Conventional and pioneer modes of glucocorticoid receptor interaction with enhancer chromatin in vivo
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE94562 | GEO | 2017/11/06
SECONDARY ACCESSION(S): PRJNA371473
REPOSITORIES: GEO
Similar Datasets
Project description:Glucocorticoid hormone plays a major role in metabolism and many related diseases. The hormone-bound glucocorticoid receptor (GR) binds to a specific set of enhancers in different cell types, resulting in unique patterns of gene expression. GR-responsive enhancers have an accessible chromatin structure prior to hormone treatment (“pre-programmed”), whereas unresponsive enhancers specific to other cell types are inaccessible and inactive. Here we have addressed the role of chromatin structure in cell-specific GR-enhancer programming by precise mapping of nucleosome positions in mouse adenocarcinoma cells. We show that, before hormone treatment, some pre-programmed GR-enhancers are nucleosome-depleted, associated with the Brg1 chromatin remodeler and flanked by nucleosomes exchanging histones H2A.Z and H2A. However, most pre-programmed GR-enhancers are assembled into a nucleosome that exchanges H2A.Z and H2A, with little or no Brg1. After hormone treatment, nucleosomes at both types of pre-programmed GR-enhancer shift apart, coinciding with increased levels of Brg1, and continue to exchange H2A.Z and H2A. Hormone removal rapidly reverses these nucleosome shifts. In contrast, inactive GR-enhancers are nucleosomal, lack Brg1, do not exchange H2A.Z or H2A and do not respond to hormone. Thus, pre-programmed GR-enhancers are marked by a dynamic, mutable chromatin structure characterized by high levels of H2A.Z exchange. We propose that nucleosome-depleted GR-enhancers result from the binding of other transcription factors together with Brg1 to assist loading of GR after hormone treatment. At nucleosomal enhancers, GR binding may be directly facilitated by increased transient exposure of enhancer DNA associated with H2A.Z exchange.
2017-11-06 | GSE92505 | GEO
Project description: Not available
| S-EPMC5758879 | biostudies-literature
Project description:Glucocorticoid receptor (GR) is an essential transcription factor (TF), controlling metabolism, development and immune responses. SUMOylation regulates chromatin occupancy and target gene expression of GR in a locus-selective manner, but the mechanism of regulation has remained elusive. Here, we show using selective isolation of chromatin-associated proteins that the protein network around chromatin-bound GR is affected by SUMOylation, with several nuclear receptor coregulators and chromatin modifiers being more avidly associated with SUMOylation-deficient than SUMOylation competent GR. This difference is reflected in our chromatin accessibility and gene expression data, showing that the SUMOylation-deficient GR is more potent in opening chromatin at glucocorticoid-regulated enhancers and inducing expression of their target loci. Our results thus show that SUMOylation determines GR specificity by regulating the chromatin protein network and accessibility at GR-driven enhancers. We speculate that a similar mechanism is utilized by many other SUMOylated TFs.
2021-09-08 | PXD015183 | Pride
Project description:The glucocorticoid receptor (GR) regulates transcription through binding to specific DNA motifs, particularly at enhancers. While the motif to which it binds is constant across cell types, GR has cell-type specific binding at genomic loci, resulting in expression of different genes. The presence of other bound transcription factors (TFs) is hypothesized to specify where GR binds. Here, we addressed the roles of other TFs in the glucocorticoid response by comparing changes in GR binding and nascent transcription at candidate cis-regulatory elements in two distinct cell types. We found that each cell type binds GR at thousands of non-overlapping loci, but only a small fraction of these sites also show changes in transcription. GR binding is associated with pioneer factor binding, whereas transcription is induced at sites bound by AP-1. These results support a model of transcriptional regulation in which multiple classes of TFs are required. The pioneer factors increase chromatin accessibility, facilitating the binding of GR and additional factors. AP-1 then poises a fraction of sites to be rapidly activated upon glucocorticoid-induced GR binding. GR also induces transcription at a specific set of enhancers. The coordinated activity of multiple TFs then results in cell-type specific changes in gene expression. We anticipate that many models of inducible gene expression also require multiple distinct TFs that act at multiple rate-limited steps of transcriptional regulation.
2021-06-01 | GSE168767 | GEO
Project description:The glucocorticoid receptor (GR) is a nuclear hormone receptor critical to the regulation of energy metabolism and the inflammatory response. The actions of GR are highly dependent on cell type and environmental context. Here, we demonstrate the necessity for liver lineage-determining factor hepatocyte nuclear factor 4A (HNF4A) in defining liver-specificity of GR action. In normal mouse liver, the HNF4 motif lies adjacent to the glucocorticoid response element (GRE) at GR binding sites found within regions of open chromatin. In the absence of HNF4A, the liver GR cistrome is remodelled, with both loss and gain of GR recruitment evident. Loss of chromatin accessibility at HNF4A-marked sites leads to loss of GR binding at weak GRE motifs. GR binding is gained at sites characterised by strong GRE motifs, which typically show GR recruitment in non-liver tissues. The functional importance of these HNF4A-regulated GR sites is further demonstrated by evidence of an altered transcriptional response to glucocorticoid treatment in the Hnf4a-null liver.
