Deciphering the TET3 interactome in primary thymic developing T cells

Theofilatos, Dimitris; Ho, Tricia; Waitt, Greg; Äijö, Tarmo; Schiapparelli, Lucio M.; Soderblom, Erik J.; Tsagaratou, Ageliki

doi:10.1016/j.isci.2024.109782

Cited by 4 publications

References 135 publications

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Concomitant loss of TET2 and TET3 results in T cell expansion and genomic instability in mice

Gioulbasani,

Äijö,

Liu

et al. 2024

Commun Biol

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Ten eleven translocation (TET) proteins are tumor suppressors that through their catalytic activity oxidize 5-methylcytosine to 5-hydroxymethylcytosine, to promote DNA demethylation and to regulate gene expression. Notably, TET2 is one of the most frequently mutated genes in hematological malignancies, including T cell lymphomas. However, murine models with deletion of TET2 do not exhibit T cell expansion, presumably due to redundancy with other members of the TET family of proteins. In order to gain insight on the TET mediated molecular events that safeguard T cells from aberrant proliferation we performed serial adoptive transfers of murine CD4 T cells that lack concomitantly TET2 and TET3 to fully immunocompetent congenic mice. Here we show a progressive acquisition of malignant traits upon loss of TET2 and TET3 that is characterized by loss of genomic integrity, acquisition of aneuploidy and upregulation of the protooncogene Myc .

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Concomitant loss of TET2 and TET3 results in T cell expansion and genomic instability in mice

Gioulbasani,

Äijö,

Liu

et al. 2024

Commun Biol

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Predicting Differentially Methylated Cytosines in TET and DNMT3 Knockout Mutants via a Large Language Model

Sereshki,

Lonardi

2024

Preprint

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DNA cytosine methylation is an epigenetic marker which regulates many cellular processes. Mammalian genomes typically maintain consistent methylation patterns over time, except in specific regulatory regions like promoters and certain types of enhancers. The dynamics of DNA methylation is controlled by a complex cellular machinery, in which the enzymes DNMT3 and TET play a major role. This study explores the identification of differentially methylated cytosines (DMCs) in TET and DNMT3 knockout mutants in mice and human embryonic stem cells. We investigate (i) whether a large language model can be trained to recognize DMCs from the sequence surrounding the cytosine of interest, (ii) whether a classifier trained on human knockout data can predict DMCs in the mouse genome (and vice versa), (iii) whether a classifier trained on DNMT3 knockout can predict DMCs for TET knockout (and vice versa). Our study identifies statistically significant motifs associated with the prediction of DMCs each mutant, shedding new light on the understanding of DNA methylation dynamics in stem cells. Our software tool is available at https://github.com/ucrbioinfo/dmc_prediction.

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TET proteins regulate Drosha expression and impact microRNAs in iNKT cells

Gioulbasani,

Äijö,

Valenzuela

et al. 2024

Front. Immunol.

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DNA demethylases TET2 and TET3 play a fundamental role in thymic invariant natural killer T (iNKT) cell differentiation by mediating DNA demethylation of genes encoding for lineage specifying factors. Paradoxically, differential gene expression analysis revealed that significant number of genes were upregulated upon TET2 and TET3 loss in iNKT cells. This unexpected finding could be potentially explained if loss of TET proteins was reducing the expression of proteins that suppress gene expression. In this study, we discover that TET2 and TET3 synergistically regulate Drosha expression, by generating 5hmC across the gene body and by impacting chromatin accessibility. As DROSHA is involved in microRNA biogenesis, we proceed to investigate the impact of TET2/3 loss on microRNAs in iNKT cells. We report that among the downregulated microRNAs are members of the Let-7 family that downregulate in vivo the expression of the iNKT cell lineage specifying factor PLZF. Our data link TET proteins with microRNA expression and reveal an additional layer of TET mediated regulation of gene expression.

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Deciphering the TET3 interactome in primary thymic developing T cells

Cited by 4 publications

References 135 publications

Concomitant loss of TET2 and TET3 results in T cell expansion and genomic instability in mice

Concomitant loss of TET2 and TET3 results in T cell expansion and genomic instability in mice

Predicting Differentially Methylated Cytosines in TET and DNMT3 Knockout Mutants via a Large Language Model

TET proteins regulate Drosha expression and impact microRNAs in iNKT cells

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