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TET proteins regulate T cell and iNKT cell lineage specification in a TET2 catalytic dependent manner [CUT&RUN]

ABSTRACT: TET proteins mediate DNA demethylation by oxidizing 5-methylcytosine to 5-hydroxymethylcytosine (5hmC) and other oxidative derivatives. We have previously demonstrated a dynamic enrichment of 5hmC during T and invariant natural killer T cell lineage specification. Here, we investigate shared signatures in gene expression of Tet2/3 DKO CD4 single positive (SP) and iNKT cells in the thymus. We discover that TET proteins exert a fundamental role in regulating the expression of the lineage specifying factor Th-POK, which is encoded by Zbtb7b. We demonstrate that TET proteins mediate DNA demethylation - surrounding a proximal enhancer, critical for the intensity of Th-POK expression. In addition, TET proteins drive the DNA demethylation of site A at the Zbtb7b locus to facilitate GATA3 binding. GATA3 induces Th-POK expression in CD4 SP cells. Finally, by introducing a novel mouse model that lacks TET3 and expresses full length, catalytically inactive TET2, we establish a causal link between TET2 catalytic activity and lineage specification of both conventional and unconventional T cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE190228 | GEO | 2022/07/15

REPOSITORIES: GEO

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TET proteins regulate T cell and iNKT cell lineage specification in a TET2 catalytic dependent manner [CATCH-SEQ]

Project description:TET proteins mediate DNA demethylation by oxidizing 5-methylcytosine to 5-hydroxymethylcytosine (5hmC) and other oxidative derivatives. We have previously demonstrated a dynamic enrichment of 5hmC during T and invariant natural killer T cell lineage specification. Here, we investigate shared signatures in gene expression of Tet2/3 DKO CD4 single positive (SP) and iNKT cells in the thymus. We discover that TET proteins exert a fundamental role in regulating the expression of the lineage specifying factor Th-POK, which is encoded by Zbtb7b. We demonstrate that TET proteins mediate DNA demethylation - surrounding a proximal enhancer, critical for the intensity of Th-POK expression. In addition, TET proteins drive the DNA demethylation of site A at the Zbtb7b locus to facilitate GATA3 binding. GATA3 induces Th-POK expression in CD4 SP cells. Finally, by introducing a novel mouse model that lacks TET3 and expresses full length, catalytically inactive TET2, we establish a causal link between TET2 catalytic activity and lineage specification of both conventional and unconventional T cells.

2022-07-15 | GSE190227 | GEO

TET proteins regulate T cell and iNKT cell lineage specification in a TET2 catalytic dependent manner [RNA-Seq]

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Concomitant loss of TET2 and TET3 results in T cell expansion and genomic instability [BGI-RNA-Seq]

Project description:TET proteins mediate DNA demethylation by oxidizing 5-methylcytosine to 5-hydroxymethylcytosine (5hmC) and other oxidative derivatives. While we have previously demonstrated a dynamic enrichment of 5hmC during T cell lineage specification, the impact of TET proteins in CD4 cell lineage differentiation remains largely unknown. Here, we discover that TET proteins exert a fundamental role in regulating the differentiation and maturation of the CD4 lineage by controlling the expression of the lineage specifying factor Th-POK, which is encoded by Zbtb7b. We demonstrate that TET proteins mediate DNA demethylation of a proximal enhancer, critical for the stability of Th-POK expression. In addition, TET proteins drive the DNA demethylation of site A at the Zbtb7b locus to facilitate GATA3 binding, an event critical for Th-POK expression and subsequent CD4 maturation. The impaired maturation of Tet2/3 DKO CD4 cells leads to the acquisition of a stemness signature and results in acquisition of malignant traits.

