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The Stat3/GR interaction code: predictive value of direct/indirect DNA recruitment for transcription outcome

ABSTRACT: Transcription factor recruitment to genomic sites of action is primarily due to direct protein:DNA interactions. The subsequent recruitment of co-regulatory complexes leads to either transcriptional activation or repression. In contrast to this canonical scheme, some transcription factors such as the glucocorticoid receptor (GR) behave as transcriptional repressors when recruited to target genes through protein tethering. We have investigated the genome-wide prevalence of tethering between GR and Stat3 and found non-reciprocal interactions, namely that GR tethering to DNA-bound Stat3 results in transcriptional repression whereas Stat3 tethering to GR results in synergism. Further, other schemes of GR and Stat3 co-recruitment to regulatory modules result in transcriptional synergism, including neighbouring and composite binding sites. The results indicate extensive transcriptional interactions between Stat3 and GR; further, they provide a genome-wide assessment of transcriptional regulation by tethering and a molecular basis for integration of signals mediated by GR and Stats in health and disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE37235 | GEO | 2012/06/07

SECONDARY ACCESSION(S): PRJNA163115

REPOSITORIES: GEO

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The Stat3/GR interaction code: predictive value of direct/indirect DNA recruitment for transcription outcome

Project description:Transcription factor recruitment to genomic sites of action is primarily due to direct protein:DNA interactions. The subsequent recruitment of co-regulatory complexes leads to either transcriptional activation or repression. In contrast to this canonical scheme, some transcription factors such as the glucocorticoid receptor (GR) behave as transcriptional repressors when recruited to target genes through protein tethering. We have investigated the genome-wide prevalence of tethering between GR and Stat3 and found non-reciprocal interactions, namely that GR tethering to DNA-bound Stat3 results in transcriptional repression whereas Stat3 tethering to GR results in synergism. Further, other schemes of GR and Stat3 co-recruitment to regulatory modules result in transcriptional synergism, including neighbouring and composite binding sites. The results indicate extensive transcriptional interactions between Stat3 and GR; further, they provide a genome-wide assessment of transcriptional regulation by tethering and a molecular basis for integration of signals mediated by GR and Stats in health and disease. ChIP-seq analysis of Stat3 and GR binding sites in pituitary corticotroph AtT-20 cell model. Five independant ChIPs were pooled prior library preparation for each contitions: STAT3 (LIF), STAT3 (Dex+LIF), GR (Dex+LIF), GR (Dex) and control IgG.

2012-06-06 | E-GEOD-37235 | biostudies-arrayexpress

ChIP-MS of GR and GR-DZn in mouse embryonic fibroblasts

Project description:The Glucocorticoid Receptor (GR) is both one of the most widely used clinical drug targets and a very potent metabolic regulator. GR belongs to the nuclear hormone receptor family of ligand-gated transcription factors that govern mammalian physiology. Upon ligand binding, GR enters the nucleus to regulate gene expression both positively and negatively. It is known to bind to consensus DNA sequences termed glucocorticoid response elements (GREs), but the mechanisms determining transcriptional activation versus repression remain an unresolved molecular paradox. Prevailing models suggest that tethering of GR to AP-1 or NF-κB via protein-protein interactions, rather than direct DNA binding, specifies negative regulation. However, here we show that the repression of inflammatory genes as well as all other glucocorticoid responses, require direct DNA binding of GR. Generating GR point mutant mice that retain the ability to tether via protein-protein interactions while unable to recognize DNA sequences, we demonstrate that response element recognition via the Zinc finger is absolutely required for both transcriptional activation and repression. We have used ChIP-Seq and RNA-Seq in inflammatory and metabolic cells and tissues together with proteomics to reveal that DNA binding of GR is necessary for the assembly of a functional SWI/SNF coregulator complex. Generally, the desired anti-inflammatory actions of GR are attributed to the silencing of inflammatory genes, while its adverse effects are believed to result from the transcriptional upregulation of metabolic targets. Our findings not only challenge classical models and dogmas of GR mediated gene regulation, but will provide an important basis for the development of novel immunosuppressants with reduced side effect profiles.

2020-07-07 | PXD013772 | Pride

Gene-specific mechanisms dictate glucocorticoid receptor-mediated repression of inflammatory response genes in macrophages [RNA-seq]

Project description:The Glucocorticoid Receptor (GR) potently represses macrophage-elicited inflammation, however, the underlying mechanisms remain obscure. Our genome-wide analysis reveals that pro-inflammatory paused genes, activated via global negative elongation factor (NELF) dissociation and RNA Polymerase (Pol)2 release from early elongation arrest, and non-paused genes, induced by de novo Pol2 recruitment, are equally susceptible to acute glucocorticoid repression. Moreover, in both cases the dominant mechanism involves rapid GR tethering to p65 at NF-kB binding sites. Yet, specifically at paused genes, GR activation triggers widespread promoter accumulation of NELF, with myeloid cell-specific NELF deletion conferring glucocorticoid resistance. Conversely, at non-paused genes, GR attenuates the recruitment of p300 and histone acetylation, leading to a failure to assemble BRD4 and Mediator at promoters and enhancers, ultimately blocking Pol2 initiation. Thus, GR displays no preference for a specific pro-inflammatory gene class, however, it effects repression by targeting distinct temporal events and components of transcriptional machinery

2018-02-28 | GSE110243 | GEO

Gene-specific mechanisms dictate glucocorticoid receptor-mediated repression of inflammatory response genes in macrophages [ChIP-seq]

