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Series GSE149693 Query DataSets for GSE149693
Status Public on May 28, 2024
Title Dynamic Foxp3-chromatin interaction controls tunable Treg cell function [RNA-seq]
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary Nuclear factor Foxp3 determines regulatory T (Treg) cell fate and function via mechanisms that remain unclear. Here we investigate the nature of Foxp3-mediated gene regulation in suppressing autoimmunity and antitumor immune response. Contrasting with previous models, we find that Foxp3-chromatin binding is regulated by Treg activation states, tumor microenvironment, and antigen and cytokine stimulations. Proteomics studies uncovered dynamic proteins within the Foxp3 proximity upon TCR or IL-2 receptor signaling in vitro, reflecting intricate interactions among Foxp3, signal transducers, and chromatin. Pharmacological inhibition and genetic knockdown experiments indicate that NFAT and AP-1 protein Batf are required for enhanced Foxp3-chromatin binding in activated Treg cells and tumor-infiltrating Treg cells to modulate target gene expression. Furthermore, mutations at Foxp3 DNA-binding domain destabilize Foxp3-chromatin association. These representative settings delineate context-dependent Foxp3-chromatin interaction, suggesting that Foxp3 associates with chromatin by hijacking DNA-binding proteins resulting from Treg activation or differentiation, which is stabilized by direct Foxp3-DNA binding, to dynamically regulate Treg cell function according to immunological contexts.
Overall design We developed a comparative proteomics method by projecting the spatial information (PSI) of nuclear proteins with peroxidase–mediated proximity ligation, thus revealing the protein components of the cis-regulatory elements bound by Treg lineage–specifying factor Foxp3. We performed RNA sequencing for naïve CD4 T cells (Tn, CD4+ GFP- CD25- CD44low CD62Lhigh), effector CD4 T cells (aTe, CD4+ GFP- CD44high CD62Llow), resting Treg cells (rTreg, CD4+ GFP+ CD44low CD62Lhigh), and activated Treg cells (aTreg, CD4+ GFP+ CD44high CD62Llow) sorted from 8-10 week old male Foxp3-gfp knockin mice. To reveal signal-dependent transcriptional regulation, we first induced Treg cells in vitro (iTreg) from CD4 naïve T cells isolated from male Foxp3-gfp mice with TCR agonists, Interleukion-2 (IL-2), TGF-beta, and ascorbic acid and then stimulated them with IL-2 for 30 min or with plate-bound anti-CD3 and anti-CD28 antibodies for 3 hours. After stimulation, cells were immediately lysed with the TRIzol reagent for RNA extraction and sequencing.
Contributor(s) Zong X, Xu B, Cross R, Feng Y
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Submission date May 01, 2020
Last update date May 29, 2024
Contact name Beisi Xu
Organization name St Jude Children's Research Hosipital
Department Center for Applied Bioinformatics
Street address 262 Danny Thomas Pl
City Memphis
State/province Tennessee
ZIP/Postal code 38105
Country USA
Platforms (1)
GPL24247 Illumina NovaSeq 6000 (Mus musculus)
Samples (16)
GSM4509061 RNA-1835231_minusIL2a
GSM4509062 RNA-1835232_minusIL2b
GSM4509063 RNA-1835233_plusIL2a
This SubSeries is part of SuperSeries:
GSE149674 Dynamic Foxp3-chromatin interaction controls tunable Treg cell function
BioProject PRJNA629759
SRA SRP259916

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SOFT formatted family file(s) SOFTHelp
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Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE149693_RAW.tar 2.4 Mb (http)(custom) TAR (of TXT)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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