Ligand-insensitive PPARγ controls progressive or reinforcing macrophage polarization as an epigenomic ratchet of transcriptional memory
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PROVIDER: PRJNA476688 | ENA |
REPOSITORIES: ENA
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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
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
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 | GSE115085 | GEO
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 | GSE115083 | GEO
Project description:Macrophages polarize into distinct phenotypes in response to complex environmental cues. We found that the nuclear receptor PPARγ drove robust phenotypic changes in macrophages upon repeated stimulation with interleukin (IL)-4. The functions of PPARγ on macrophage polarization in this setting were independent of ligand binding. Ligand-insensitive PPARγ bound DNA and recruited the coactivator P300 and the architectural protein RAD21. This established a permissive chromatin environment that conferred transcriptional memory by facilitating the binding of the transcriptional regulator STAT6 and RNA polymerase II, leading to robust production of enhancer and mRNAs upon IL-4 re-stimulation. Ligand-insensitive PPARγ binding controlled the expression of an extracellular matrix remodeling-related gene network in macrophages. Expression of these genes increased during muscle regeneration in a mouse model of injury, and this increase coincided with the detection of IL-4 and PPARγ in the affected tissue. Thus, a predominantly ligand-insensitive PPARγ:RXR cistrome regulates progressive and/or reinforcing macrophage polarization.
| S-EPMC6197058 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2018-06-20 | GSE115505 | GEO
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
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
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
Project description:Retinoid X receptor (RXR) is an obligate heterodimeric partner of several nuclear receptors (NRs), and as such a central component of NR signaling regulating the immune and metabolic phenotype of macrophages. Importantly, the binding motifs of RXR heterodimers are enriched in the tissue-selective open chromatin regions of resident macrophages, suggesting specific roles in subtype specification. Recent genome-wide studies revealed that RXR binds to thousands of sites in the genome, but the mechanistic details how the cistrome is established and serves ligand-induced transcriptional activity remained elusive. Here we show that IL-4-mediated macrophage plasticity results in a greatly extended RXR cistrome via the direct and indirect actions of the transcription factor STAT6. Activation of STAT6 leads to chromatin remodeling and RXR recruitment to de novo enhancers. In addition, STAT6 triggers a secondary transcription factor wave, including PPARγ. PPARγ appears to be indispensable for the development of RXR-bound de novo enhancers, whose activities can be modulated in a very restricted manner by the ligands of the PPARγ:RXR heterodimer. Collectively, these data reveal the mechanisms leading to the dynamic extension of the RXR cistrome, identify the lipid-sensing enhancer set of alternatively polarized macrophages and suggest a pervasive ligand-independent mechanism of action of the receptors.
2019-12-19 | GSE142249 | GEO