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Series GSE128480 Query DataSets for GSE128480
Status Public on Sep 08, 2019
Title Downregulation of Uhrf1 activity by TGF-β signaling controls Foxp3 methylation and iTreg cell differentiation
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Methylation profiling by high throughput sequencing
Summary Foxp3+ regulatory T cells (Treg cells) are essential for immune system homeostasis and suppression of excessive immune responses. Both TGF-β signaling and epigenetic modifications are important in the regulation of Foxp3 induction, but whether TGF-β signaling participates in the epigenetic regulation of Foxp3 has not been fully clarified. Here, we show that Uhrf1, which is induced by TCR stimulation and regulated by TGF-β signaling, controls Foxp3 methylation and iTreg cell differentiation. T cell-specific ablation of Uhrf1 led to Treg-biased differentiation in naïve T cells, with DNA hypomethylation upon TCR stimulation, and these Foxp3+ T cells had suppressive function. Uhrf1 maintained Foxp3 DNA methylation by recruiting Dnmt1 during cell division upon TCR stimulation. TGF-β treatment led to passive demethylation of the Foxp3 promoter to initiate its expression. Mechanistically, Uhrf1 was phosphorylated upon TGF-β stimulation and largely sequestered in the cytoplasm. Phosphorylated Uhrf1 underwent proteasomal degradation through inhibition of Usp7-mediated deubiquitination. Collectively, our study reveals a novel epigenetic mechanism of TGF-β-mediated iTreg cell differentiation regulated by Uhrf1 and reveals the differential role of active and passive demethylation in Foxp3 induction and stability.
Overall design Wild-type (WT) and Uhrf1-/- mice T lymphocytes were analysed for: gene expression by RNA-seq, DNA methylation by whole-genome bisulfite sequencing (WGBS)
Contributor(s) Sun X, Cui Y, Feng H, Liu H, Liu X
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Submission date Mar 18, 2019
Last update date Sep 10, 2019
Contact name Xiang Sun
Organization name Institute of Biochemistry and Cell Biology, SIBS, CAS
Street address 320 Yue Yang Road
City Shanghai
ZIP/Postal code 200031
Country China
Platforms (2)
GPL21273 HiSeq X Ten (Mus musculus)
GPL24247 Illumina NovaSeq 6000 (Mus musculus)
Samples (8)
GSM3676894 RNA Seq-WT T cells
GSM3676895 RNA Seq-KO T cells
GSM3684262 WGBS-WT T cells
BioProject PRJNA527822
SRA SRP188734

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Supplementary file Size Download File type/resource
GSE128480_KO_vs_WT.DMR.result.txt.gz 58.1 Mb (ftp)(http) TXT
GSE128480_RAW.tar 336.6 Mb (http)(custom) TAR (of TXT)
GSE128480_RNA_raw_gene_counts.txt.gz 17.2 Mb (ftp)(http) TXT
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Raw data are available in SRA
Processed data are available on Series record
Processed data provided as supplementary file

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