Foxp3 imparts regulatory T cell epigenetic identity through a transcription factor relay
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA647187 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12264700_1.fastq.gz | Fastqsanger.gz | |||
| SRR12264700_2.fastq.gz | Fastqsanger.gz | |||
| SRR12264701_1.fastq.gz | Fastqsanger.gz | |||
| SRR12264701_2.fastq.gz | Fastqsanger.gz | |||
| SRR12264702_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 230 |
Similar Datasets
Project description:RNA-seq, ATAC-seq, and CUT&RUN analysis in Foxp3+ regulatory T cells, Foxp3- conventional CD4 T cells and Foxp3 reporter-null cells subdivided based on cell surface activation markers CD44 and CD62L
2020-11-12 | GSE154680 | GEO
Project description:Regulatory T cells 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 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. ATP was secreted by both T effector and regulatory T cells and was reduced by mitochondrial respiration inhibitors. Thus Foxp3 imparts a selective advantage in ATP generation capacity to the cell and may exploit this as a source of adenosine for functional immunomodulation. In order to explore possible mechanisms for these differences in metabolism we conducted a comparative 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 T cells and Foxp3 positive iTreg and Foxp3 negative activated CD4 T cells in addition to human peripheral blood natural Treg. Gene set enrichment analysis of our proteomic datasets demonstrated that Foxp3 drives a significant up regulation of several members of the mitochondrial electron transport chain.
2017-02-15 | PXD001789 | Pride
Project description:Foxp3+ regulatory T (Treg) cells restrict immune pathology in inflamed tissues; however, an inflammatory environment presents a threat to Treg cell identity and function. We here establish a transcriptional signature of central nervous system (CNS) Treg cells that accumulate during experimental autoimmune encephalitis (EAE) and identify a pathway that maintains Treg cell function and identity during severe inflammation. This pathway was dependent on the transcriptional regulator Blimp1, which prevented dismantling of Foxp3 expression and "toxic" gain-of-function of Treg cells in the inflamed CNS. Blimp1 negatively regulated IL-6- and STAT3-mediated methylation of Treg cell-specific conserved non-coding sequence 2 (CNS2) in the Foxp3 locus. Consequently, CNS2 was heavily methylated when Blimp1 was ablated, leading to loss of Foxp3 expression and severe disease. These findings identify a Blimp1-dependent epigenetic pathway that preserves Treg cell stability in inflamed non-lymphoid tissues.
2018-10-26 | GSE121764 | GEO
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.
2017-02-15 | PXD001906 | Pride
Project description:Regulatory CD4+ T cells (Tregs) are functionally distinct from conventional CD4+ T cells (Tconvs). To understand Treg identity, we compared by proteomics and transcriptomics human naïve (n) and effector (e)Tregs, Tconvs and transitional FOXP3+ cells. Only 12% of 422 differentially expressed proteins was identified as such at the mRNA level, demonstrating the importance of direct proteome measurement. Fifty-one proteins discriminated Tregs from Tconvs. This common Treg protein signature indicates altered signaling by TCR-, TNF receptor-, NFB-, PI3 kinase/mTOR-, NFAT- and STAT pathways, and unique cell biological and metabolic features. Another protein signature uniquely identified eTregs and revealed active cell division, apoptosis sensitivity and suppression of NFB- and STAT signaling. eTreg fate appears consolidated by FOXP3 outnumbering its partner transcription factors. These features explain why eTregs cannot produce inflammatory cytokines, whereas transitional FOXP3+ cells can. Collectively, our data reveal that Treg identity is defined and protected by uniquely “wired” signaling pathways.
2018-05-18 | PXD007745 | Pride
Project description:Regulatory CD4+ T cells (Tregs) are functionally distinct from conventional CD4+ T cells (Tconvs). To understand Treg identity, we compared by proteomics and transcriptomics human naïve (n) and effector (e)Tregs, Tconvs and transitional FOXP3+ cells. Only 12% of 422 differentially expressed proteins was identified as such at the mRNA level, demonstrating the importance of direct proteome measurement. Fifty-one proteins discriminated Tregs from Tconvs. This common Treg protein signature indicates altered signaling by TCR-, TNF receptor-, NFB-, PI3 kinase/mTOR-, NFAT- and STAT pathways, and unique cell biological and metabolic features. Another protein signature uniquely identified eTregs and revealed active cell division, apoptosis sensitivity and suppression of NFB- and STAT signaling. eTreg fate appears consolidated by FOXP3 outnumbering its partner transcription factors. These features explain why eTregs cannot produce inflammatory cytokines, whereas transitional FOXP3+ cells can. Collectively, our data reveal that Treg identity is defined and protected by uniquely “wired” signaling pathways.
