TET2 coactivates gene expression through demethylation of enhancers
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ABSTRACT:
PROVIDER: PRJNA494397 | ENA |
REPOSITORIES: ENA
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Project description:The tet methylcytosine dioxygenase 2 (TET2) enzyme catalyzes the conversion of the modified DNA base 5-methylcytosine to 5-hydroxymethylcytosine. TET2 is frequently mutated or dysregulated in multiple human cancers, and loss of TET2 is associated with changes in DNA methylation patterns. Here, using newly developed TET2-specific antibodies and the estrogen response as a model system for studying the regulation of gene expression, we demonstrate that endogenous TET2 occupies active enhancers and facilitates the proper recruitment of ERalpha. Knockout of TET2 by CRISPR-CAS9 leads to a global increase of DNA-methylation at enhancers resulting in attenuation of the estrogen response. We further identified a positive feedback loop between TET2 and ERalpha, which further requires MLL3/COMPASS at these enhancers. Together, this study reveals an epigenetic axis coordinating a transcriptional program through enhancer activation via DNA demethylation.
2018-10-04 | GSE120756 | GEO
Project description: Not available
| S-EPMC6221537 | biostudies-literature
Project description:DNA methylation at enhancers and CpG islands usually leads to gene repression, which is counteracted by DNA demethylation through the TET protein family. However, how TET enzymes are recruited and regulated at these genomic loci is not fully understood. Here, we identify TET2 and a previously undescribed proline and serine rich protein, PROSER1 as interactors of UTX, a component of the enhancer-associated MLL3/4 complexes. Affinity purification of PROSER1 resulted in the identification of OGT and TET1-3. We find that PROSER1 mediates the interaction between OGT and TET2, thus promoting TET2 O-GlcNAcylation and protein stability. Additionally, PROSER1, UTX, OGT, and TET1/2 colocalize on many genomic elements genome-wide. Loss of PROSER1 results in lower enrichment of UTX, and TET1/2 at enhancers and CpG islands, with a concomitant increase in DNA methylation and transcriptional downregulation of associated target genes and increased DNA hypermethylation encroachment at H3K4me1-predisposed CpG islands. Taken together, this study describes for the first time a regulator of TET2 O-GlcNAcylation and its implications in mediating DNA demethylation at UTX-dependent enhancers and CpG islands.
2021-10-13 | GSE172143 | GEO
Project description:T cell function is regulated by epigenetic mechanisms. 5-methylcytosine (5mC) conversion to 5-hydroxymethylcytosine (5hmC) by ten-eleven translocation (Tet) proteins was identified to mediate DNA demethylation. Here, we characterize the genome-wide distribution of 5hmC in T cells using DNA immunoprecipitation coupled with high-throughput DNA sequencing. 5hmC marks signature genes associated with effector cell differentiation in the putative regulatory elements. Moreover, Tet2 protein is recruited to 5hmC-containing regions, dependent on lineage-specific transcription factors. Deletion of the Tet2 gene in T cells decreased their cytokine expression, associated with reduced p300 recruitment. In vivo, Tet2 plays a critical role in the expression of cytokine genes. Collectively, our findings for the first time demonstrate a key role of Tet-mediated active DNA demethylation in T cells. A total of 8 samples were analyzed. The expression patterns in Tet2 wild-type and deficient Th1 and Th17 cells were analyzed.
2015-04-12 | E-GEOD-66944 | biostudies-arrayexpress
Project description:DNA methylation at enhancers and CpG islands usually leads to gene repression, which is counteracted by DNA demethylation through the TET protein family. However, how TET enzymes are recruited and regulated at these genomic loci is not fully understood. Here, we identify TET2 and a previously undescribed proline and serine rich protein, PROSER1 as interactors of UTX, a component of the enhancer-associated MLL3/4 complexes. Affinity purification of PROSER1 resulted in the identification of OGT and TET1-3. We find that PROSER1 mediates the interaction between OGT and TET2, thus promoting TET2 O-GlcNAcylation and protein stability. Additionally, PROSER1, UTX, OGT, and TET1/2 colocalize on many genomic elements genome-wide. Loss of PROSER1 results in lower enrichment of UTX, and TET1/2 at enhancers and CpG islands, with a concomitant increase in DNA methylation and transcriptional downregulation of associated target genes and increased DNA hypermethylation encroachment at H3K4me1-predisposed CpG islands. Taken together, this study describes for the first time a regulator of TET2 O-GlcNAcylation and its implications in mediating DNA demethylation at UTX-dependent enhancers and CpG islands.
