The role of Vitamin C and TET dioxygenases in genome-wide features of regulatory T cells [CMS-IP]
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PROVIDER: PRJNA592358 | ENA |
REPOSITORIES: ENA
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Project description:TET enzymes are essential for the stability and function of regulatory T cells (Tregs), which maintain immune homeostasis and self-tolerance and express the lineage-determining transcription factor Foxp3. We previously showed that Vitamin C acts through TET enzymes to maintain the demethylated status of CNS2, a key intronic enhancer of the Foxp3 gene that is essential for the stability of Foxp3 expression both in vivo and in vitro. Here we show that Vitamin C enables genome-wide features of “induced” T regulatory cells (iTregs) in vitro that overlap with those induced by TET proteins during Treg differentiation in vivo. Vitamin C enhances IL-2 responsiveness in iTregs by increasing phospho-STAT5 levels, STAT5 occupancy and DNA demethylation at key Treg-specific enhancers, and maintains the stable expression of Treg-specific genes including Foxp3 and Il2ra. Our data will be relevant to future studies of the association between plasma Vitamin C levels, Treg function and autoimmunity in humans.
2021-07-21 | GSE141150 | GEO
Project description:TET enzymes are dioxygenases that promote DNA demethylation by oxidizing the methyl group of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). Here we report a close correspondence between 5hmC-marked regions, chromatin accessibility and enhancer activity in B cells, and a strong enrichment for consensus binding motifs for basic region-leucine zipper (bZIP) transcription factors at TET-responsive genomic regions. Functionally, Tet2 and Tet3 regulate class switch recombination (CSR) in murine B cells by enhancing expression of Aicda, encoding the cytidine deaminase AID essential for CSR. TET enzymes deposit 5hmC, demethylate and maintain chromatin accessibility at two TET-responsive elements, TetE1 and TetE2, located within a superenhancer in the Aicda locus. Transcriptional profiling identified BATF as the bZIP transcription factor involved in TET-dependent Aicda expression. 5hmC is not deposited at TetE1 in activated Batf-deficient B cells, indicating that BATF recruits TET proteins to the Aicda enhancer. Our data emphasize the importance of TET enzymes for bolstering AID expression, and highlight 5hmC as an epigenetic mark that captures enhancer dynamics during cell activation.
2019-04-29 | GSE116201 | GEO
Project description:TET enzymes augment AID expression via 5hmC modifications at the Aicda superenhancer [CMS-IP]
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Project description:Itaconate is an inhibitor of TET DNA dioxygenases
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Project description:TET enzymes are essential for the stability and function of regulatory T cells (Tregs), which maintain immune homeostasis and self-tolerance and express the lineage-determining transcription factor Foxp3. We previously showed that Vitamin C acts through TET enzymes to maintain the demethylated status of CNS2, a key intronic enhancer of the Foxp3 gene that is essential for the stability of Foxp3 expression both in vivo and in vitro. Here we show that Vitamin C enables genome-wide features of “induced” T regulatory cells (iTregs) in vitro that overlap with those induced by TET proteins during Treg differentiation in vivo. Vitamin C enhances IL-2 responsiveness in iTregs by increasing phospho-STAT5 levels, STAT5 occupancy and DNA demethylation at key Treg-specific enhancers, and maintains the stable expression of Treg-specific genes including Foxp3 and Il2ra. Our data will be relevant to future studies of the association between plasma Vitamin C levels, Treg function and autoimmunity in humans.
2021-07-21 | GSE141151 | GEO
Project description:The role of Vitamin C and TET dioxygenases in genome-wide features of regulatory T cells
| PRJNA592355 | ENA
Project description:TET enzymes are essential for the stability and function of regulatory T cells (Tregs), which maintain immune homeostasis and self-tolerance and express the lineage-determining transcription factor Foxp3. We previously showed that Vitamin C acts through TET enzymes to maintain the demethylated status of CNS2, a key intronic enhancer of the Foxp3 gene that is essential for the stability of Foxp3 expression both in vivo and in vitro. Here we show that Vitamin C enables genome-wide features of “induced” T regulatory cells (iTregs) in vitro that overlap with those induced by TET proteins during Treg differentiation in vivo. Vitamin C enhances IL-2 responsiveness in iTregs by increasing phospho-STAT5 levels, STAT5 occupancy and DNA demethylation at key Treg-specific enhancers, and maintains the stable expression of Treg-specific genes including Foxp3 and Il2ra. Our data will be relevant to future studies of the association between plasma Vitamin C levels, Treg function and autoimmunity in humans.
2021-07-21 | GSE141149 | GEO
Project description:TET enzymes are essential for the stability and function of regulatory T cells (Tregs), which maintain immune homeostasis and self-tolerance and express the lineage-determining transcription factor Foxp3. We previously showed that Vitamin C acts through TET enzymes to maintain the demethylated status of CNS2, a key intronic enhancer of the Foxp3 gene that is essential for the stability of Foxp3 expression both in vivo and in vitro. Here we show that Vitamin C enables genome-wide features of “induced” T regulatory cells (iTregs) in vitro that overlap with those induced by TET proteins during Treg differentiation in vivo. Vitamin C enhances IL-2 responsiveness in iTregs by increasing phospho-STAT5 levels, STAT5 occupancy and DNA demethylation at key Treg-specific enhancers, and maintains the stable expression of Treg-specific genes including Foxp3 and Il2ra. Our data will be relevant to future studies of the association between plasma Vitamin C levels, Treg function and autoimmunity in humans.
2021-07-21 | GSE141148 | GEO
Project description:Mammalian genomes are subjected to epigenetic modifications, including cytosine methylation by DNA methyltransferases (Dnmt) and further oxidation by Ten-eleven-translocation (Tet) family of dioxygenases. Cytosine methylation plays key roles in multiple processes such as genomic imprinting and X-chromosome inactivation. However, the functional significance of cytosine methylation and the further oxidation has remained undetermined in mouse embryogenesis. Here we show that global inactivation of all three Tet genes in mice led to consistent defects in gastrulation. The defects include reduced specification of the axial mesoderm and paraxial mesoderm, mimicking phenotypes in embryos with gain-of-function Nodal signaling, a cardinal cue for gastrulation. Introduction of a single mutant allele of Nodal in the Tet mutant background partially restored patterning, suggesting that hyperactive Nodal signaling is a leading cause for the gastrulation failure of Tet mutants. Increased Nodal signaling is likely due to diminished expression of the Lefty1 and Lefty2 genes, inhibitors of Nodal signaling. Moreover, reduction in the Lefty gene expression can be ascribed to elevated DNA methylation as both Lefty-Nodal signaling and normal morphogenesis are largely restored in Tet-deficient embryos when the Dnmt3a and Dnmt3b genes are disrupted. Additionally, specific inactivation of Tet by point mutations abolishing the dioxygenase activity causes similar molecular and gastrulation abnormalities. Taken together, our results show that Tet-mediated DNA oxidation modulates the Lefty-Nodal signaling by promoting demethylation of the shared target genes with Dnmt3a and Dnmt3b. These findings reveal a fundamental epigenetic mechanism featuring dynamic DNA methylation and demethylation and their role in the regulation of key signaling in body plan formation during early embryogenesis. Examine RNA expression and DNA methylation differences between Tet-null and wild type samples of mouse epiblast in E6.5.
2016-10-27 | E-GEOD-76261 | biostudies-arrayexpress
Project description:The role of Vitamin C and TET dioxygenases in genome-wide features of regulatory T cells [WGBS]
| PRJNA592357 | ENA