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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) |
[email protected]
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| Organization name |
Institute of Biochemistry and Cell Biology, SIBS, CAS
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| Street address |
320 Yue Yang Road
|
| 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 |
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