Downregulation of Uhrf1 activity by TGF-β signaling controls Foxp3 methylation and iTreg cell differentiation
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ABSTRACT:
PROVIDER: PRJNA527822 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8745433_1.fastq.gz | Fastqsanger.gz | |||
| SRR8745433_2.fastq.gz | Fastqsanger.gz | |||
| SRR8745434_1.fastq.gz | Fastqsanger.gz | |||
| SRR8745434_2.fastq.gz | Fastqsanger.gz | |||
| SRR8772212_1.fastq.gz | Fastqsanger.gz |
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Project description:Foxp3+ regulatory T cells (Treg cells) are essential for immune system homeostasis and suppression of excessive immune responses. Both TGF-β signaling and epigenetic modifications are important in the regulation of Foxp3 induction, but whether TGF-β signaling participates in the epigenetic regulation of Foxp3 has not been fully clarified. Here, we show that Uhrf1, which is induced by TCR stimulation and regulated by TGF-β signaling, controls Foxp3 methylation and iTreg cell differentiation. T cell-specific ablation of Uhrf1 led to Treg-biased differentiation in naïve T cells, with DNA hypomethylation upon TCR stimulation, and these Foxp3+ T cells had suppressive function. Uhrf1 maintained Foxp3 DNA methylation by recruiting Dnmt1 during cell division upon TCR stimulation. TGF-β treatment led to passive demethylation of the Foxp3 promoter to initiate its expression. Mechanistically, Uhrf1 was phosphorylated upon TGF-β stimulation and largely sequestered in the cytoplasm. Phosphorylated Uhrf1 underwent proteasomal degradation through inhibition of Usp7-mediated deubiquitination. Collectively, our study reveals a novel epigenetic mechanism of TGF-β-mediated iTreg cell differentiation regulated by Uhrf1 and reveals the differential role of active and passive demethylation in Foxp3 induction and stability.
2019-09-08 | GSE128480 | GEO
Project description:Although the master transcription factors (TFs) are the key to the development of specific T cell subsets, whether additional transcriptional regulators are induced by the same stimuli that dominantly repress development of other T cell lineages has not been fully elucidated. Using Transforming growth factor-b (TGF-b) induced regulatory T cell (iTreg) system, we identify the TF Musculin (MSC) as critical for iTreg development by repression of TH2 transcriptional program. Loss of MSC reduces Foxp3 expression and induces TH2 differentiation even under TGF-b induced iTreg differentiation conditions. MSC mediates this effect by interrupting binding of GATA3 to TH2 locus and reducing intrachromosomal interactions within the Th2 locus. MSC-deficient iTregs are not able to suppress TH2 responses and the Msc–/– mice spontaneously develop gut and lung inflammation with age. Our data indicate that MSC enforces Foxp3 expression and promotes unidirectional induction of iTregs by repressing development of the TH2 developmental program.
2016-12-10 | GSE91075 | GEO
Project description:Induced Treg (iTreg) cells are essential for tolerance and can be used therapeutically, yet their stability in vivo and mechanisms of suppression are unresolved. Here, we used a treatment model of colitis to examine the role of autologous IL-10 in iTreg cell function. Mice treated with IL-10+/+ iTreg cells in combination with IL-10–/– natural Treg (nTreg) cells survived and gained weight, even though iTreg cells were numerically disadvantaged and comprised just ~20% of all Treg cells in treated mice. Notably, ~85% of the transferred iTreg cells lost Foxp3 expression (ex-iTreg) but retained a portion of the iTreg transcriptome which failed to limit their pathogenic potential. The TCR repertoires of iTreg and ex-iTreg cells exhibited almost no overlap, which indicates that the two populations are clonally unrelated and maintained by different selective pressures. These data demonstrate a potent and critical role for iTreg cell produced IL-10 that can supplant the IL-10 produced by nTreg cells and compensate for the inherent instability of the iTreg population.
2012-12-06 | GSE35543 | GEO
Project description:iTreg cells from Tbmc mLN mice treated with one week of 1% Oral Ova were compared to Total Treg from WT mice. Tbmc mice were treated with 1% Oral Ova and Foxp3 GFP+ CD4+ cells were sorted from mLN. CD4+ Foxp3+ cells were also sorted from WT Foxp3 GFP Balb/c mice.
2012-08-30 | E-GEOD-40443 | biostudies-arrayexpress
Project description:Induced Treg (iTreg) cells are essential for tolerance and can be used therapeutically, yet their stability in vivo and mechanisms of suppression are unresolved. Here, we used a treatment model of colitis to examine the role of autologous IL-10 in iTreg cell function. Mice treated with IL-10+/+ iTreg cells in combination with IL-10–/– natural Treg (nTreg) cells survived and gained weight, even though iTreg cells were numerically disadvantaged and comprised just ~20% of all Treg cells in treated mice. Notably, ~85% of the transferred iTreg cells lost Foxp3 expression (ex-iTreg) but retained a portion of the iTreg transcriptome which failed to limit their pathogenic potential. The TCR repertoires of iTreg and ex-iTreg cells exhibited almost no overlap, which indicates that the two populations are clonally unrelated and maintained by different selective pressures. These data demonstrate a potent and critical role for iTreg cell produced IL-10 that can supplant the IL-10 produced by nTreg cells and compensate for the inherent instability of the iTreg population. BALB/c Rag1-/- mice were treated with 500,00 WT nTreg cells plus 500,000 WT in-vitro-derived iTreg cells. After 125 days cells were sorted by flow cytometry from spleens and mesenteric lymph nodes from 14 treated mice. EGFP+ Thy1.1+ iTreg cells, EGFP+ Thy1.1– nTreg cells, and EGFP–Thy1.1+ ex-iTreg cells were pooled and used to generate total RNA for each iTreg, nTreg, and ex-iTreg array set, which was labeled and hybridized to Affymetrix 430 2.0 GeneChips in accordance to the manufacturer’s protocol. Two sets of arrays were performed, and the results were averaged. Both iTreg and nTreg array sets were compared to a) naïve CD4+EGFP– Tconv cells from Foxp3EGFP. The subset of probe sets whose expression increased or decreased by twofold or more relative to Tconv cells as a common standard was identified and used for further analysis.
