-wide expression and GR binding data in primary mouse and human macrophages responding to 100 nM dexamethasone (Dex), a GR agonist (Jubb et al, 2016)
Summary
Glucocorticoids (GCs) are clinically important metabolic hormones with powerful anti-inflammatory effects. GR binding can initiate the formation of a more nuclease-sensitive local chromatin structure (Biddie et al, 2011; Burd and Archer 2013; John et al, 2008; Hakim et al, 2011; Stavreva et al, 2015). This may be transient, disappearing rapidly upon hormone withdrawal, or may persist well beyond the period of hormone treatment (Stavreva et al, 2015)
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