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Genome-wide occupancy of PPARG and RXRA after treatment with PPARG inverse agonist

ABSTRACT: We report our mechanistic investigation into the conformationally-driven activation bias of PPARG in muscle-invasive urothelial cancer (MIUC) and our efforts to pharmacologically reverse this activation bias through covalent PPARG inverse agonism. Studies into tumor-associated mutations in both PPARG and RXRA were integrated with structure-based drug design as well as insights from biochemical mechanistic studies to discover FX-909, a first-in-class clinical PPARG inverse agonist that robustly enforces a conformationally repressive state of PPARG, even in highly activated biological contexts. FX-909 is a potent, highly selective, and powerful suppressor of PPARG transcriptional activity through enhancement of PPARG-NCOR (Nuclear Co-Repressor) binding affinity. Treatment with FX-909 resulted in selective growth inhibition in PPARG-activated MIUC cell lines. Further, FX-909 achieved durable regressions in xenograft models of MIUC. FX-909 is the first chemical tool that is capable of recapitulating PPARG genetic knockout in vivo and is currently in clinical development for the treatment of intractable MIUC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE298628 | GEO | 2026/05/28

REPOSITORIES: GEO

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Global gene expression response to PPARG inhibition in three urothelial cancer cell lines

Project description:We report our mechanistic investigation into the conformationally-driven activation bias of PPARG in muscle-invasive urothelial cancer (MIUC) and our efforts to pharmacologically reverse this activation bias through covalent PPARG inverse agonism. Studies into tumor-associated mutations in both PPARG and RXRA were integrated with structure-based drug design as well as insights from biochemical mechanistic studies to discover FX-909, a first-in-class clinical PPARG inverse agonist that robustly enforces a conformationally repressive state of PPARG, even in highly activated biological contexts. FX-909 is a potent, highly selective, and powerful suppressor of PPARG transcriptional activity through enhancement of PPARG-NCOR (Nuclear Co-Repressor) binding affinity. Treatment with FX-909 resulted in selective growth inhibition in PPARG-activated MIUC cell lines. Further, FX-909 achieved durable regressions in xenograft models of MIUC. FX-909 is the first chemical tool that is capable of recapitulating PPARG genetic knockout in vivo and is currently in clinical development for the treatment of intractable MIUC.

2026-05-28 | GSE298581 | GEO

Effect of PPARG modulators on gene expression in HT-1197 cells.

Project description:To investigate gene expression changes in a bladder cancer cell line with RXRA p.S427F hotspot mutation after 24 hour treatment with PPARG agonist, rosiglitzone, and PPARG inverse-agonists; T0070907, SR10221, and BAY-4931

2022-12-01 | GSE210693 | GEO

ChIP-seq for PPARg, RXRa, and H3K27Ac in inflammation-associated unsaturated fatty acid-supplemented Th2 cells

Project description:A unique subpopulation of memory Th2 cells expressing the interleukin-33 receptor ST2 contributes to the pathogenesis of allergic diseases; however, the immune-metabolic mechanisms that induce ST2hi memory Th2 cells in inflamed tissues remain uncertain. We revealed that linoleic and oleic acids increased in the inflamed lungs induced ST2 expression through activating PPARg. Furthermore, this activation of PPARg was dependent on ATGL activity.

2025-10-24 | GSE255762 | GEO

PPARg regulated gene expression in human dendritic cells

2007-08-20 | GSE8658 | GEO

Placental PPARg-Regulated Genes

2012-07-10 | GSE39233 | GEO

PPARG interactions with UBR5 and MRE11-RAD50-NBS1 are required for DNA damage response and repair.

Project description:PPARG interactome datasets containing (1) Flag-PPARG AP-MS, identifying MRE11, RAD50 and NBS1 as novel interactors, (2) tandem-IP (in solution and silver fragments) of PPARG-Strep and Flag-NBS1, which identifies PPARG interaction with UBR5 (3) tandem-IP (same as 2) with BS3 cross-linking illustrates the binding interface between PPARG and NBS1. These mass spec data and other biochemical data demonstrate PPARG novel roles in promoting DNA damage response and repair, by activating the ATM pathway.

