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Chemical crosslinking mass spectrometry reveals the conformational landscape of the activation helix of PPARγ; a model for ligand-dependent antagonism

ABSTRACT: the project presents solution analysis of PPARγ H12 conformational mobility driven by pharmaceutically distinct compounds and sequence specific regulatory peptides by label-free quantitative cross-linking mass spectrometry. This study reveals a model of ligand-dependent antagonism of PPARγ by precisely characterizing H12 mobility as a function of ligand and peptide bound.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Jie Zheng

LAB HEAD: Pat Griffin

PROVIDER: PXD010222 | Pride | 2018-08-29

REPOSITORIES: Pride

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Dataset's files

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			Action	DRS
	1PPARGRXRA_LBD_023.HCD.FTMS.dat	Other
	1PPARGRXRA_LBD_023.raw	Raw
	1PPARGRXRA_LBD_023_NCOR13.HCD.FTMS.dat	Other
	1PPARGRXRA_LBD_023_NCOR13.raw	Raw
	1PPARGRXRA_LBD_023_SMRT2.HCD.FTMS.dat	Other

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Publications

Chemical Crosslinking Mass Spectrometry Reveals the Conformational Landscape of the Activation Helix of PPARγ; a Model for Ligand-Dependent Antagonism.

Zheng Jie J Corzo Cesar C Chang Mi Ra MR Shang Jinsai J Lam Vinh Q VQ Brust Richard R Blayo Anne-Laure AL Bruning John B JB Kamenecka Theodore M TM Kojetin Douglas J DJ Griffin Patrick R PR

Structure (London, England : 1993) 20180823 11

Peroxisome proliferator-activated receptors (PPARs) are pharmacological targets for the treatment of metabolic disorders. Previously, we demonstrated the anti-diabetic effects of SR1664, a PPARγ modulator lacking classical transcriptional agonism, despite its poor pharmacokinetic properties. Here, we report identification of the antagonist SR11023 as a potent insulin sensitizer with significant plasma exposure following oral administration. To determine the structural mechanism of ligand-depende ...[more]

PMID: 30146169

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Multi-tissue, selective PPARγ modulation of insulin sensitivity and metabolic pathways in obese rats

Project description:We characterized the insulin sensitivity and multi-tissue gene expression profiles of lean and insulin resistant, obese Zucker rats untreated or treated with one of four PPARγ ligands (pioglitazone, rosiglitazone, troglitazone, and AG035029). We analyzed the transcriptional profiles of adipose tissue, skeletal muscle, and liver from the rats and determined whether ligand insulin-sensitizing potency was related to ligand-induced alteration of functional pathways. Ligand treatments improved insulin sensitivity in obese rats, albeit to varying degrees. Male Zucker fatty (fa/fa) and lean (fa/+) rats (Charles River, Wilmington, MA) were received at 6 weeks of age. Fatty rats were weight-matched upon arrival and randomly divided into one of five experimental groups. The fatty rat groups varied by the type of chow they were fed - normal chow alone or with a PPARγ ligand admixture: normal chow (fatty control, FC), rosiglitazone-treated (Rosi), pioglitazone-treated (Pio), troglitazone-treated (Tro), or AG035029-treated (AG). Lean control (LC) rats were all fed normal chow. Rats groups were maintained on the diets for 21 days. Adipose tissue (epididymal), skeletal muscle (gastrocnemius), and liver were harvested from lean (LC) and insulin resistant, obese Zucker rats untreated (FC) or treated with one of four PPARγ ligands (pioglitazone [Pio], rosiglitazone [Rosi], troglitazone [Tro], and AG035029 [AG]).

2011-02-11 | E-GEOD-21329 | biostudies-arrayexpress

Definition of functionally and structurally distinct repressive states in the nuclear receptor PPARγ

Project description:The repressive states of nuclear receptors (i.e., apo or bound to antagonists or inverse agonists) are poorly defined, despite the fact that nuclear receptors are a major drug target. Most ligand bound structures of nuclear receptors, including peroxisome proliferator-activated receptor γ (PPARγ), are similar to the apo structure. Here we use NMR, accelerated molecular dynamics and hydrogen-deuterium exchange mass spectrometry to define the PPARγ structural ensemble. We find that the helix 3 charge clamp positioning varies widely in apo and is stabilized by efficacious ligand binding. We also reveal a previously undescribed mechanism for inverse agonism involving an omega loop to helix switch which induces disruption of a tripartite salt-bridge network. We demonstrate that ligand binding can induce multiple structurally distinct repressive states. One state recruits peptides from two different corepressors, while another recruits just one, providing structural evidence of ligand bias in a nuclear receptor.

2020-01-13 | PXD016401 | Pride

Ligand-insensitive PPARγ controls progressive or reinforcing macrophage polarization as an epigenomic ratchet of transcriptional memory [RNA-Seq2]

Project description:Macrophages change their phenotype in response to complex (reinforcing or opposing) environmental cues. The molecular components providing the epigenomic basis of progressive or reinforcing polarization are largely unknown. Here we show that the normally ligand-activated nuclear receptor, Peroxisome Proliferator-Activated Receptor gamma (PPARγ), is a predominantly ligand-insensitive, epigenomic driver of a robust phenotypic change in macrophages uniquely upon repeated/reinforcing IL-4 stimulation. Ligand-insensitive PPARγ recruits P300, RAD21 and establishes a permissive chromatin environment, conferring transcriptional memory by facilitating the binding of STAT6 and RNAPII leading to more robust eRNA production upon IL-4 restimulation. PPARγ-mediated transcriptional memory allows the progressive, functional transition of macrophages upon repeated cytokine exposure by controlling the expression of an extracellular matrix remodeling related gene network, also expressed in macrophages from a mouse model of muscle regeneration and show progressive upregulation during the course of regeneration after muscle injury, coinciding with the appearance of IL-4 and PPARγ. Collectively, in contrast to the current prevailing view, alternative polarization gives rise to a predominantly ligand-insensitive PPARγ:RXR cistrome, regulating progressive/reinforcing macrophage polarization.

