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IL-4 orchestrates STAT6-mediated DNA demethylation leading to dendritic cell differentiation

ABSTRACT: IL-4 orchestrates STAT6-mediated DNA demethylation leading to dendritic cell differentiation

PROVIDER: PRJNA305743 | ENA |

REPOSITORIES: ENA

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IL-4 orchestrates STAT6-mediated DNA demethylation leading to dendritic cell differentiation.

Project description:BackgroundThe role of cytokines in establishing specific transcriptional programmes in innate immune cells has long been recognized. However, little is known about how these extracellular factors instruct innate immune cell epigenomes to engage specific differentiation states. Human monocytes differentiate under inflammatory conditions into effector cells with non-redundant functions, such as dendritic cells and macrophages. In this context, interleukin 4 (IL-4) and granulocyte macrophage colony-stimulating factor (GM-CSF) drive dendritic cell differentiation, whereas GM-CSF alone leads to macrophage differentiation.ResultsHere, we investigate the role of IL-4 in directing functionally relevant dendritic-cell-specific DNA methylation changes. A comparison of DNA methylome dynamics during differentiation from human monocytes to dendritic cells and macrophages identified gene sets undergoing dendritic-cell-specific or macrophage-specific demethylation. Demethylation is TET2-dependent and is essential for acquiring proper dendritic cell and macrophage identity. Most importantly, activation of the JAK3-STAT6 pathway, downstream of IL-4, is required for the acquisition of the dendritic-cell-specific demethylation and expression signature, following STAT6 binding. A constitutively activated form of STAT6 is able to bypass IL-4 upstream signalling and instruct dendritic-cell-specific functional DNA methylation changes.ConclusionsOur study is the first description of a cytokine-mediated sequence of events leading to direct gene-specific demethylation in innate immune cell differentiation.

| S-EPMC4711003 | biostudies-literature

IL-4 orchestrates STAT6-mediated DNA demethylation leading to dendritic cell differentiation

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2015-12-12 | E-GEOD-75939 | biostudies-arrayexpress

IL-4 orchestrates STAT6-mediated DNA demethylation leading to dendritic cell differentiation

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

2015-12-12 | GSE75939 | GEO

Exosome mediated genetic reprogramming of tumor associated macrophages by exoASO-STAT6 leads to potent monotherapy anti-tumor activity

Project description:The M2 phenotype is controlled by key transcription factors such as STAT6. We describe an engineered exosome therapeutic candidate delivering an antisense oligonucleotide (ASO) targeting STAT6 (exoASO-STAT6), which preferentially silences STAT6 expression in tumor-associated macrophages (TAMs). We demonstrate that administration of exoASO-STAT6 reprograms TAMs to an M1 phenotype, leading to the induction of nitric oxide synthase 2 (NOS2) and remodeling of the TAMs.

2021-12-31 | GSE174068 | GEO

RNAseq of WT and Stat6 knockout Tfh21 and Tfh4 cells

Project description:We report that Stat6-driven gene transcription regulates the transition from Tfh21 to Tfh4 cells, suppressing IL-21 production and promoting IL-4 secretion. We identified a cis-enhancer in the second intron of Il21 as a regulator of Tfh cell cytokine transition, via an effect of Stat6 on chromatin accessibility with repression of Il21 transcription. We conclude that Stat6 is necessary for coordinated regulation of IL-21 and IL-4 production by Tfh cells, leading to appropriate maturation of the germinal center B cell response.

2025-03-04 | GSE198066 | GEO

Role of Stat6

Project description:Role of Stat6

| PRJNA813553 | ENA

LKB1 orchestrates dendritic cell metabolic quiescence and anti-tumor immunity

Project description:LKB1 orchestrates dendritic cell metabolic quiescence and anti-tumor immunity

| PRJNA527815 | ENA

ATACseq of WT and Stat6 knockout Tfh21, Tfh214, and Tfh4 cells

2025-03-04 | GSE198060 | GEO

Identification of novel STAT6-regulated proteins in mouse B cells by comparative transcriptome and proteome analysis

Project description:IL-4/STAT6-regulated transcriptome and proteome were compared in primary B cells isolated from wild-type and STAT6-deficient mice. B cells were purified from the spleen and stimulated in vitro with anti-CD40 and LPS or anti-IgM-F(ab)2 in the presence or absence of IL-4. Transcriptome analysis was performed with oligonucleotide microarrays. Global relative quantification of proteins was achieved by gel-enhanced label-free liquid chromatography/mass spectrometry (LC/MS). Hierarchical clustering and principal component analysis revealed that IL-4-induced changes of the transcriptome were almost completely dependent on STAT6. In contrast, the quantitative proteome analysis revealed that the expression of many IL-4-regulated proteins changes even in the absence of STAT6. The top 75 proteins with changes in abundance levels induced by IL-4 in a STAT6-dependent manner were also found to be regulated at the transcriptional level. Most of these proteins were not previously known to be regulated by STAT6 in B cells. We confirmed the MS-based quantitative proteome data by flow cytometric and Western blot analysis of selected proteins. This study provides a framework for further functional characterization of STAT6-regulated proteins in B cells that might be involved in germinal center formation and class switch recombination.

2017-03-06 | PXD005224 | Pride

STAT6 mutations compensate for CREBBP mutations and hyperactivate IL4/STAT6/RRAGD/mTOR signaling in Follicular Lymphoma

Project description:Activating mutations in STAT6 are common in Follicular Lymphoma (FL) and transformed FL and various other B cell lymphomas. Here, we report RNA-seq based gene expression data on normal human lymph node derived B lymphocytes (NBC; N = 6), and primary human FL WT (N = 11) or mutant (N = 4) for STAT6 before and after ex vivo stimulation with IL4. We found that STAT6 mutants result in broad based augmentation of IL4-induced gene expression. Unexpectedly, in FL with WT STAT6 we measured reduced baseline and IL4-induced gene expression levels when compared with NBC lymphocytes or FL with STAT6 mutations. We tracked the attenuated IL4/JAK/STAT6 response to co-existing CREBBP mutations and experimentally verified that intact CREBBP is required for the induction of many IL4-induced genes. One of the IL4-induced genes here identified is RRAGD, a small G-protein involved in lysosomal mTOR activation. We show that IL4 treatment induced RRAGD expression, that RRAGD is required for mTOR activation in lymphoma cells and that IL4-enhanced BCR signaling induced mTOR activation. The IL4 and BCR-induced mTOR activation was reduced by CREBBP mutants and augmented by mutant STAT6, establishing a link between STAT6 mutations and mTOR regulated pro-growth pathways in lymphoma.

2025-03-14 | GSE280295 | GEO

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