Mus musculus breed:C57BL/6
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA318630 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10012603.fastq.gz | Fastqsanger.gz | |||
| SRR10012604.fastq.gz | Fastqsanger.gz | |||
| SRR10012605.fastq.gz | Fastqsanger.gz | |||
| SRR10012606.fastq.gz | Fastqsanger.gz | |||
| SRR23683735.fastq.gz | Fastqsanger.gz |
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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.
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.
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Project description:Prior exposure to certain signals can fundamentally change the response of innate immune cells to other stimuli underpinning phenomena such as cellular memory, tissue type-specific reactions, cytokine storm or anergy/tolerance. Our understanding about the molecular details of such interactions especially at the level of chromatin accessibility and gene expression regulation is fragmented. In particular our knowledge about the molecular links between two fundamental signaling pathways, alternative macrophage polarization signals and TLR signaling pathway is rather limited and neither the epigenomic mechanisms at play nor the biological output is well understood. Here we combined systematic signaling, epigenomic and transcriptomic approaches to map and uncover that the activation of the IL-4-STAT6 signaling pathway results in enhanced LPS responsiveness of a large, but distinct set of genes in macrophages. This interaction, we termed extreme synergy, is brought about by IL-4 priming-induced STAT6-dependent epigenomic remodeling, which includes the expansion of the LPS-activated NFκB-p65 cistrome, increased chromatin accessibility, epigenomic activation and increased enhancer activity at the genomic loci of synergistically activated genes. The IL-4-induced EGR2 transcription factor is required to enable the LPS-induced de novo and enhanced NFκB-p65 binding and synergistic gene activation. As a consequence, the previously alternatively polarized macrophages produce secreted immune-modulatory factors, including CCL17, CCL22, CCL2, and EDN1, at an extremely high level in vitro and in vivo in a murine Th2-type airway inflammation and asthma model following LPS exposure. Our findings establish that the IL-4-STAT6-EGR2 signaling pathway-induced epigenetic reprogramming is responsible for the development of a defined, robust inflammatory hyperresponsiveness to TLR4 activation in alternatively polarized macrophages and likely contribute to pathologies.
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