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Genome Wide Association Study:GR@ACE Stage I

ABSTRACT: The Genome Research program at Fundacio ACE (GR@ACE, Barcelona, Spain), represents a new effort to study Alzheimer's Disease susceptibility. The GR@ACE study comprises 7,409 unrelated individuals. 4,120 AD cases were diagnosed at Fundació ACE Memory Clinic (Barcelona, Spain). 3,289 Controls were obtained from three collections (Fundació ACE, Barcelona; DNA National Biobank, Salamanca and HU Valme, Seville). Genotyping was carried out using the 815K Axiom Spain Biobank array (Affymetrix.) in the Spanish national center for genotyping (CEGEN, Santiago de Compostela, Spain). After genotyping, an extensive quality control was conducted, including re-sampling, gender match, stratification, relatedness, heterozygosity, differential missingness and HWD analyses.

PROVIDER: EGAS00001003424 | EGA |

REPOSITORIES: EGA

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GR and Klf15 regulate gene expression dynamics and integrate signals through feed forward circuitry

Project description:The glucocorticoid receptor (GR) regulates adaptive transcriptional programs that alter metabolism in response to stress. Network properties that allow GR to tune gene expression to match specific physiologic demands are poorly understood. We analyzed the transcriptional consequences of GR activation in murine lungs deficient for Klf15, a transcriptional regulator of amino acid metabolism that is induced by glucocorticoids and fasting

2013-05-13 | GSE44695 | GEO

GR and Klf15 regulate gene expression dynamics and integrate signals through feed forward circuitry

2013-05-13 | E-GEOD-44695 | 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

LSD1/GR crosstalk

Project description:LSD1/GR crosstalk

| PRJNA961742 | ENA

In vitro phosphorylated GR LBD LC-MSMS

Project description:Glucocorticoid receptor (GR) is a ligand dependent transcription factor that plays a central role in inflammation. Part of a complex cellular network, GR activity is further modulated via protein–protein interactions . The regulation of GR by 14-3-3 proteins has been previously reported, though with differing sites of phosphorylation identified and variable consequences assigned. Hence, we sought to examine this protein–protein interaction and, using phosphorylated GR peptides, biophysical studies and X-ray crystallography, we identified key residues within the ligand binding domain of GR, T524 and S617, whose phosphorylation results in recognition by 14-3-3. Investigation of the kinases responsible for phosphorylation of these sites assigned a key role for MINK1 and cell-based approaches confirmed the importance of these two GR phosphosites and MINK1 in GR–14-3-3 binding. Together our results provide a molecular-level insight into 14-3-3 regulation of GR and highlight both MINK1 and the GR–14-3-3 axis as potential targets for future therapeutic intervention.

2021-09-09 | PXD022364 | Pride

Microarray analysis of rat hepatic gene expression identifies new genes associated with postprandial triglyceridemia

Project description:The acute response four hours after a fat load of extra virgin olive oil was investigated using DNA microarrays. Hepatic gene expression was analysed in Wistar Rats. Male rats, weighing 250- 300 g (purchased from Charles River, Barcelona, Spain), were used for experiments. Rats, housed in sterile filter-top cages (3-4 per cage), were acclimatized in a room maintained at 20ºC with a 12-h light-dark cycle for 10 days, allowed ad libitum access to water and standard chow diet (Pascual S.A., Barcelona, Spain), and fasted for 18 h before experiments. Two study groups were established: a) The control group did not receive any fat meal. The other group was fed 5 ml of olive oil (Aceites Toledo, Spain) as a bolus and sacrificed 4 hours after the feeding, respectively. This amount represents the use of a dose of 16 mL olive oil/ kg.

