Homo sapiens
Ontology highlight
ABSTRACT:
OTHER RELATED OMICS DATASETS IN: MODEL2101150001
PROVIDER: PRJNA117127 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:FOXP3-mediated inhibition of a global gene regulator is required for maintaining Treg cell commitment
| PRJNA117309 | ENA
Project description:Regulatory T (Treg) cells are involved in self tolerance, immune homeostasis, prevention of autoimmunity, and suppression of immunity to pathogens or tumours. The forkhead transcription factor FOXP3 is essential for Treg cell development and function as mutations in FOXP3 cause severe autoimmunity in mice and humans. However, the FOXP3-dependent molecular mechanisms leading to this severe phenotype are not well understood. Here we introduce the chromatin remodelling enzyme SATB1 (special AT-rich sequence-binding protein-1) as an important target gene of FOXP3. So far, SATB1 has been associated with normal thymic T-cell development, peripheral T-cell homeostasis, TH1/TH2 polarization, and reprogramming of gene expression. In natural and induced murine and human FOXP3+ Treg cells SATB1 expression is significantly reduced. While there is no differential epigenetic regulation of the SATB1 locus between Treg and Teffector cells, FOXP3 reduces SATB1 expression directly as a transcriptional repressor at the SATB1 locus and indirectly via miR-155 induction, which specifically binds to the 3’UTR of the SATB1 mRNA. Reduced SATB1 expression in FOXP3+ cells achieved either by overexpression or induction of FOXP3 is linked to significant reduction in TH1 and TH2 cytokines, while loss of FOXP3 function either by knock down or genetic mutation leads to significant upregulation of SATB1 and subsequent cytokine production. Alltogether, these findings demonstrate that reduced SATB1 expression in Treg cells is necessary for maintenance of a Treg-cell phenotype in vitro and in vivo and places SATB1-mediated T cell-specific modulation of global chromatin remodelling central during the decision process between effector and regulatory T-cell function. Gene expression profiling of freshly isolated CD4+ T cells, separated into CD25 negative and positive subpopulations, from three different donors. FOXP3 is stably and constitutively expressed at a high level in CD4+CD25+ regulatory T cells and at a low level in CD4+CD25- cells.
2011-08-13 | E-GEOD-15390 | biostudies-arrayexpress
Project description:Regulatory T (Treg) cells are involved in self tolerance, immune homeostasis, prevention of autoimmunity, and suppression of immunity to pathogens or tumours. The forkhead transcription factor FOXP3 is essential for Treg cell development and function as mutations in FOXP3 cause severe autoimmunity in mice and humans. However, the FOXP3-dependent molecular mechanisms leading to this severe phenotype are not well understood. Here we introduce the chromatin remodelling enzyme SATB1 (special AT-rich sequence-binding protein-1) as an important target gene of FOXP3. So far, SATB1 has been associated with normal thymic T-cell development, peripheral T-cell homeostasis, TH1/TH2 polarization, and reprogramming of gene expression. In natural and induced murine and human FOXP3+ Treg cells SATB1 expression is significantly reduced. While there is no differential epigenetic regulation of the SATB1 locus between Treg and Teffector cells, FOXP3 reduces SATB1 expression directly as a transcriptional repressor at the SATB1 locus and indirectly via miR-155 induction, which specifically binds to the 3’UTR of the SATB1 mRNA. Reduced SATB1 expression in FOXP3+ cells achieved either by overexpression or induction of FOXP3 is linked to significant reduction in TH1 and TH2 cytokines, while loss of FOXP3 function either by knock down or genetic mutation leads to significant upregulation of SATB1 and subsequent cytokine production. Alltogether, these findings demonstrate that reduced SATB1 expression in Treg cells is necessary for maintenance of a Treg-cell phenotype in vitro and in vivo and places SATB1-mediated T cell-specific modulation of global chromatin remodelling central during the decision process between effector and regulatory T-cell function.
2011-08-14 | GSE15390 | GEO
Project description:T-cell receptor (TCR) signaling by MHC class-I and -II induces thymocytes to acquire cytotoxic and helper fates via induction of Runx3 or ThPOK transcription factors, respectively. The mechanisms by which TCR signaling is translated into transcriptional programs for each cell fate remain elusive. We show that a genome organizer, Satb1, activates genes for lineage-specifying factors, including ThPOK and Runx3, in post-selection thymocytes. Indeed, Satb1-deficient thymocytes are partially redirected to inappropriate T lineages after MHC selection. Although Satb1 is dispensable for maintaining ThPOK in CD4+ T cells, it is necessary for restraining expression of the Treg factor FoxP3. Collectively, our findings demonstrate that Satb1 shapes the primary T-cell pool by initially directing lineage-specific transcriptional programs and subsequently balancing effector versus regulatory subsets via FoxP3 repression.