2018-02-28 | GSE109131 | GEO

Inducible repositioning of mouse gene tethering to the inner nuclear membrane

Project description:Nuclear compartmentalization appears to play an important role in regulating metazoan genes. While studies on immunoglobulin (Ig) and other loci have correlated positioning at the nuclear lamina with gene repression, the functional consequences of this compartmentalization remain untested. We devised an approach for inducible tethering of genes to the inner nuclear membrane (INM) and demonstrate with 3D DNA-ImmunoFISH, repositioning of chromosomal regions to the nuclear lamina. Relocalization requires mitotic nuclear envelope breakdown and reformation. Tethering leads to the accumulation of lamin and INM proteins but not to association with pericentromeric heterochromatin or nuclear pore complexes. Recruitment of genes to the INM can result in their transcriptional repression. Using DamID we show that as is the case for our model system, inactive Ig loci at the nuclear periphery are contacted by INM and lamina components. We propose that such molecular interactions are used to compartmentalize and limit the accessibility of Ig loci. Experiment Overall Design: We used microarray to analyze the transcription status of genomic regions are inducibly tethered to the INM

2008-06-11 | E-GEOD-10176 | biostudies-arrayexpress

PAXIP1 and STAG2 converge to maintain 3D genome archi-tecture and facilitate promoter/enhancer contacts to enable stress hormone-dependent transcription

Project description:How steroid hormone receptors (SHRs) orchestrate transcriptional activity remains only partly understood. Upon activation, SHRs bind the genome and recruit their co-regulators, crucial to induce gene expression. However, it remains unknown which components of the SHR-recruited coregulator complex are essential to drive transcription following hormonal stimuli. Through a FACS-based genome-wide CRISPR screen, we comprehensively dissected the Glucocorticoid Receptor (GR) co-regulatory complex involved in gene-target regulation. We describe a novel functional cross-talk between PAXIP1 and the cohesin subunit STAG2 that is critical for regulation of gene expression by GR. Without altering the GR cistrome, PAXIP1 and STAG2 depletion alter the GR transcriptome, by impairing the recruitment of 3D-genome organization proteins to the GR complex. Importantly, we demonstrate that PAXIP1 is required for stability of cohesin on the genome, its localization to GR-occupied sites, and maintenance of enhancer-promoter interactions. Moreover, in lung cancer, where GR acts as tumor suppressor, PAXIP1/STAG2 loss enhances GR-mediated tumor suppressor activity by modifying local chromatin interactions. All together, we introduce PAXIP1 and STAG2 as novel co-regulators of GR, required to maintain 3D-genome architecture and drive the GR transcriptional programme following hormonal stimuli.

2023-10-24 | PXD038902 | Pride

Inducible repositioning of genes to the inner nuclear membrane

2008-01-16 | GSE10176 | GEO

Comparison of gene expression profiles for hormone induction in the presence and absence of AP1 binding.

Project description:Gene expression array analysis component. Ligand-dependent transcription by the nuclear receptor glucocorticoid receptor (GR) is mediated by interactions with co-regulators. The role of these interactions in determining selective binding of GR to regulatory elements remains unclear. Recent findings indicate a large fraction of genomic GR binding coincides with chromatin that is accessible prior to hormone treatment, suggesting that receptor binding is dictated by proteins that maintain chromatin in an open state. Combining nucleolytic cleavage and chromatin immunoprecipitation with high-throughput sequencing, we identify the activator protein 1 (AP1) as a major partner for productive GR-chromatin interactions. AP1 is critical for GR-regulated transcription and recruitment to co-occupied regulatory elements, illustrating an extensive AP1-GR interaction network. Importantly, the maintenance of baseline chromatin accessibility facilitates GR recruitment and is dependent on AP1 binding. We propose a model where the basal occupancy of transcription factors act to prime chromatin and direct inducible transcription factors to select regions in the genome.

2011-06-30 | GSE29983 | GEO

Ep300 sequestration to functionally distinct glucocorticoid receptor binding loci underlie rapid gene activation and repression

Project description:The rapid transcriptional response to the transcription factor, glucocorticoid receptor (GR), including gene activation or repression, is mediated by the spatial association of genes with multiple GR binding sites (GBSs) over large genomic distances. However, only a minority of the GBSs have independent GR-mediated activating capacity, and GBSs with independent repressive activity were rarely reported. To understand the positive and negative effects of GR we mapped the regulatory environment of its gene targets. We show that the chromatin interaction networks of GR-activated and repressed genes are spatially separated and vary in the features and configuration of their GBS and other non-GBS regulatory elements. The convergence of the KLF4 pathway in GR-activated domains and the STAT6 pathway in GR-repressed domains, impose opposite transcriptional effects to GR, independent of hormone application. Moreover, the ROR and Rev-erb transcription factors serve as positive and negative regulators, respectively, of GR-mediated gene activation. We found that the spatial crosstalk between GBSs and non-GBSs provides a physical platform for sequestering the Ep300 co-activator from non-GR regulatory loci in both GR-activated and -repressed gene compartments. While this allows rapid gene repression, Ep300 recruitment to GBSs is productive specifically in the activated compartments, thus providing the basis for gene induction.

2020-10-31 | GSE106209 | GEO

Comparison of gene expression profiles for hormone induction in the presence and absence of AP1 binding.

2011-06-30 | E-GEOD-29983 | biostudies-arrayexpress

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