The IL-4/STAT6/PPARγ signaling axis is driving the extension of the RXR heterodimer cistrome, providing complex ligand responsiveness in macrophages
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PROVIDER: PRJNA433822 | ENA |
REPOSITORIES: ENA
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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
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.
2018-01-01 | GSE107455 | GEO
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.
2018-01-01 | GSE107456 | GEO
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.
2018-02-12 | GSE110464 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2018-02-12 | GSE110465 | GEO
Project description:Macrophages are able to differentiate into classically polarized (M1) or alternatively polarized (M2) states upon encountering pro-inflammatory cytokines such as interferon (IFN) g or anti-inflammatory cytokines such as interleukin (IL) -4/IL-13, respectively. Moreover, macrophages are known to regulate lipid metabolism via multiple members of the nuclear hormone receptor family, including the retinoid X receptors (RXR). It has been also documented that cytokines are able to modulate macrophage responses to lipid signals but the nature of these interactions and the underlying mechanisms of these processes especially at the level of the chromatinized genome are not well understood. Previous work from our laboratory suggested that STAT6 is a facilitator of nuclear receptor mediated transcriptional activity acting at the genome level. This prompted us to investigate genome-wide DNA binding events and the development of cistromes in human CD14+ monocyte-derived macrophages upon exposure to IL-4. We determined the impact of IL-4 on the PU.1, RXR and STAT6 cistromes within the active enhancer regions marked by H3K27-acetylation using chromatin immunoprecipitation followed by deep sequencing and integrated bioinformatics analyses. We found that about 2/3rd of the IL-4 induced STAT6 peaks co-localized with RXR peaks. These STAT6/RXR co-peaks differed at least in part from the non-overlapping RXR peaks regarding the most enriched de novo transcription factor binding motifs. Interestingly, RXR-binding was not regulated at the STAT6/RXR co-bound enhancers following IL-4 stimulation, but differential enhancer interactions were observed between the IL-4/STAT6 and RXR signaling pathways acting in a gene selective manner. Our results suggest that there is a novel, so far uncharacterized cistromic crosstalk between RXR and STAT6 that is likely to contribute to the formation of the active enhancer repertoire, transcriptome and differential signal-specific gene regulation of polarized macrophages.
2017-07-07 | GSE100889 | GEO
Project description:To provide structural insights into the mechanism of the specific association of the coactivator MED1 with the Vitamin D nuclear (VDR)-RXR heterodimer, we used combined structural methods including X-ray crystallography, small angle X-ray scattering (SAXS), NMR, hydrogen-deuterium exchange coupled to mass spectrometry (HDX-MS), crosslinking mass spectrometry as well as biophysical methods.
2021-02-10 | PXD019530 | Pride
Project description:Retinoic Acid Receptors (RARs) as a functional heterodimer with Retinoid X Receptors (RXRs), bind a diverse series of RA-response elements (RAREs) in regulated genes. Among them, the non-canonical DR0 elements are bound by RXR-RAR with comparable affinities to DR5 elements but DR0 elements do not act transcriptionally as independent RAREs. In this work, we present structural insight for the recognition of DR5 and DR0 elements by RXR-RAR heterodimer using x-ray crystallography, small angle x-ray scattering, and hydrogen/deuterium exchange coupled to mass spectrometry. We solved the crystal structure of RXR-RAR DNA-binding domain in complex with the Rarb2 DR5 and RXR DNA-binding domain in complex with Hoxb13 DR0. While cooperative binding was observed on DR5, on DR0 the two molecules bound non-cooperatively on opposite sides of the DNA. In addition, our data unveil the structural organization and dynamics of the multi-domain RXR-RAR DNA complexes providing evidence for DNA-dependent allosteric communication between domains. Differential binding mode between DR0 and DR5 were observed leading to differences in the conformation and structural dynamics of the multi-domain RXR-RAR DNA complex. These results reveal that the topological organization of the RAR binding element confer regulatory information by modulating the overall topology and structural dynamics of the RXR-RAR heterodimers.
2021-02-10 | PXD018172 | Pride
Project description:Genome-wide profiling of PPARγ:RXR and RNA polymerase II reveals temporal activation of distinct metabolic pathways in RXR dimer composition during adipogenesis. Chromatin immunoprecipitation combined with deep sequencing was performed to generate genome-wide maps of peroxisome prolifelator-activated receptor gamma (PPARg) and retinoid X receptor (RXR) binding sites, and RNA polymerase II (RNAPII) occupancy at high resolution throughout adipocyte differentiation of 3T3-L1 cells. The data provides the first positional and temporal map PPARγ and RXR occupancy during adipocyte differentiation at a global scale. The number of PPARγ:RXR shared binding sites is steadily increasing from D0 to D6. At Day6 there are over 5000 high confidence shared PPARy:RXR binding sites. We show that at the early days of differentiation several of these sites bind not only PPARγ:RXR but also other RXR dimers. The data also provides a comprehensive temporal map of RNAPII occupancy at genes throughout 3T3-L1 adipogenesis thereby uncovering groups of similarly regulated genes belonging to glucose and lipid metabolic pathways. The majority of the upregulated but very few downregulated genes have assigned PPARγ:RXR target sites, thereby underscoring the importance of PPARγ:RXR in gene activation during adipogenesis and indicating that a hitherto unrecognized high number of adipocyte genes are directly activated by PPARγ:RXR
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Project description:Characterization of the interaction between the full nuclear receptor VDR-RXR heterodimer and VDR antagonist ZK168281
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