Mus musculus
Ontology highlight
ABSTRACT:
OTHER RELATED OMICS DATASETS IN: E-GEOD-36095
PROVIDER: PRJNA151799 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Histone/Protein Deacetylase-6, -9, and Sirtuin-1 Control Foxp3+ Treg Through Shared and Isotype-Specific Mechanisms
2014-07-10 | E-GEOD-36095 | ExpressionAtlas
Project description:Targeting histone/protein deacetylase (HDAC)-6, -9, or Sirtuin-1 (Sirt1) augments the suppressive functions of Foxp3+ T regulatory (Treg) cells, but it is unclear if this involves different mechanisms, such that combined inhibition would be beneficial. We compared the suppressive functions of Tregs from wild-type C57BL/6 mice or mice with global (HDAC6-/-, HDAC9-/-, dual HDAC6/9-/-) or conditional deletion (CD4-Cre or Foxp3-Cre and floxed Sirt1; GSE26425) alone, or after treatment with isoform-selective HDAC inhibitors (HDACi). We found the heat shock response was crucial in mediating the effects of HDAC6, but not Sirt1 inhibition. Furthermore, while HDAC6, HDAC9 and Sirt1 all deacetylate Foxp3, each has diverse effects on Foxp3 transcription, and loss of HDAC9 is associated with stabilization of Stat5 acetylation and its transcriptional activity. Targeting different HDAC can increase Treg function by multiple and additive mechanisms, indicating the therapeutic potential for combinations of HDACi in the management of autoimmunity and alloresponses post-transplant. RNA from three independent samples of magnetically separated CD4+CD25+ Treg of HDAC9-/- mice, compared to wild type (C57BL/6) control.
2012-06-20 | E-GEOD-36095 | biostudies-arrayexpress
Project description:Sirtuin-1 (Sirt1), a class III histone/protein deacetylase is central to cellular metabolism, stress responses and aging, but its contributions to various host immune functions have been little investigated. To study the role of Sirt1 in T-cell functions, we undertook targeted deletions by mating mice with a floxed Sirt1 gene to mice expressing CD4-cre or Foxp3-cre recombinase, respectively. We found that Sirt1 deletion left conventional T-effector cell activation, proliferation and cytokine production largely unaltered. However, Sirt1 targeting promoted the expression and acetylation of Foxp3, a key transcription factor in T-regulatory (Treg) cells, and increased Treg suppressive functions in vitro and in vivo. Consistent with these data, mice with targeted deletions of Sirt1 in either CD4+ T-cells or Foxp3+ Treg cells exhibited prolonged survival of MHC-mismatched cardiac allografts. Allografts in Sirt1 targeted recipients showed long-term preservation of myocardial histology and infiltration by Foxp3+ Treg cells. Comparable results were seen in wild-type allograft recipients treated with Sirt1 inhibitors, such as EX-527 and splitomicin. Hence, Sirt1 may inhibit Treg functions and its targeting may have therapeutic value in autoimmunity and transplantation. RNA from three independent samples from magnetically separated CD4+CD25+ Treg of Sirt1 knock out, compared to wild type (C57BL6) control
2011-01-05 | E-GEOD-26425 | biostudies-arrayexpress
Project description:Histone/protein deacetylase 11 targeting promotes Foxp3+ Treg function
| PRJNA376611 | ENA
Project description:Targeting histone/protein deacetylase (HDAC)-6, -9, or Sirtuin-1 (Sirt1) augments the suppressive functions of Foxp3+ T regulatory (Treg) cells, but it is unclear if this involves different mechanisms, such that combined inhibition would be beneficial. We compared the suppressive functions of Tregs from wild-type C57BL/6 mice or mice with global (HDAC6-/-, HDAC9-/-, dual HDAC6/9-/-) or conditional deletion (CD4-Cre or Foxp3-Cre and floxed Sirt1; GSE26425) alone, or after treatment with isoform-selective HDAC inhibitors (HDACi). We found the heat shock response was crucial in mediating the effects of HDAC6, but not Sirt1 inhibition. Furthermore, while HDAC6, HDAC9 and Sirt1 all deacetylate Foxp3, each has diverse effects on Foxp3 transcription, and loss of HDAC9 is associated with stabilization of Stat5 acetylation and its transcriptional activity. Targeting different HDAC can increase Treg function by multiple and additive mechanisms, indicating the therapeutic potential for combinations of HDACi in the management of autoimmunity and alloresponses post-transplant.
2012-06-21 | GSE36095 | GEO
Project description:Sirtuin-1 (Sirt1), a class III histone/protein deacetylase is central to cellular metabolism, stress responses and aging, but its contributions to various host immune functions have been little investigated. To study the role of Sirt1 in T-cell functions, we undertook targeted deletions by mating mice with a floxed Sirt1 gene to mice expressing CD4-cre or Foxp3-cre recombinase, respectively. We found that Sirt1 deletion left conventional T-effector cell activation, proliferation and cytokine production largely unaltered. However, Sirt1 targeting promoted the expression and acetylation of Foxp3, a key transcription factor in T-regulatory (Treg) cells, and increased Treg suppressive functions in vitro and in vivo. Consistent with these data, mice with targeted deletions of Sirt1 in either CD4+ T-cells or Foxp3+ Treg cells exhibited prolonged survival of MHC-mismatched cardiac allografts. Allografts in Sirt1 targeted recipients showed long-term preservation of myocardial histology and infiltration by Foxp3+ Treg cells. Comparable results were seen in wild-type allograft recipients treated with Sirt1 inhibitors, such as EX-527 and splitomicin. Hence, Sirt1 may inhibit Treg functions and its targeting may have therapeutic value in autoimmunity and transplantation.
2011-01-05 | GSE26425 | GEO
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 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 TGFβ-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.
2012-12-07 | GSE35164 | GEO
Project description:We hypothesize that nuclear factors co-occupying the genetic elements with regulatory T (Treg) cell lineage–specifying factor Foxp3 play critical roles in transcriptional regulation of Treg immune suppression function, thus, offering a unique approach to investigate the factors and their mechanisms controlling Treg-mediated immune tolerance involved in self-tolerance and antitumor immunity. We seek to identify the proteins occupying Foxp3 targets in the resting state or after cells receiving stimulation. To this end, we projected the spatial information (PSI) of Foxp3, Histone H3, or Stat5 onto their adjacent proteins with peroxidase–catalyzed biotin-phenoxyl radicals and identify these biotinylated proteins with tandem mass tag (TMT)–based quantitative mass spectrometry (MS).
2024-06-08 | PXD019050 | Pride
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