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Distinct and stage-specific contributions of TET1 and TET2 to stepwise cytosine oxidation in the transition from naive to primed pluripotency

Project description:Cytosine DNA bases can be methylated by DNA methyltransferases and subsequently oxidized by TET proteins. The resulting 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC) are considered demethylation intermediates as well as stable epigenetic marks. To dissect the contribution of these cytosine modifying enzymes, we generated combinations of Tet knockout (KO) embryonic stem cells (ESCs) and systematically measured protein and DNA modification levels at the transition from naive to primed pluripotency. Whereas the increase of genomic 5-methylcytosine (5mC) levels during exit from pluripotency correlated with an upregulation of the de novo DNA methyltransferases DNMT3A and DNMT3B, the subsequent oxidation steps turned out to be far more complex. The strong increase of oxidized cytosine bases (5hmC, 5fC, and 5caC) was accompanied by a drop in TET2 levels, yet the analysis of KO cells suggested that TET2 is responsible for most 5fC formation. The comparison of modified cytosine and enzyme levels in Tet KO cells revealed distinct and differentiation-dependent contributions of TET1 and TET2 to 5hmC and 5fC formation arguing against a processive mechanism of 5mC oxidation. The apparent independent steps of 5hmC and 5fC formation suggest yet to be identified mechanisms regulating TET activity and may constitute another layer of epigenetic regulation.

2020-07-24 | PXD019514 | Pride

TET2 is a component of the ER complex and controls 5mC to 5hmC conversion at ER cis-regulatory regions

Project description:Estrogen receptor-alpha (ER) drives tumour development and metastasis in ER positive (ER+) breast cancer. GATA3 is a transcription factor that has been closely linked to ER function, but the role of GATA3 in ER-transcriptional activity is not clear. We sought to identify the contribution of GATA3 to the ER complex, by conducting quantitative multiplexed rapid immunoprecipitation mass spectrometry of endogenous proteins (qPLEX-RIME), to assess changes to the ER complex in response to GATA3 depletion. Unexpectedly, very few proteins were dissociated from the ER complex in the absence of GATA3, with the only major change being loss of TET2 in the ER complex. In breast cancer cells and Patient-Derived Xenograft (PDX) tissue, TET2 binding events were shown to constitute a near-total subset of ER binding events, and loss of TET2 was functionally associated with reduced activation of proliferative pathways. To investigate the TET2-ER relationship, the role of TET2 in regulating DNA modifications in ER+ breast cancer cells was examined. TET2 knockdown did not appear to result in changes to global DNA methylation, however, oxidation of methylated DNA to 5-hydroxymethylcytosine (5hmC) was significantly reduced after TET2 depletion and these events occurred at ER enhancers. These findings implicate TET2 in the production and maintenance of 5hmC at ER sites, providing a potential mechanism for TET2-mediated regulation of ER target genes.

2021-02-10 | PXD019438 | Pride

Tet2-mediated DNA demethylation controls T cell cytokine expression [seq]

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. Examination of both 5mC and 5hmC modifications in 5 Th cell types. CD2(Cre)Tet2(f/f) mice (previously described in Moran-Crusio et al.,2011) and wild-type littermates on the mixed background were used in experiments.

2015-04-12 | E-GEOD-49139 | biostudies-arrayexpress

Regulation of T cell cytokine expression by Tet2-mediated DNA demethylation [gene expression]

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

Gene expression in mammary glands of lactating wild-type or Th-POK-deficient mice.

Project description:The Th-inducing POK (Th-POK, also known as cKrox or ZBTB7B) transcription factor is a key regulator of lineage commitment of immature T cell precursors. It is yet unclear the physiological functions of Th-POK besides helper T cell differentiation. We found that Th-POK is restrictedly expressed in the luminal epithelial cells in the mammary glands. Th-POK is not required for mammary gland development in puberty and alveologenesis in pregnancy. Th-POK-deficient mice are defective in secretory activation upon parturition with large cellular lipid droplets retained within alveolar epithelial cells. We compared microarray gene expression in mammary glands of lactating wild-type or Th-POK-deficient mice. We show that Th-POK directly regulates expression of insulin receptor substrate-1 (IRS-1) and insulin-induced Akt-mTOR-SREBP signaling. Th-POK deficiency compromises IRS-1 expression and Akt-mTOR-SREBP signaling in the mammary glands. Thus, Th-POK function as an important regulator of insulin signaling in mammary gland lactation.

2018-02-06 | GSE97566 | GEO

Tet2-mediated DNA demethylation controls T cell cytokine expression [array]

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

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