Dynamics of chromatin accessibility and long-range interactions in response to glucocorticoid pulsing

Abstract

Although physiological steroid levels are often pulsatile (ultradian), the genomic effects of this pulsatility are poorly understood. By utilizing glucocorticoid receptor (GR) signaling as a model system, we uncovered striking spatiotemporal relationships between receptor loading, lifetimes of the DNase I hypersensitivity sites (DHSs), long-range interactions, and gene regulation. We found that hormone-induced DHSs were enriched within ±50 kb of GR-responsive genes and displayed a broad spectrum of lifetimes upon hormone withdrawal. These lifetimes dictate the strength of the DHS interactions with gene targets and contribute to gene regulation from a distance. Our results demonstrate that pulsatile and constant hormone stimulations induce unique, treatment-specific patterns of gene and regulatory element activation. These modes of activation have implications for corticosteroid function in vivo and for steroid therapies in various clinical settings.

Forkhead box A3 mediates glucocorticoid receptor function in adipose tissue

“…This tissue-specific induction of Foxa3 may provide a mechanistic explanation of why Foxa3 ablation protects selectively against the expansion of adipose tissue associated with chronic GC treatment but does not prevent any of the morphological and functional alterations induced by GC treatment in liver, muscle, and spleen. It remains to be established experimentally whether Dex may lead to selective induction of Foxa3 in fat tissue because of the unique accessibility of GR to binding elements present at the Foxa3 promoter though specific cofactors available in fat (13,17,46). It is conceivable that GR may rely on tissue-specific factors to activate Foxa3, given that GR previously has been shown to form distinct complexes in a tissueand agonist-selective manner, leading to differential geneexpression programs (1).…”

SMARCA4 regulates gene expression and higher-order chromatin structure in proliferating mammary epithelial cells

“…The intersection of these two factors increased by twofold when the vicinity (±1 kb) of both SMARCA4 and CTCF peaks were considered. To assess whether the effects of SMARCA4 on TAD boundaries result from changes in the local chromatin structure around the CTCF sites, we analyzed publicly available SMARCA4-dependent accessibility and nucleosome positioning DNase I-and MNase-seq data sets (Tolstorukov et al 2013;Morris et al 2014;Stavreva et al 2015). SMARCA4 perturbation affected nucleosome positioning within hundreds of base pairs of CTCF binding sites in mouse fibroblast cells (Supplemental Fig.…”

Twenty-First Century Glucocorticoid Receptor Molecular Biology

“…See also Figure 1 where human TSC22D3 is shown. However, upon glucocorticoid receptor activation, contact intensities changed two-fold at most [71].…”

“…In 2011, the same research group reported that "the predominant hormone-induced changes for Lcn2-contacting loci can be attributed to an increased frequency of pre-existing interactions" [70]. More recently, the 4C approach and genome-wide chromatin structure analysis were applied to characterize GR-associated DNA interactions [71]. In the 3134 murine cell line, this showed that activated GR response elements can interact with a downstream enhancer of the Tsc22d3 transcription repressor gene, whose transcription is strongly upregulated by glucocorticoids.…”

“…In this model, TFs hardly affect enhancer-promoter interaction frequencies, although they do affect the histone-borne epigenetic marks such as H3K27 acetylation (see Figure 1). Currently, available data suggest that GR-responsive loci fit the second type of models, since dexamethasone-mediated GR activation does not greatly alter TAD structure [70,71] (Figure 2). …”