2017-01-19 | GSE77000 | GEO
Project description:Regulatory T-cell comittment is ensured by inhibition of the global gene regulator SATB1
| PRJNA117597 | ENA
Project description:Foxp3low inflammatory non-suppressive (INS)-regulatory T cells (Tregs) were discovered recently. Unlike conventional Tregs, they produce proinflammatory-cytokines, exhibit reduced suppressiveness, and promote rather than impair anti-tumor immunity. The role of mitochondria in Foxp3low INS-Treg formation in vivo is unclear. We showed that the Foxp3low INS-Treg equivalents in human tumors demonstrate attenuated expression of CRIF1, a vital mitochondrial regulator. Mice with CRIF1 deficiency in Tregs bore Foxp3low INS-Tregs with mitochondrial dysfunction. The -ketoglutarate-mTORC1 axis was enhanced in these cells. This promoted proinflammatory-cytokine expression by inducing EOMES and SATB1 expression. Moreover, chromatin openness of the regulatory regions of the Ifng and Il4 genes was increased, which facilitated EOMES/SATB1 binding. The increased -ketoglutarate-derived 2-hydroxyglutarate downregulated Foxp3 expression by methylating the Foxp3-gene regulatory regions. Furthermore, CRIF1-deficiency-induced Foxp3low INS-Tregs suppressed tumor growth in an IFN- dependent manner. Thus, CRIF1-mediated mitochondrial homeostasis is critical for inducing Foxp3low INS-Tregs that promote anti-tumor immunity.
2024-02-28 | GSE233901 | GEO
Project description:Foxp3low inflammatory non-suppressive (INS)-regulatory T cells (Tregs) were discovered recently. Unlike conventional Tregs, they produce proinflammatory-cytokines, exhibit reduced suppressiveness, and promote rather than impair anti-tumor immunity. The role of mitochondria in Foxp3low INS-Treg formation in vivo is unclear. We showed that the Foxp3low INS-Treg equivalents in human tumors demonstrate attenuated expression of CRIF1, a vital mitochondrial regulator. Mice with CRIF1 deficiency in Tregs bore Foxp3low INS-Tregs with mitochondrial dysfunction. The -ketoglutarate-mTORC1 axis was enhanced in these cells. This promoted proinflammatory-cytokine expression by inducing EOMES and SATB1 expression. Moreover, chromatin openness of the regulatory regions of the Ifng and Il4 genes was increased, which facilitated EOMES/SATB1 binding. The increased -ketoglutarate-derived 2-hydroxyglutarate downregulated Foxp3 expression by methylating the Foxp3-gene regulatory regions. Furthermore, CRIF1-deficiency-induced Foxp3low INS-Tregs suppressed tumor growth in an IFN- dependent manner. Thus, CRIF1-mediated mitochondrial homeostasis is critical for inducing Foxp3low INS-Tregs that promote anti-tumor immunity.
2024-02-28 | GSE233902 | GEO
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 FoxP3 and its candidate cofactors (Eos, Gata1, Helios, Irf4, Lef1, Satb1, Xbp1) on the expression of the Treg transcriptional signature, CD4+ conventional T cells (Tconv) activated with anti-CD3+CD28 beads were retrovirally transduced with cDNAs encoding FOXP3, candidate TFs, or a combination of FOXP3 and candidate TFs. After 3 days in culture, the transduced cells were sorted into Trizol, and RNA was purified, labeled and hybridized to Affymetrix arrays.
2012-08-23 | E-GEOD-40274 | biostudies-arrayexpress
Project description:SATB1 is a genetic master regulator in dopaminergic neurons. We try to identify the downstream regulated genes and pathways of SATB1 in human dopaminergic and CTX neurons. The RNA-Seq experiment was performed to investigate the role of the genetic master regulator SATB1 in human dopaminergic neurons in comparison to cortical neurons. We generated a human embryonic stem cell knockout clone for SATB1 and differentiated this clone into either dopaminergic or cortical neurons. Immature dopaminergic (day 30 of differentiation), mature dopaminergic (day 50 of differentiation) and mature cortical neurons (day 30 of differentiation) were subsequently subjected to RNA-Seq. We compared wild type and SATB1-KO neurons at the afore mentioned time points, to characterize the regulatory role of SATB1 in the different neuron subtypes.
2019-09-20 | E-MTAB-5965 | biostudies-arrayexpress
Project description:The Foxp3 transcription factor is a crucial determinant of both regulatory T (TREG) cell development and their functional maintenance. Appropriate modulation of tolerogenic immune responses therefore requires tight regulation of Foxp3 transcriptional output, and this involves both transcriptional and post-translational regulation. Here, we show that during T cell activation, phosphorylation of Foxp3 in TREG cells can be regulated by a TGFβ Activated Kinase 1 (TAK1)-Nemo Like Kinase (NLK) signaling pathway. NLK interacts with Foxp3 in TREG cells and directly phosphorylates Foxp3 on multiple serine residues. This phosphorylation results in stabilization of Foxp3 protein levels by preventing association with the STUB1 E3-ubiquitin protein ligase, resulting in both reduced ubiquitination and proteasome-mediated degradation. Conditional TREG cell NLK-knockout (NLKTREG) results in decreased TREG cell-mediated immunosuppression in vivo and NLK-deficient TREG cell animals develop more severe experimental autoimmune encephalomyelitis. Our data suggest a molecular mechanism, in which stimulation of TCR-mediated signaling can induce a TAK1-NLK pathway to sustain Foxp3 transcriptional activity through stabilization of protein levels, thereby maintaining TREG cell suppressive function. Pharmacological manipulation of this phosphorylation-ubiquitination axis may provide therapeutic opportunities for regulating TREG cell function, for example during cancer immunotherapy.
2019-09-02 | PXD011164 | Pride