Role of TET proteins in B cells and Treg cells
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Role of TET proteins in B cells and Treg cells

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DNA demethylation is promoted by TET enzymes, a family of three proteins -TET1, TET2 and TET3- which oxidize methyl group of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). TET proteins have been previously associated to cancer. In particular, Tet2 loss of function is strongly associated to haematopoietic malignancies in humans, such as B cell and T cell lymphoma. In this dissertation we explore the role of TET proteins in B and Treg cells. To do this we rely in the use of in vivo and in vitro models. We generated a mouse model with Tet2/3 deletion, CD19 Tet2/3 DKO mice. The TET deficient mice showed an expansion of Germinal Center B cells and developed B cell lymphoma, as early as 6 weeks of age; coupled to this, we observed an increase of G-quaruplexes and R-loops and increase of DNA damage. Mice generated with the adiddtional deletion of DNMT1, the enzyme responsible to maintain DNA methylation and also a G-quadruplex binding protein, on top of the Tet2/3 deletion, showed an inhibition of Germinal Center B cells and a significant delay on B cell lymphoma. We also explored the role of TET proteins in Treg cells using genomic and epigenomic approaches in in vivo and in vitro models. The Tet2/3 deficient Treg cells showed a loss of Treg-specific molecular features, and an impairement of IL-2/STAT5 signaling pathway. In our in vitro system, we induced Treg (iTreg) cells with TGF and treated them with Vitamin C, a potent activator of TET proteins and other dioxygenases. Oposite to what we observed in vivo, boosting TET activity with Vitamin C enhanced IL-2 responsiveness in iTreg cells by increasing IL2R expression and STAT5 activity.

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This item is under embargo until June 27, 2024.