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

ABSTRACT: Ligand-insensitive PPARγ controls progressive or reinforcing macrophage polarization as an epigenomic ratchet of transcriptional memory

PROVIDER: PRJNA476688 | ENA |

REPOSITORIES: ENA

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

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 | 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

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

2018-06-20 | GSE115504 | GEO

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

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

| PRJNA476691 | ENA

The Nuclear Receptor PPARγ Controls Progressive Macrophage Polarization as a Ligand-Insensitive Epigenomic Ratchet of Transcriptional Memory.

Project description: Not available

| S-EPMC6197058 | biostudies-literature

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

Project description:This SuperSeries is composed of the SubSeries listed below.

2018-06-20 | GSE115505 | GEO

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

Project description: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.

2018-08-29 | PXD010222 | Pride

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

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

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