2018-05-18 | PXD005477 | Pride
Project description:Regulatory CD4+ T cells (Tregs) are functionally distinct from conventional CD4+ T cells (Tconvs). To understand Treg identity, we compared by proteomics and transcriptomics human naïve (n) and effector (e)Tregs, Tconvs and transitional FOXP3+ cells. Only 12% of 422 differentially expressed proteins was identified as such at the mRNA level, demonstrating the importance of direct proteome measurement. Fifty-one proteins discriminated Tregs from Tconvs. This common Treg protein signature indicates altered signaling by TCR-, TNF receptor-, NFB-, PI3 kinase/mTOR-, NFAT- and STAT pathways, and unique cell biological and metabolic features. Another protein signature uniquely identified eTregs and revealed active cell division, apoptosis sensitivity and suppression of NFB- and STAT signaling. eTreg fate appears consolidated by FOXP3 outnumbering its partner transcription factors. These features explain why eTregs cannot produce inflammatory cytokines, whereas transitional FOXP3+ cells can. Collectively, our data reveal that Treg identity is defined and protected by uniquely “wired” signaling pathways. Associated GEO dataset is available at GSE90600.
2018-05-18 | PXD007744 | Pride
Project description:Regulatory T (Treg) cells, whose identity and function are defined by the transcription factor Foxp3, are indispensable for immune homeostasis. It is unclear whether Foxp3 exerts its Treg lineage specification function through active modification of the chromatin landscape and establishment of new enhancers or by exploiting a pre-existing enhancer landscape. Analysis of the chromatin accessibility of Foxp3-bound enhancers in Treg and Foxp3-negative T cells showed that Foxp3 was bound overwhelmingly to pre-accessible enhancers occupied by its cofactors in precursor cells or a structurally related predecessor. Furthermore, the bulk of Foxp3-bound Treg cell enhancers inaccessible in Foxp3- CD4+ cells became accessible upon T cell receptor activation prior to Foxp3 expression with only a small subset associated with several functionally important genes being exclusively Treg cell-specific. Thus, in a late cellular differentiation process Foxp3 defines Treg cell functionality in an “opportunistic” manner by largely exploiting the preformed enhancer network instead of establishing a new enhancer landscape. Array expression. Three cell types with 3-5 replicates each.
2012-09-28 | E-GEOD-40685 | biostudies-arrayexpress
Project description:Regulatory T cells (Tregs) are responsible for limiting autoimmunity and chronic inflammation. Foxp3 is a transcription factor that acts as a master regulator of Treg development and function. A serendipitous observation led to the realization that a well-characterized Foxp3gfp reporter mouse, which expresses an N-terminal GFP-Foxp3 fusion protein, is a hypomorph that causes profoundly accelerated autoimmune diabetes on a NOD background. Although natural Treg development and in vitro function is not significantly altered in Foxp3gfp NOD and C57BL/6 mice, Treg fitness function in inflammatory environments is perturbed and TGF?-induced Treg development reduced. Foxp3gfpis unable to interact with the histone acetyltransferase Tip60, the histone deacetylase HDAC7, and the Ikaros family zinc finger 4, Eos, which leads to reduced Foxp3 acetylation and enhanced K48-linked polyubiquitylation. Collectively this leads to an altered transcriptional landscape and reduced Foxp3-mediated gene repression, notably at the hallmark IL-2 promoter. Loss of controlled Foxp3-driven epigenetic modification leads to Treg insufficiency that causes autoimmunity in prone environments. 16 samples overall split between 2 genotypes (wild type and Foxp3 knock in) and two cell types (Tregs and Tconv)
2012-12-07 | E-GEOD-35164 | biostudies-arrayexpress
Project description:Regulatory T (Treg) cells, whose identity and function are defined by the transcription factor Foxp3, are indispensable for immune homeostasis. It is unclear whether Foxp3 exerts its Treg lineage specification function through active modification of the chromatin landscape and establishment of new enhancers or by exploiting a pre-existing enhancer landscape. Analysis of the chromatin accessibility of Foxp3-bound enhancers in Treg and Foxp3-negative T cells showed that Foxp3 was bound overwhelmingly to pre-accessible enhancers occupied by its cofactors in precursor cells or a structurally related predecessor. Furthermore, the bulk of Foxp3-bound Treg cell enhancers lacking in Foxp3- CD4+ cells became accessible upon T cell receptor activation prior to Foxp3 expression with only a small subset associated with several functionally important genes being exclusively Treg cell-specific. Thus, in a late cellular differentiation process Foxp3 defines Treg cell functionality in an “opportunistic” manner by largely exploiting the preformed enhancer network instead of establishing a new enhancer landscape. Four transcription factors (Foxp3, Ets1, Elf1, and Cbfb) were immunoprecipated while crosslinked to chromatin. These experiments were then combined with DNase-seq data (being uploaded separately as part of ENCODE project) to find that Foxp3 binds exclusively to open chromatin. Data was also leveraged from GSE40657 and GSE33653.
2012-09-28 | E-GEOD-40684 | biostudies-arrayexpress