2022-01-20 | E-MTAB-10266 | biostudies-arrayexpress
Project description:Precise nucleosome positioning is an increasingly recognized feature of promoters and enhancers, reflecting complex contributions of DNA sequence, nucleosome positioning, histone modification and transcription factor binding to enhancer activity and regulation of gene expression. Changes in nucleosome position and occupancy, histone variants and modifications, and chromatin remodeling are also critical elements of dynamic transcriptional regulation, but poorly understood at enhancers. We investigated glucocorticoid receptor-associated (GR) nucleosome dynamics at enhancers in acute lymphoblastic leukemia. For the first time, we demonstrate functionally distinct modes of nucleosome remodeling upon chromatin binding by GR, which we term central, non-central, phased, and minimal. Central and non-central remodeling reflect nucleosome eviction by GR and cofactors, respectively. Phased remodeling involves nucleosome repositioning and is associated with rapidly activated enhancers and induction of gene expression. Minimal remodeling sites initially have low levels of enhancerassociated histone modification, but the majority of these regions gain H3K4me2 or H3K27Ac to become de novo enhancers. Minimal remodeling regions are associated with gene ontologies specific to decreased B cell number and mTOR inhibition and may make unique contributions to glucocorticoid-induced leukemia cell death. Our findings form a novel framework for understanding the dynamic interplay between transcription factor binding, nucleosome remodeling, enhancer function, and gene expression in the leukemia response to glucocorticoids.
2015-10-01 | GSE71616 | GEO
Project description:Glucocorticoid receptor (GR) is a ligand-inducible transcription factor with an intricate role in cancer biology. Using an in silico designed GR activity signature we show that GR is a tumor suppressor across diverse primary cancers. In breast cancer, GR activity status determines luminal identity, and importantly, relates to patients’ outcomes. We illustrate that GR suppresses tumor growth, mediated through its engagement with the estrogen receptor-α (ER). This steroid hormone receptor cross-talk leads to redistribution of ERα on chromatin, ultimately leading to expression of ZBTB16 gene. We define ZBTB16 as a transcriptional repressor and a tumor suppressor in ER-positive breast cancer. Importantly, highly aggressive ER-positive breast cancer cells displaying absence of GR activity can be eradicated if GR-induced gene repression is mimicked by inhibitors of the epigenetic pathway. In line with this, epigenetic regulators are highly expressed upon GR activity loss, leading to vulnerability of aggressive breast cancer cells to clinically available epigenetic inhibitors. Our findings indicate that GR functions as a tumor suppressor by repositioning ER to specific sites on chromatin, modulating targetable pathways, which has important implications for patients’ prognosis and therapeutic interventions.
2023-10-02 | PXD039209 | Pride
Project description:The glucocorticoid receptor (GR) is a nuclear hormone receptor critical to the regulation of energy metabolism and the inflammatory response. The actions of GR have been shown to be highly dependent on context. Here, we demonstrate the necessity for liver lineage-determining factor hepatocyte nuclear factor 4A (HNF4A) in defining tissue-specificity of GR action. In normal liver, the HNF4 motif lies adjacent to the glucocorticoid response element (GRE) at GR binding sites found within regions of open chromatin. In the absence of HNF4A, the liver GR cistrome is remodelled, with both loss and gain of GR recruitment evident. Lost sites are characterised by HNF4 motifs and weak GRE motifs. Gained sites are characterised by strong GRE motifs, and typically show GR recruitment in non-liver tissues. These RNA-seq data demonstrate the functional importance of these HNF4A-regulated GR sites by showing evidence of an altered transcriptional response to glucocorticoid treatment in the Hnf4a-null liver. In Hnf6-null liver, a far more minor effect on the glucocorticoid response is observed.
2021-04-09 | E-MTAB-10247 | biostudies-arrayexpress
Project description:The Glucocorticoid Receptor (GR) alters transcriptional activity in response to hormones by interacting with chromatin at GR binding sites (GBSs) throughout the genome. Our work in human breast cancer cells identifies three classes of GBSs with distinct epigenetic characteristics and reveals that BRG1 interacts with GBSs prior to hormone exposure. The GBSs pre-occupied by BRG1 are more accessible and transcriptionally active than other GBSs. BRG1 is required for a proper and robust transcriptional hormone response and knockdown of BRG1 blocks recruitment of the pioneer factors FOXA1 and GATA3 to GBSs. Finally, GR interaction with FOXA1 and GATA3 binding sites was restricted to sites pre-bound by BRG1. These findings demonstrate that BRG1 establishes specialized chromatin environments that define multiple classes of GBS. This in turn predicts that GR and other transcriptional activators function via multiple distinct chromatin-based mechanisms to modulate the transcriptional response.
2018-05-22 | GSE112491 | GEO
Project description:The glucocorticoid receptor (GR) is a nuclear hormone receptor critical to the regulation of energy metabolism and the inflammatory response. The actions of GR have been shown to be highly dependent on context. Here, we performed GR ChIP-seq in mouse liver to demonstrate the necessity for liver lineage-determining factor hepatocyte nuclear factor 4A (HNF4A) in defining tissue-specificity of GR action. In normal liver, the HNF4 motif lies adjacent to the glucocorticoid response element (GRE) at GR binding sites found within regions of open chromatin. In the absence of HNF4A, the liver GR cistrome is remodelled, with both loss and gain of GR recruitment evident. Lost sites are characterised by HNF4 motifs and weak GRE motifs. Gained sites are characterised by strong GRE motifs, and typically show GR recruitment in non-liver tissues. The functional importance of these HNF4A-regulated GR sites is further demonstrated by evidence of an altered transcriptional response to glucocorticoid treatment in the Hnf4a-null liver.
2021-04-09 | E-MTAB-10224 | biostudies-arrayexpress