2018-06-20 | GSE115504 | GEO

Ligand-insensitive PPARγ controls progressive or reinforcing macrophage polarization as an epigenomic ratchet of transcriptional memory [RNA-Seq]

2018-06-20 | GSE115502 | GEO

Ligand-insensitive PPARγ controls progressive or reinforcing macrophage polarization as an epigenomic ratchet of transcriptional memory [ATAC-seq]

2018-06-20 | GSE115085 | GEO

Ligand-insensitive PPARγ controls progressive or reinforcing macrophage polarization as an epigenomic ratchet of transcriptional memory [ChIP-seq]

2018-06-20 | GSE115083 | GEO

PPARγ lipodystrophy mutants reveal intermolecular interactions required for enhancer activation

Project description:The peroxisome proliferator-activated receptor γ (PPARγ) is the master regulator of adipocyte differentiation, and mutations that interfere with PPARγ function cause lipodystrophy. Structural studies indicate that PPARγ domains engage in several intra- and inter-moleuclar interactions; however, how these interactions modulate the ability of PPARγ to activate target genes in a cellular context is currently poorly understood. Here we analysed the transcriptional potential of R212Q and E379K two previously uncharacterised lipodystrophy-associated PPARγ mutants that are located in distinct PPARγ domains but are both predicted to affect intermolecular interactions. Using a combination of biochemical and genome-wide approaches we show that these mutations impair binding to an overlapping subset of enhancers that are less accessible and specifically require PPARγ for chromatin remodeling. Based on these findings we propose a model in which recruitment of PPARγ to chromatin is determined by several intermolecular interfaces. Furthermore, our data exemplify that relatively subtle molecular defects in transcription factors are sufficient to significantly affect enhancer binding and thereby transcriptional output.

2022-09-08 | PXD036589 | Pride

Multi-tissue, selective PPARγ modulation of insulin sensitivity and metabolic pathways in obese rats

2011-02-11 | GSE21329 | GEO

Histone H3K9 Methyltransferase G9a Represses PPARγ Expression and Adipogenesis [Affymetrix expression data]

Project description:PPARγ promotes adipogenesis while Wnt proteins inhibit adipogenesis. However, the mechanisms that control expression of these positive and negative master regulators of adipogenesis remain incompletely understood. By genome-wide histone methylation profiling in preadipocytes, we find that among gene loci encoding adipogenesis regulators, histone methyltransferase (HMT) G9a-mediated repressive epigenetic mark H3K9me2 is enriched on the entire PPARγ locus. H3K9me2 and G9a levels decrease during adipogenesis, which correlates inversely with induction of PPARγ. Removal of H3K9me2 by G9a deletion enhances chromatin opening and binding of adipogenic transcription factor C/EBP-beta to PPARγ promoter, which promotes PPARγ expression. Interestingly, G9a represses PPARγ expression in an HMT activity-dependent manner but facilitates Wnt10a expression independent of its enzymatic activity. Consistently, deletion of G9a or inhibiting G9a HMT activity promotes adipogenesis. Finally, deletion of G9a in mouse adipose tissues increases adipogenic gene expression and tissue weight. Thus, by inhibiting PPARγ expression and facilitating Wnt10a expression, G9a represses adipogenesis. Examination of gene expression changes in G9a KO brown preadipocytes

2013-02-01 | E-GEOD-41456 | biostudies-arrayexpress

Acute Genome-Wide Effects of Rosiglitazone on PPARγ Transcriptional Networks in Adipocytes

Project description:Here we report, for the first time, the acute effects of the synthetic PPARγ agonist rosiglitazone on the transcriptional network of PPARγ in adipocytes. Treatment with Rosiglitazone for 1 hour leads to acute transcriptional activation as well as repression of a number of genes as determined by genome-wide RNA polymerase II occupancy. Unlike what has been shown for many other nuclear receptors, agonist treatment does not lead to major changes in the occurrence of PPARγ binding sites. However, rosiglitazone promotes PPARγ occupancy at many preexisting sites, and this is paralleled by increased occupancy of the mediator subunit MED1. The increase in PPARγ and MED1 binding is correlated with an increase in transcription of nearby genes indicating that rosiglitazone, in addition to activating the receptor, also promotes its association with DNA, and that this is causally linked to recruitment of mediator and activation of genes. Notably, both Rosiglitazone-activated and -repressed genes are induced during adipogenesis. However, Rosiglitazone-activated genes are markedly more associated with PPARγ than repressed genes and are highly dependent on PPARγ for expression in adipocytes. By contrast, repressed genes are associated with the other key adipocyte transcription factor CCAAT-Enhancer binding protein (C/EBPα), and their expression is more dependent on C/EBPα. This suggests that the relative occupancies of PPARγ and C/EBPα are critical for whether genes will be induced or repressed by PPARγ agonist. Examination of binding of PPARγ, C/EBPα, RNAPII, CBP and MED1 in mature 3T3-L1 adipocytes treated with 1 μM Rosiglitazone and/or 0.1% DMSO for 1 hour.

2013-08-01 | E-GEOD-49423 | biostudies-arrayexpress

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