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TET proteins regulate lineage specification and TCR-mediated expansion of iNKT cells (WGBS)

ABSTRACT: TET proteins oxidize 5-methylcytosine to 5-hydroxymethylcytosine and further oxidation products in DNA. Here we report that simultaneous deletion of Tet2 and Tet3 in mouse double-positive thymocytes resulted in dysregulated development and proliferation of invariant natural killer T (iNKT) cells. Tet2-Tet3-double-deficient (DKO) iNKT cells displayed pronounced skewing towards the NKT17 lineage, with increased DNA methylation and impaired expression of genes encoding the key lineage-specifying factors T-bet and ThPOK. Transfer of purified Tet2-Tet3 DKO iNKT cells into immunocompetent recipient mice resulted in uncontrolled expansion dependent on the nonclassical MHC protein CD1d, which presents lipid antigens to iNKT cells. Our data indicate that TET proteins regulate iNKT cell fate by ensuring proper development and maturation and suppressing aberrant T cell antigen receptor (TCR)-mediated proliferation.

ORGANISM(S): Mus musculus

PROVIDER: GSE72116 | GEO | 2016/11/21

SECONDARY ACCESSION(S): PRJNA293086

REPOSITORIES: GEO

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TET proteins regulate lineage specification and TCR-mediated expansion of iNKT cells (ATAC-Seq)

Project description:TET proteins oxidize 5-methylcytosine to 5-hydroxymethylcytosine and further oxidation products in DNA. Here we report that simultaneous deletion of Tet2 and Tet3 in mouse double-positive thymocytes resulted in dysregulated development and proliferation of invariant natural killer T (iNKT) cells. Tet2-Tet3-double-deficient (DKO) iNKT cells displayed pronounced skewing towards the NKT17 lineage, with increased DNA methylation and impaired expression of genes encoding the key lineage-specifying factors T-bet and ThPOK. Transfer of purified Tet2-Tet3 DKO iNKT cells into immunocompetent recipient mice resulted in uncontrolled expansion dependent on the nonclassical MHC protein CD1d, which presents lipid antigens to iNKT cells. Our data indicate that TET proteins regulate iNKT cell fate by ensuring proper development and maturation and suppressing aberrant T cell antigen receptor (TCR)-mediated proliferation.

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Combined deficiency of Tet1 and Tet2 is compatible with development but leads to epigenetic instability

Project description:Tet enzymes (Tet1/2/3) convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). Tet1 and Tet2 mediate 5hmC generation in mouse embryonic stem cells (ESCs) and various embryonic and adult tissues. To investigate the effects of combined deficiency of Tet1 and Tet2 on pluripotency and development, we have generated Tet1 and Tet2 double knockout (DKO) ESCs and mice. DKO ESCs were depleted of 5hmC, but remained pluripotent with subtle defects in differentiation and changes in gene expression. Double mutant embryos and chimeras exhibited mid-gestation defects and postnatal DKO mice displayed partially penetrant neonatal lethality and stochastic perturbation of imprinting. Viable DKO animals developed normally to adulthood but had reduced 5hmC level, increased 5mC level and lacked 5hmC in germ cells. Nevertheless, DKO mice of both sexes were fertile with females having smaller ovaries and reduced fertility. Our data suggest that both Tet1 and Tet2 contribute to 5hmC levels during development. Their combined loss does not block differentiation and embryogenesis, but leads to partially penetrant embryonic and perinatal abnormalities and compromised viability. Moreover, the presence of substantial levels of 5hmC in DKO embryos and adult mice suggests a significant contribution of Tet3 in hydroxylation of 5mC during development. Methylation patterns in tissue samples from a series of wt and Tet1/Tet2 DKO embryos, neonates and adults were generated using methylated DNA immunoprecipitation with antibodies against 5mC (MeDIP) and 5hmC (hMeDIP) followed by deep sequencing.

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

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

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

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Tet inactivation disrupts YY1 binding and long-range chromatin interactions to cause developmental defects in embryonic heart

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