2021-10-13 | GSE172144 | GEO
Project description:DNA methylation at enhancers and CpG islands usually leads to gene repression, which is counteracted by DNA demethylation through the TET protein family. However, how TET enzymes are recruited and regulated at these genomic loci is not fully understood. Here, we identify TET2 and a previously undescribed proline and serine rich protein, PROSER1 as interactors of UTX, a component of the enhancer-associated MLL3/4 complexes. Affinity purification of PROSER1 resulted in the identification of OGT and TET1-3. We find that PROSER1 mediates the interaction between OGT and TET2, thus promoting TET2 O-GlcNAcylation and protein stability. Additionally, PROSER1, UTX, OGT, and TET1/2 colocalize on many genomic elements genome-wide. Loss of PROSER1 results in lower enrichment of UTX, and TET1/2 at enhancers and CpG islands, with a concomitant increase in DNA methylation and transcriptional downregulation of associated target genes and increased DNA hypermethylation encroachment at H3K4me1-predisposed CpG islands. Taken together, this study describes for the first time a regulator of TET2 O-GlcNAcylation and its implications in mediating DNA demethylation at UTX-dependent enhancers and CpG islands.
2021-10-13 | GSE172142 | GEO
Project description:DNA methylation at enhancers and CpG islands usually leads to gene repression, which is counteracted by DNA demethylation through the TET protein family. However, how TET enzymes are recruited and regulated at these genomic loci is not fully understood. Here, we identify TET2 and a previously undescribed proline and serine rich protein, PROSER1 as interactors of UTX, a component of the enhancer-associated MLL3/4 complexes. Affinity purification of PROSER1 resulted in the identification of OGT and TET1-3. We find that PROSER1 mediates the interaction between OGT and TET2, thus promoting TET2 O-GlcNAcylation and protein stability. Additionally, PROSER1, UTX, OGT, and TET1/2 colocalize on many genomic elements genome-wide. Loss of PROSER1 results in lower enrichment of UTX, and TET1/2 at enhancers and CpG islands, with a concomitant increase in DNA methylation and transcriptional downregulation of associated target genes and increased DNA hypermethylation encroachment at H3K4me1-predisposed CpG islands. Taken together, this study describes for the first time a regulator of TET2 O-GlcNAcylation and its implications in mediating DNA demethylation at UTX-dependent enhancers and CpG islands.
2021-10-13 | GSE172141 | GEO
Project description:Host antiviral innate immune response is regulated by epigenetic mechanisms. TET2 oxidizes the methyl group of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) in a process that activates demethylation of CpG DNA. Here, we characterize the genome-wide distribution of 5hmC in both wild-type and TET2-knockout THP-1 cells infected with the influenza A virus (IAV) using DNA immunoprecipitation by anti-5hmc antibody coupled with high-throughput DNA sequencing. 5hmC marks signature genes associated with host innate immune response against IAV infection. Moreover, TET2 expression is inhibited by IAV infection via viral endoribonuclease PA-X . Deletion of the TET2 gene in THP-1 cells decreased expression of genes related to interferon signaling. We further verified that TET2 plays a critical role in the expression of STAT1 and some interferon-stimulated genes through demethylation. Collectively, our findings demonstrate a key role of TET2-mediated active DNA demethylation in anti-IAV immunity. Hydroxymethylated DNA immunoprecipitation-sequencing (hMeDIP-Seq) in IAV-infected wild-type and TET2-knockout THP-1 cells.
2023-07-13 | GSE223191 | GEO
Project description:The conversion of 5-methylcytosine (5mC) into 5-Hydroxymethylcytosine (5hmC) by ten-eleven translocation (Tet) family has recently been identified as a key process for active DNA demethylation, whose effects in the immune response is currently unknown. We used microarrays to characterize the regulation of Tet2 in T cells. We found that deletion of the Tet2 gene in T cells decreased expression of effector cytokines such as IFN-?, IL-17, and IL-10. To analyze the regulation of Tet2 in Th subset differentation, CD2(Cre)Tet2(f/f) mice were used to derive Tet2-deficient Th1 and Th17 cells, and Tet2(f/f) mice were used for Tet2-enriched Th1 and Th17 cells.
2015-04-12 | E-GEOD-48657 | biostudies-arrayexpress
Project description:T cell function is regulated by epigenetic mechanisms. 5-methylcytosine (5mC) conversion to 5-hydroxymethylcytosine (5hmC) by ten-eleven translocation (Tet) proteins was identified to mediate DNA demethylation. Here, we characterize the genome-wide distribution of 5hmC in T cells using DNA immunoprecipitation coupled with high-throughput DNA sequencing. 5hmC marks signature genes associated with effector cell differentiation in the putative regulatory elements. Moreover, Tet2 protein is recruited to 5hmC-containing regions, dependent on lineage-specific transcription factors. Deletion of the Tet2 gene in T cells decreased their cytokine expression, associated with reduced p300 recruitment. In vivo, Tet2 plays a critical role in the expression of cytokine genes. Collectively, our findings for the first time demonstrate a key role of Tet-mediated active DNA demethylation in T cells.
2015-04-12 | GSE66944 | GEO