FOXP3-dependent repression of a chromatin remodellimg enzyme ensures regulatory T-cell commitment
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE16840 | GEO | 2018/12/31
REPOSITORIES: GEO
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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:Regulatory T (Treg) cells are characterized by the forkhead transcription factor FOXP3. Mutations in FOXP3 cause autoimmunity in mice and humans. Here, Treg cells as well as conventional T cells were isolated from B-CLL patients and analyzed by global gene expression analysis in order to identify biological differences in Treg cells of CLL patients.
2017-05-31 | GSE16990 | 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:STAT5 transcription factor activation downstream of the Interleukin-2 receptor (IL-2R) induces expression of Foxp3, a critical step in the differentiation of regulatory T (Treg) cells. Due to the pleiotropic outputs of IL-2R signaling, it is unclear whether STAT5 acts directly on the Foxp3 locus to promote its expression . Here, we report that IL-2 – STAT5 signaling converged on an enhancer (CNS4) during Foxp3 induction. CNS4 facilitated and sustained the IL-2 dependent CD25+Foxp3– precursor to Treg cell transition in the thymus. Its deficiency resulted in markedly impaired Treg cell generation in neonates, which was partially mitigated with age. While the thymic Treg cell paucity caused by CNS4 deficiency did not result in autoimmunity on its own, it exacerbated autoimmune manifestations caused by disruption of the Aire gene. Thus, CNS4 enhancer activity ensures robust Treg cell differentiation early in postnatal life and cooperatively with other tolerance mechanisms, minimizes autoimmunity.
2021-03-16 | GSE168942 | GEO
Project description:STAT5 activation downstream of the Interleukin-2 receptor (IL-2R) facilitates Foxp3 expression, which is required for the differentiation and function of regulatory T (Treg) cells. However, due to the pleiotropic roles of IL-2R signaling, it is unclear how STAT5 acts on the Foxp3 locus to promote Treg cell lineage commitment. Here, we report that IL-2–STAT5 signaling converges on an enhancer (CNS4) during early Foxp3 induction. CNS4 facilitates and sustains the IL-2–dependent CD25+Foxp3– precursor to Treg cell transition in the thymus. Its deficiency results in markedly impaired Treg cell generation in neonates, which is partially mitigated with age. While the thymic Treg cell paucity caused by CNS4 deficiency did not result in autoimmunity on its own, it exacerbated autoimmune manifestations caused by disruption of the Aire gene. Thus, CNS4 enhancer activity ensures robust Treg cell differentiation early in postnatal life and, cooperatively with other tolerance mechanisms, minimizes autoimmunity.
2021-03-16 | GSE164117 | GEO
Project description:STAT5 activation downstream of the Interleukin-2 receptor (IL-2R) facilitates Foxp3 expression, which is required for the differentiation and function of regulatory T (Treg) cells. However, due to the pleiotropic roles of IL-2R signaling, it is unclear how STAT5 acts on the Foxp3 locus to promote Treg cell lineage commitment. Here, we report that IL-2–STAT5 signaling converges on an enhancer (CNS4) during early Foxp3 induction. CNS4 facilitates and sustains the IL-2–dependent CD25+Foxp3– precursor to Treg cell transition in the thymus. Its deficiency results in markedly impaired Treg cell generation in neonates, which is partially mitigated with age. While the thymic Treg cell paucity caused by CNS4 deficiency did not result in autoimmunity on its own, it exacerbated autoimmune manifestations caused by disruption of the Aire gene. Thus, CNS4 enhancer activity ensures robust Treg cell differentiation early in postnatal life and, cooperatively with other tolerance mechanisms, minimizes autoimmunity.
2021-03-16 | GSE163760 | GEO
Project description:STAT5 transcription factor activation downstream of the Interleukin-2 receptor (IL-2R) induces expression of Foxp3, a critical step in the differentiation of regulatory T (Treg) cells. Due to the pleiotropic outputs of IL-2R signaling, it is unclear whether STAT5 acts directly on the Foxp3 locus to promote its expression . Here, we report that IL-2 – STAT5 signaling converged on an enhancer (CNS4) during Foxp3 induction. CNS4 facilitated and sustained the IL-2 dependent CD25+Foxp3– precursor to Treg cell transition in the thymus. Its deficiency resulted in markedly impaired Treg cell generation in neonates, which was partially mitigated with age. While the thymic Treg cell paucity caused by CNS4 deficiency did not result in autoimmunity on its own, it exacerbated autoimmune manifestations caused by disruption of the Aire gene. Thus, CNS4 enhancer activity ensures robust Treg cell differentiation early in postnatal life and cooperatively with other tolerance mechanisms, minimizes autoimmunity.
2021-03-17 | GSE169043 | GEO
Project description:STAT5 transcription factor activation downstream of the Interleukin-2 receptor (IL-2R) induces expression of Foxp3, a critical step in the differentiation of regulatory T (Treg) cells. Due to the pleiotropic outputs of IL-2R signaling, it is unclear whether STAT5 acts directly on the Foxp3 locus to promote its expression . Here, we report that IL-2 – STAT5 signaling converged on an enhancer (CNS4) during Foxp3 induction. CNS4 facilitated and sustained the IL-2 dependent CD25+Foxp3– precursor to Treg cell transition in the thymus. Its deficiency resulted in markedly impaired Treg cell generation in neonates, which was partially mitigated with age. While the thymic Treg cell paucity caused by CNS4 deficiency did not result in autoimmunity on its own, it exacerbated autoimmune manifestations caused by disruption of the Aire gene. Thus, CNS4 enhancer activity ensures robust Treg cell differentiation early in postnatal life and cooperatively with other tolerance mechanisms, minimizes autoimmunity.
2021-03-16 | GSE168829 | 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 alone or together with GATA1 on the expression of the Treg transcriptional signature, we sorted and profiled matched bins of FOXP3-transduced cells bearing various levels of FOXP3, alone or co-transduced with GATA1, chosen as a representative of the quintet factors.
2012-08-23 | E-GEOD-40276 | biostudies-arrayexpress