2018-12-18 | MSV000083257 | MassIVE

Placental PPARg-Regulated Genes

Project description:Robust identification of placental PPARg target genes via mutliple PPARg-dependence criteria. Integration of differential expression data from Pparg-null, Rxra-null, Med1-nul and Ncoa6-null placentas and from WT and Pparg-null Trophoblast stem cells (TSC) differentiated for 2 or 4 days in the presence or absence of the PPARg agonist Rosiglitazone (Rosi). [Placentas] Three pools of three WT placentas, each vs a litter-matched pool of three Pparg-null placentas Three pools of three WT placentas, each vs a litter-matched pool of three Rxra-null placentas Three pools of three WT placentas, each vs a litter-matched pool of three Med1-null placentas Three pools of three WT placentas, each vs a litter-matched pool of three Ncoa6-null placentas [Trophoblast stem cells (TSC)] Three independent WT TSC lines differentiated for two and four days in the presence or absence of Rosi vs two independent Pparg-null TSC lines differntiated for the same durations in the presence of Rosi

2012-07-09 | E-GEOD-39233 | biostudies-arrayexpress

Transcription profiling of human monocytes from patients with dominant negative mutations in PPARg and rosiglitazone treated cells to investigate PPARg regulated gene expression in human dendritic cells

Project description:In order to gain insights into how PPARg regulates different facets of dendritic cell (DC) differentiation, we sought to identify PPARg regulated genes and gene networks in monocyte-derived dendritic cells using global gene expression profiling. We employed an exogenous ligand activation approach using a selective PPARg ligand (rosiglitazone abbreviated as RSG). In addition, we have defined culture conditions in which human serum (HS) induces PPARg activation via a yet uncharacterized endogenous mechanism. We also compared the gene expression profile of developing dendritic cells obtained from patients harboring dominant negative mutations of the PPARg receptor (C114R and C131Y). Experiment Overall Design: Monocytes were cultured for 6, 24 hours or 5 days with 500 U/ml IL-4 and 800 U/ml GM-CSF; cytokine treatment was repeated at day 3. Cells were obtained from 12 healthy individuals (6 biological replicates; the 6 and 24 hours samples were obtained from a single individual but the 5 days samples from a different one). Ligands were added at the beginning of differentiation. The 6 and 24 hours cells were treated with vehicle (DC) or 1 uM rosiglitazone (DC RSG), in the case of 5 day cultured cells 2.5 uM RSG was used. Cells were cultured in RPMI plus 10% FBS, in the case of DC4-DC6 cells were also cultured in human AB serum (DC HS). Finally we also obtained cells from patients harboring point mutations of the PPARg receptor (C114R and C131Y)

2008-06-16 | E-GEOD-8658 | biostudies-arrayexpress

Inverse Agonists of the Androgen Receptor

Project description:Inverse Agonists of the Androgen Receptor

| PRJNA848752 | ENA

PPARg and IL-4-induced gene expression data from PPARg +/- LysCre and PPARg fl/- LysCre mouse bone marrow-derived macrophages

Project description:Conditional macrophage-specific PPARg knockout mice were generated on C57Bl/6 background by breeding PPARg fl/- (one allele is floxed, the other is null) and lysozyme Cre transgenic mice. PPARg and IL-4 signaling was analyzed on bone marrow-derived macrophages. Bone marrow of 3 mice per group was isolated and differentiated to macrophages with M-CSF (20 ng/ml). 20 ng/ml IL-4 was used to induce alternative macrophage activation and 1 uM Rosiglitazone (RSG) was used to activate PPARg. From each mouse 4 samples were generated: 1. M-CSF, 2. M-CSF+RSG, 3. IL-4 and 4. IL-4+RSG. All compounds were added throughout the whole differentiation process, and fresh media was added every other day. Control cells were treated with vehicle (DMSO:ethanol). After 10 days, RNA was isolated and gene expression profiles were analyzed using Mouse Genome 430 2.0 microarrays from Affymetrix. 3 PPARg +/- LysCre and 3 PPARg fl/- LysCre mice were used to isolate bone marrow and from each macrophages were differentiated with or without IL-4 and simultaneously treated with vehicle or RSG. Altogether we analyzed 24 samples with 3 biological replicates as below.

2010-11-18 | E-GEOD-25123 | biostudies-arrayexpress

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