2010-08-28 | E-GEOD-17859 | biostudies-arrayexpress

Novel assays monitoring direct GR protein activity exhibit high predictive power for ligand activity on endogenous GR gene targets

Project description:Exogenous glucocorticoids are widely used in the clinic for the treatment of inflammatory disorders and auto-immune diseases. Unfortunately, their use is hampered by many side effects and therapy resistance. Efforts to find more selective glucocorticoid receptor (GR) agonists and modulators (called SEGRAMs), able to separate anti-inflammatory effects via gene suppression from metabolic effects via gene activation, have been unsuccessful so far. In this study, we characterized a set of functionally diverse GR ligands in A549 cells, first using a panel of luciferase-based reporter gene assays evaluating GR-driven gene activation and gene suppression. We expanded this minimal assay set with novel luciferase-based read-outs monitoring GR protein levels, GR dimerization and GR Serine 211 (Ser211) phosphorylation status and compared their outcomes with compound effects on the mRNA levels of known GR target genes in A549 cells and primary hepatocytes. We found that luciferase reporters evaluating GR-driven gene activation and gene repression were not always reliable predictors for effects on endogenous target genes. Remarkably, our novel assay monitoring GR Ser211 phosphorylation levels proved to be the most reliable predictor for compound effects on almost all tested endogenous GR targets, both driven by gene activation and repression. The integration of this novel assay in existing screening platforms may therefore increase chances to find novel GR ligands with an improved therapeutic benefit.

2022-04-10 | PXD031319 | Pride

ChIP-MS of GR and in mouse liver

Project description:The Glucocorticoid Receptor (GR) is a potent metabolic regulator and a major drug target. While GR was shown to play various important roles in circadian biology, its rhythmic genomic actions have never been studied. Here we mapped GR’s genome-wide chromatin occupancy in mouse livers throughout the day/night cycle. We show how GR partitions metabolic processes during fasting (cellular maintenance, gluconeogenesis) and feeding (lipid and amino acid metabolism) by time-dependent binding and target gene regulation. Highlighting the dominant role GR plays in synchronizing circadian pathways, we find that the majority of oscillating genes harbor GR binding sites and depend on GR for amplitude stability . Surprisingly, this rhythmic pattern is altered by exposure to high fat diet in a ligand-independent manner. We show how the remodeling of oscillatory gene expression and GR binding result from a concomitant increase with Stat5 co-occupancy in obese mice, and that loss of GR reduces circulating glucose and triglycerides differentially during feeding and fasting. Altogether, our findings highlight GR’s fundamental role in the rhythmic orchestration of hepatic metabolism.

2019-10-24 | PXD014030 | Pride

Identifying FOXA1-GR transcriptional targets in FOXA1-GR dependent NSCLC

Project description:Identifying FOXA1-GR transcriptional targets in FOXA1-GR dependent NSCLC

| PRJNA838217 | ENA

Translation deficits drive C9orf72 associated poly-GR/PR toxicity

Project description:Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) patients with the C9orf72 mutation show predominantly cytoplasmic aggregates of poly-GR and poly-PR proteins that are acutely toxic in various model systems. To identify the molecular mediators of neurotoxicity of poly-GR/PR, we analyzed their interactomes in primary neurons. GFP-(GR)149 and (PR)175-GFP preferentially interacted with RNA-binding proteins, including stress granule-associated and nucleolar proteins, as well as ribosomes. Overexpression of the poly-GR/PR interactors Staufen 1/2 (STAU1/2) and YBX1 led to cytoplasmic aggregation of poly-GR/PR into large stress granule-like inclusions, while the poly-GR/PR interactor nucleophosmin (NPM1) recruited poly-GR into the nucleolus. In addition, poly-PR expression reduced ribosome levels and translation, which is consistent with the widespread reduction of synaptic proteins detected by proteomics. Surprisingly, only GFP-(GR)53, but not GFP-(GR)149, localized to the nucleolus and reduced ribosome levels and translation in neurons, suggesting impaired ribosome biogenesis is driving the acute toxicity commonly observed in vitro. In C9orf72 patient brains, we detected co-aggregation of poly-GR/PR inclusions with ribosomes, but not stress granules. Partial sequestration of ribosomes may chronically impair protein synthesis and contribute to C9orf72 ALS/FTD pathogenesis.

2018-06-27 | PXD008691 | Pride

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