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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:The 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.Here, 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.Our 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

LKB1 orchestrates dendritic cell metabolic quiescence and anti-tumor immunity

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

| PRJNA527815 | ENA

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

Gene expression in WT and Stat6 KO intestinal stem cells

Project description:Purpose: To examine the expression profile of WT and Stat6 KO intestinal stem cells. Methods: We isolated Lgr5+ ISCs from the intestine tissue, and generated Stat6 KO ISCs through CRISPR/Cas9 approach. Results: Many genes are changed upon Stat6 KO cells. We pay special attention on Wnt/β-catenin signaling that is the most critical pathway in ISCs, and discovered Stat6 drove the expression of Wnt target genes. Conclusions: Stat6 crosstalks with Wnt signaling to drive ISC self-renewal.

2018-12-05 | GSE123353 | GEO

LKB1 orchestrates dendritic cell metabolic quiescence and anti-tumor immunity [HT_MG-430_PM]

Project description:LKB1 orchestrates dendritic cell metabolic quiescence and anti-tumor immunity [HT_MG-430_PM]

| PRJNA527819 | ENA

Activation of STAT6 by STING Is Critical for Antiviral Innate Immunity

Project description:Analysis of the transcriptional response of HEK293 or HEK293-STAT6 stable cell lines to poly(I:C) transfection. The hypothesis tested was that poly(I:C) transfection is capable of inducing the expression of STAT6-dependent antiviral genes. mRNA isolated from HEK293 or HEK293-STAT6 stable cell lines with control treatment or poly(I:C) transfection for 16 hours.

2011-11-21 | E-GEOD-26435 | biostudies-arrayexpress

Gene activation precedes DNA demethylation in response to infection in human dendritic cells

Project description:DNA methylation is considered to be a relatively stable epigenetic mark. Yet, a growing body of evidence indicates that DNA methylation levels can change rapidly, for example, in innate immune cells facing an infectious agent. Nevertheless, the causal relationship between changes in DNA methylation and gene expression during infection remains to be elucidated. Here, we generated time-course data on DNA methylation, gene expression, and chromatin accessibility patterns during infection of human dendritic cells with Mycobacterium tuberculosis. We found that the immune response to infection is accompanied by active demethylation of thousands of CpG sites overlapping distal enhancer elements. However, virtually all changes in gene expression in response to infection occur prior to detectable changes in DNA methylation, indicating that the observed losses in methylation are a downstream consequence of transcriptional activation. Footprinting analysis revealed that immune-related transcription factors (TF), such as NF-κB/Rel, are recruited to enhancer elements prior to the observed losses in methylation, suggesting that DNA demethylation is mediated by TF binding to cis-acting elements. Collectively, our results show that DNA demethylation is not necessarily required for the establishment of the core regulatory program engaged upon infection.

2018-07-03 | GSE116399 | GEO

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