Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Conserved non-coding sequence 2 (CNS2) of the Foxp3 genomic locus is essential for the function and stability of regulatory T cells during their activation

ABSTRACT: Regulatory T (Treg) cells play an indispensable role in immune homeostasis. The development and function of Tregs are dependent on transcriptional factor Foxp3, but how constant expression of Foxp3 is maintained in Tregs is not clear. Here we show that ablation of the conserved non-coding DNA sequence 2 (CNS2) at the Foxp3 locus in mice led to spontaneous lymphoproliferative disease and exacerbation of experimental autoimmune encephalomyelitis (EAE). CNS2 is required for activated Treg cells to maintain elevated Foxp3 expression, which is critical for their suppressor function and lineage stability. Mechanistically, upon TCR stimulation, NFAT binds to both CNS2 and Foxp3 promoter and mediates the interaction between CNS2 and Foxp3 promoter. Our findings demonstrated an essential role for CNS2 in maintaining the stability and function of activated Treg cells and identified NFAT as a key mediator of its function.

ORGANISM(S): Mus musculus

PROVIDER: GSE57272 | GEO | 2014/09/04

SECONDARY ACCESSION(S): PRJNA246149

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Conserved non-coding sequence 2 (CNS2) of the Foxp3 genomic locus is essential for the function and stability of regulatory T cells during their activation

Project description:Regulatory T (Treg) cells play an indispensable role in immune homeostasis. The development and function of Tregs are dependent on transcriptional factor Foxp3, but how constant expression of Foxp3 is maintained in Tregs is not clear. Here we show that ablation of the conserved non-coding DNA sequence 2 (CNS2) at the Foxp3 locus in mice led to spontaneous lymphoproliferative disease and exacerbation of experimental autoimmune encephalomyelitis (EAE). CNS2 is required for activated Treg cells to maintain elevated Foxp3 expression, which is critical for their suppressor function and lineage stability. Mechanistically, upon TCR stimulation, NFAT binds to both CNS2 and Foxp3 promoter and mediates the interaction between CNS2 and Foxp3 promoter. Our findings demonstrated an essential role for CNS2 in maintaining the stability and function of activated Treg cells and identified NFAT as a key mediator of its function. Gene expression was profiled in T regulatory cells (Treg) in WT and CNS2 knockout mice. CNS2 knockout mice lack a conserved non-coding DNA sequence 2 (CNS2) at the Foxp3 locus. Treg cells were further sorted into Foxp3-high and Foxp3-low populations based on the expression level of Foxp3. mRNA was profiled using RNA-Seq (unstranded, polyA+, SE100) in replicate for each condition

2014-09-04 | E-GEOD-57272 | biostudies-arrayexpress

Effect of Sin3a deletion on gene expression within FoxP3+ T-regulatory cells

Project description:Foxp3 (forkhead box protein 3) functions as the master transcriptional regulator of Treg phenotype. Histone deacetylases 1 and 2 (HDAC1/2) contribute to the regulation of FoxP3 expression via interactions with a myriad of co-regulatory factors. While the nuclear scaffolding protein, Sin3a, has been well established as a co-factor of HDAC1/2, its role within FoxP3+ Tregs has not been. We analyzed the effects of conditional deletion of Sin3a in Foxp3+ Treg cells using three orthogonal approaches. Deletion of Sin3a from FoxP3+ Tregs resulted in the rapid onset of severe and fatal autoimmunity mirroring the phenotype of Scurfy mice. Numbers of Tregs were greatly reduced, residual Tregs had virtually complete loss of suppressive function, and inducible Treg production was blocked. Mice also showed activation of effector T cells, autoantibody production and widespread tissue injury. Mechanistically, Sin3a deletion resulted in decreased transcription of Foxp3 and other Treg signature genes. The reduction of Foxp3 expression was accompanied by the reduction of TET1 and 3 expression and a complete lack of CpG demethylation of the Foxp3 enhancer region CNS2. In addition, Foxp3 protein stability was impaired and fate mapping studies showed conversion of Tregs to ex-Tregs and increased rates of programmed cell death. Thus, Sin3a plays a critical role in the maintenance of Treg identity and function and is essential for the expression and stability of Foxp3.

2024-06-07 | GSE263830 | GEO

Two Histone/Protein Acetyltransferases, CBP and p300, Are Indispensable for Foxp3+ T-regulatory Cell Development and Function

Project description:T-regulatory (Treg) cells are important to immune homeostasis, and Treg cell deficiency or dysfunction leads to autoimmune disease. An histone/protein acetyltransferase (HAT), p300, was recently found important for Treg function and stability, but further insights into the mechanisms by which p300 or other HATs affect Treg biology are needed. Here we show that CBP, a p300 paralog, is also important in controlling Treg function and stability. Thus, while mice with Treg-specific deletion of CBP or p300 developed minimal autoimmune disease, the combined deletion of CBP and p300 led to fatal autoimmunity by 3-4 weeks of age. The effects of CBP and p300 deletion on Treg development are dose-dependent, and involve multiple mechanisms. CBP and p300 cooperate with several key Treg transcription factors that act on the Foxp3 promoter to promote Foxp3 production. CBP and p300 also act on the Foxp3 CNS2 region to maintain Treg stability in inflammatory environments by regulating pCREB function and GATA3 expression, respectively. Lastly, CBP and p300 regulate the epigenetic status and function of Foxp3. Our findings provide insights into how HATs orchestrate multiple aspects of Treg development and function, and identify overlapping but also discrete activities for p300 and CBP in control of Treg cells. RNA from three independent samples from magnetically separated CD4+CD25+ Treg of fl-p300/Foxp3cre mice and fl-CBP/Foxp3cre, compared to wild type (Foxp3cre) control (all C57Bl/6 background).

2014-08-12 | E-GEOD-60318 | biostudies-arrayexpress

Quantitative Proteomics Reveals Specialized Wiring of Signaling Pathways that Protects Human Regulatory T Cell Identity - 6 populations ex vivo

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

Quantitative Proteomics Reveals Specialized Wiring of Signaling Pathways that Protects Human Regulatory T Cell Identity - 5 populations ex vivo

2018-05-18 | PXD005477 | Pride

Quantitative Proteomics Reveals Specialized Wiring of Signaling Pathways that Protects Human Regulatory T Cell Identity - 2 populations in vitro

2018-05-18 | PXD007745 | Pride

The role of Vitamin C and TET dioxygenases in genome-wide features of regulatory T cells [WGBS]

Project description:TET enzymes are essential for the stability and function of regulatory T cells (Tregs), which maintain immune homeostasis and self-tolerance and express the lineage-determining transcription factor Foxp3. We previously showed that Vitamin C acts through TET enzymes to maintain the demethylated status of CNS2, a key intronic enhancer of the Foxp3 gene that is essential for the stability of Foxp3 expression both in vivo and in vitro. Here we show that Vitamin C enables genome-wide features of “induced” T regulatory cells (iTregs) in vitro that overlap with those induced by TET proteins during Treg differentiation in vivo. Vitamin C enhances IL-2 responsiveness in iTregs by increasing phospho-STAT5 levels, STAT5 occupancy and DNA demethylation at key Treg-specific enhancers, and maintains the stable expression of Treg-specific genes including Foxp3 and Il2ra. Our data will be relevant to future studies of the association between plasma Vitamin C levels, Treg function and autoimmunity in humans.

2021-07-21 | GSE141151 | GEO