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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
E-mail(s) sunxiang2013@sibcb.ac.cn
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
Relations
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
SRA Run SelectorHelp
Raw data are available in SRA
Processed data are available on Series record
Processed data provided as supplementary file

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