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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
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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.
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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)
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Contributor(s) |
Sun X, Cui Y, Feng H, Liu H, Liu X |
Citation missing |
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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
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Organization name |
Institute of Biochemistry and Cell Biology, SIBS, CAS
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Street address |
320 Yue Yang Road
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City |
Shanghai |
ZIP/Postal code |
200031 |
Country |
China |
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Platforms (2) |
GPL21273 |
HiSeq X Ten (Mus musculus) |
GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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Samples (8)
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Relations |
BioProject |
PRJNA527822 |
SRA |
SRP188734 |