Anti-inflammatory functions of the glucocorticoid receptor require DNA binding

Escoter-Torres, Laura; Greulich, Franziska; Quagliarini, Fabiana; Wierer, Michael; Uhlenhaut, N. Henriette

doi:10.1093/nar/gkaa565

Cited by 54 publications

(50 citation statements)

References 48 publications

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“…2a ). A similar effect has been observed on a recent report comparing GRwt and a DBD binding mutant in primary mouse embryonic fibroblast cells 25 . A closer inspection revealed that only 43 genes (out of 13,465) are differentially regulated (using a 0.6 log 2 FC and 0.001 FDR) between GRwt and GRmon backgrounds, with only 5 genes overlapping with hormone-dependent action.…”

Section: Resultssupporting

confidence: 88%

“…activities 25 . Given the complexity of potential mechanisms of action, a fully dissociated, independent transactivation vs transrepression model requires revision.…”

Section: Discussionmentioning

confidence: 99%

“…While the existence of tethering cannot be ruled out as a viable option for GR-NFκB antagonism 51 , 52 , alternative pathways were also reported, such as GR inhibiting p65 binding 9 , 53 , 54 . In fact, a recent report demonstrated that GR direct DNA binding is essential for both transcriptional activation and repression activities 25 . Given the complexity of potential mechanisms of action, a fully dissociated, independent transactivation vs transrepression model requires revision.…”

Section: Discussionmentioning

confidence: 99%

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Genome-wide binding potential and regulatory activity of the glucocorticoid receptor’s monomeric and dimeric forms

et al. 2021

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A widely regarded model for glucocorticoid receptor (GR) action postulates that dimeric binding to DNA regulates unfavorable metabolic pathways while monomeric receptor binding promotes repressive gene responses related to its anti-inflammatory effects. This model has been built upon the characterization of the GRdim mutant, reported to be incapable of DNA binding and dimerization. Although quantitative live-cell imaging data shows GRdim as mostly dimeric, genomic studies based on recovery of enriched half-site response elements suggest monomeric engagement on DNA. Here, we perform genome-wide studies on GRdim and a constitutively monomeric mutant. Our results show that impairing dimerization affects binding even to open chromatin. We also find that GRdim does not exclusively bind half-response elements. Our results do not support a physiological role for monomeric GR and are consistent with a common mode of receptor binding via higher order structures that drives both the activating and repressive actions of glucocorticoids.

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Section: Resultssupporting

confidence: 88%

“…activities 25 . Given the complexity of potential mechanisms of action, a fully dissociated, independent transactivation vs transrepression model requires revision.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Genome-wide binding potential and regulatory activity of the glucocorticoid receptor’s monomeric and dimeric forms

et al. 2021

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“…RIME (Rapid Immunoprecipitation Mass spectrometry of Endogenous proteins) with isobaric labelling has been successfully applied to identify protein interactions of estrogen receptor alpha and other TFs in breast cancer cells ( 81 , 82 ). Moreover, GR interactome has been recently investigated by ChIP coupled with MS (ChIP-MS) in mouse liver and mouse embryonic fibroblasts ( 83 ). Here, we utilized ChIP-SICAP ( 18 ), a novel proteomic methodology, to cast new light to the protein associations and chromatin function of GR, an important NR and drug target that has been widely studied for decades.…”

Section: Discussionmentioning

confidence: 99%

SUMOylation regulates the protein network and chromatin accessibility at glucocorticoid receptor-binding sites

Paakinaho

Lempiäinen

Sigismondo

et al. 2021

Nucleic Acids Research

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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 identify the protein network around chromatin-bound GR by using selective isolation of chromatin-associated proteins and show that the network is affected by receptor SUMOylation, with several nuclear receptor coregulators and chromatin modifiers preferring interaction with SUMOylation-deficient GR and proteins implicated in transcriptional repression preferring interaction with SUMOylation-competent GR. This difference is reflected in our chromatin binding, chromatin accessibility and gene expression data, showing that the SUMOylation-deficient GR is more potent in binding and opening chromatin at glucocorticoid-regulated enhancers and inducing expression of target loci. Blockage of SUMOylation by a SUMO-activating enzyme inhibitor (ML-792) phenocopied to a large extent the consequences of GR SUMOylation deficiency on chromatin binding and target gene expression. Our results thus show that SUMOylation modulates the specificity of GR by regulating its chromatin protein network and accessibility at GR-bound enhancers. We speculate that many other SUMOylated TFs utilize a similar regulatory mechanism.

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“…Following GR binding, gene activation -involving recruitment of coactivators and chromatin remodellers -occurs at sites of pre-established enhancer-promoter interactions, with the presence of GR increasing the frequency of productive interactions (8). In contrast, the mechanism by which GR downregulates gene expression remains an area of considerable debate, with evidence for protein-protein tethering, indirect mechanisms of action, and GR binding to negative or cryptic response elements presented (9)(10)(11)(12)(13)(14). Surprisingly for a transcription factor which is so widely expressed, GR action is remarkably context-specific.…”

Section: Introductionmentioning

confidence: 99%

HNF4A is required to specify glucocorticoid action in the liver

Hunter

Poolman²,

Kim³

et al. 2021

Preprint

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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. 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.

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Anti-inflammatory functions of the glucocorticoid receptor require DNA binding

Cited by 54 publications

References 48 publications

Genome-wide binding potential and regulatory activity of the glucocorticoid receptor’s monomeric and dimeric forms

Genome-wide binding potential and regulatory activity of the glucocorticoid receptor’s monomeric and dimeric forms

SUMOylation regulates the protein network and chromatin accessibility at glucocorticoid receptor-binding sites

HNF4A is required to specify glucocorticoid action in the liver

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