Next Generation Sequencing Facilitates Quantitative Analysis of Wild Type and poh1-/- splenic foxp3＋Treg cells
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ABSTRACT:
PROVIDER: PRJNA432725 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6667400_1.fastq.gz | Fastqsanger.gz | |||
| SRR6667400_2.fastq.gz | Fastqsanger.gz | |||
| SRR6667401_1.fastq.gz | Fastqsanger.gz | |||
| SRR6667401_2.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: The goals of this study are to compare the transcriptome profiling of Wild Type and poh1-/- splenic foxp3＋Treg cells Methods:Splenic CD4+Foxp3+ (YFP+) cells mRNA profiles of 2-week-old poh1+/+ Foxp3Cre+ wild type and poh1fl/fl Foxp3Cre+ mice were generated by deep sequencing, using Illumina HiSeq 2500. The sequence reads that passed quality filters were analyzed with edgeR. qRT–PCR validation was performed using SYBR Green assays Results:Using an optimized data analysis workflow, we mapped about 50 million sequence reads per sample to the mouse genome (build mm10). Among all genes expressed, 1067 genes were upregulated and1391 genes were downregulated in poh1−/− Foxp3+ Treg cells relative to their expression in POH1 +/+ Treg cells. The gene-expression altered in POH1-ablated cells adversely correlated with those expressed in Treg cells in TCR-dependent manner. The gene sets were downreglated in POH1-deficiency Treg cells encoding various cell-surface receptors and intracellular molecules involved in migration, suppressive function and signature of Treg cells. Conclusions:Gene expression in POH1-deficiency Treg cells was markedly diverse compared with that in POH1-sufficient Treg cells.
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Project description:Regulatory T cells (Treg) have been shown to adopt a catabolic metabolic programme with increased capacity for fatty acid oxidation fuelled oxidative phosphorylation (OXPHOS). The role of Foxp3 in this metabolic shift is poorly understood. Here we show that Foxp3 was sufficient to induce a significant increase in the spare respiratory capacity of the cell, the extra OXPHOS capacity available to a cell to meet increased demands on energy in response to work. Foxp3-expressing cells were enhanced in their ability to utilise palmitate for respiration and, in addition, the activity of electron transport complexes I, II and IV were enhanced following Foxp3 expression. Foxp3 also imparts a selective advantage in ATP generation capacity, one that might be exploited as a source of adenosine for functional immunomodulation. In order to explore possible mechanisms for these differences in metabolism we conducted a quantitative proteomics study to compare the contribution of TGFβ and the transcription factor Foxp3 to the Treg proteome. We used quantitative mass spectrometry to examine differences between proteomes of nuclear and cytoplasmic Foxp3-containing CD4+ T cells from various sources with Foxp3- activated CD4 T cells, as well as Treg from human peripheral blood. Gene set enrichment analysis of our proteomic datasets demonstrated that Foxp3 expression is associated with a significant up regulation of several members of the mitochondrial electron transport chain. Not only does Foxp3 influence genes directly concerned with immune function, but also with the energy generating functions of Treg.
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Project description:The transcription factor FoxP3 partakes dominantly in the specification and function of FoxP3+ CD4+ T regulatory cells (Tregs), but is neither strictly necessary nor sufficient to determine the characteristic Treg transcriptional signature. Computational network inference and experimental testing assessed the contribution of several other transcription factors (TFs). Enforced expression of Helios or Xbp1 elicited specific signatures, but Eos, Irf4, Satb1, Lef1 and Gata1 elicited exactly the same outcome, synergizing with FoxP3 to activate most of the Treg signature, including key TFs, and enhancing FoxP3 occupancy at its genomic targets. Conversely, the Treg signature was robust to inactivation of any single cofactor. A redundant genetic switch thus locks-in the Treg phenotype, a model which accounts for several aspects of Treg physiology, differentiation and stability. To study the impact of deficiency of candidate FoxP3 cofactors (Xbp1, Eos, Gata1) on the expression of the Treg transcriptional signature, gene expression profiles were generated from purified splenic CD4+CD25hi Tregs of these mutant or knockout mice and their wildtype littermates.
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Project description:These are the FastQ files used for the RNA-seq analysis of WT and Bach2-deficient splenic Foxp3+ Treg cells.
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Project description:These are the FastQ files used for scRNA-Seq analysis of WT and Bach2-deficient splenic Foxp3+ Treg cells
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Project description:Natural CD4+FOXP3+ regulatory T (Treg) cells constitute a unique T-cell lineage that plays a pivotal role in maintaining immune homeostasis and immune tolerance. Recent studies provide evidence for the heterogeneity and plasticity of the Treg cell lineage. However, the fate of human Treg cells after loss of FOXP3 expression and the underlying epigenetic mechanisms remain to be fully elucidated. Here, we compared gene expression profiles and histone methylation status on two histone H3 lysine residues (H3K4me3 and H3K27me3) of expanded FOXP3+ and corresponding FOXP3-losing Treg cells. DGE assay showed that human Treg cells down-regulated Treg signature genes, whereas up-regulated a set of Th lineages-associated genes, especially for Th2, such as GATA3, GFI1 and IL13, after in vitro expansion. Furthermore, we found that reprogramming of Treg cells was associated with histone modifications, as shown by decreased abundance of permissive H3K4me3 within down-regulated Treg signature genes, such as FOXP3, CTLA4 and LRRC32 loci, although with no significant changes in H3K27me3 modification. Thus, our results indicate that human Treg cells could convert into a Th-like cells upon in vitro expansion, displaying a gene expression signature dominated by Th2 lineage associated genes, and the histone methylation might contribute to such conversion. mRNA profiles of in-vitro-expanded FOXP3+ Treg and FOXP3-losing Treg cells generated by deep sequencing.
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Project description:Nuclear factor Foxp3 determines regulatory T (Treg) cell fate and function via mechanisms that remain unclear. Here we investigate the nature of Foxp3-mediated gene regulation in suppressing autoimmunity and antitumor immune response. Contrasting with previous models, we find that Foxp3-chromatin binding is regulated by Treg activation states, tumor microenvironment, and antigen and cytokine stimulations. Proteomics studies uncovered dynamic proteins within the Foxp3 proximity upon TCR or IL-2 receptor signaling in vitro, reflecting intricate interactions among Foxp3, signal transducers, and chromatin. Pharmacological inhibition and genetic knockdown experiments indicate that NFAT and AP-1 protein Batf are required for enhanced Foxp3-chromatin binding in activated Treg cells and tumor-infiltrating Treg cells to modulate target gene expression. Furthermore, mutations at Foxp3 DNA-binding domain destabilize Foxp3-chromatin association. These representative settings delineate context-dependent Foxp3-chromatin interaction, suggesting that Foxp3 associates with chromatin by hijacking DNA-binding proteins resulting from Treg activation or differentiation, which is stabilized by direct Foxp3-DNA binding, to dynamically regulate Treg cell function according to immunological contexts.
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