2012-12-06 | E-GEOD-35543 | biostudies-arrayexpress
Project description:Regulatory T cells (Tregs) expressing the transcription factor FOXP3 are crucial mediators of self-tolerance, preventing autoimmune diseases but possibly hampering tumor rejection. Clinical manipulation of Tregs is of great interest, and first- in-man trials of Treg transfer achieved promising outcomes. Yet, the mechanisms governing induced Treg (iTreg) differentiation and the regulation of FOXP3 are incompletely understood. To gain a comprehensive and unbiased molecular understanding of FOXP3 induction, we performed time-series RNA sequencing (RNA-Seq) and proteomics profiling on the same samples during human iTreg differentiation. To enable the broad analysis of universal FOXP3-inducing pathways, we used five differentiation protocols in parallel. Integrative analysis of the transcriptome and proteome confirmed involvement of specific molecular processes, as well as overlap of a novel iTreg subnetwork with known Treg regulators and autoimmunity-associated genes. Importantly, we propose 37 novel molecules putatively involved in iTreg differentiation. Their relevance was validated by: a targeted shRNA screen confirming a functional role in FOXP3 induction; discriminant analyses classifying iTregs accordingly; and comparable expression in an independent novel iTreg RNA-Seq data set. The data generated by this novel approach facilitate understanding the molecular mechanisms underlying iTreg generation as well as the concomitant changes in the transcriptome and proteome. Our results provide a reference map exploitable for future discovery of markers and drug candidates governing control of Tregs, which has important implications for the treatment of cancer, autoimmune and inflammatory diseases.
2018-04-06 | GSE94396 | GEO
Project description:Recent data have shown that Hypermethylated in cancer 1 (HIC1) is an important contributor to iTreg cell development and function. Using affinity-purification and tandem mass spectrometry we systematically characterized the HIC-1 interactome in human iTreg cells. On the basis of these data, we have shown that HIC1 is a part of FOXP3-RUNX1-CBFβ protein complex that regulates Treg signature genes and is indispensable for the suppressive function of FOXP3+ regulatory T cells. SRM was used to validate HIC1 interactors
2023-10-16 | PXD039337 | Pride
Project description:Dynamic Foxp3-chromatin interaction controls tunable Treg cell function [ATAC-seq iTreg]
| PRJNA629581 | ENA
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:The relative contribution of induced and natural Foxp3+ regulatory T cells (iTreg and nTreg cells, respectively) to the maintenance of tolerance is unknown. We examined their respective roles by in vivo adoptive transfer immunotherapy of newborn Foxp3-deficient BALB/c mice. Survival, weight gain, tissue infiltration, T cell activation, and the concentration of proinflammatory cytokines were used as outcome measurements. Treatment with iTreg cells alone was not successful. While effective in preventing death, treatment with nTreg cells alone was associated with chronic inflammation and autoimmunity. Outcomes markedly improved when conventional T (Tconv) cells were transferred together with the nTreg cells, where 10% of the peripheral Treg cell pool was derived by in-situ conversion. This enhancement depended upon the capacity of Tconv cells to express Foxp3. The gene expression profile of in vivo derived iTreg cells was similar to the established nTreg cell genetic signature. These results identify iTreg cells as an essential regulatory subset that supplements tolerance maintained by nTreg cells. Purified cells sorted by flow cytometry from 4-8 treated mice(pooled EGFP+ Thy1.1+ iTreg cells with that of EGFP+ Thy1.1+ nTreg cells sorted from the spleens and lymph nodes of treated mice) were used to generate total RNA for each iTreg and nTreg array set, which was labeled and hybridized to Affymetrix 430 2.0 GeneChips in accordance to the manufacturer’s protocol. Three sets of arrays were performed, and the results were averaged. Both iTreg and nTreg array sets were compared to a) naïve CD4+EGFP– Tconv cells from Foxp3EGFP mice and b) in vitro derived iTreg cells 72 hours after Foxp3 induction, generated earlier. The subset of probe sets whose expression increased or decreased by twofold or more relative to Tconv cells as a common standard was identified and used for further analysis. Naïve CD4+EGFP– Tconv cells from Foxp3EGFP mice and in vitro derived iTreg cells 72 hours after Foxp3 induction datasets obtained from GSE14415: Naïve CD4+EGFP– Tconv cells from Foxp3EGFP mice: GSM360171 - GSM360173 In vitro derived iTreg cells 72 hours after Foxp3 induction: GSM360147 - GSM360151
2011-06-30 | E-GEOD-19512 | biostudies-arrayexpress