Ten eleven translocation (TET) enzymes are composed of three representatives: TET1/2/3 which are involved in the hydroxymethylation of methylated cytosines. Because of the wide array of processes that are governed by these epigenetic marks, there have been a wide range of clinical effects associated with TET alterations. Even though many research groups have focused on analyzing the effect of TET alterations within certain cells, few have taken into consideration the effect of TET in the context of intercellular communication. One important entity through which intercellular communication occurs is represented by exosomes. Thus, in the current viewpoint we discussed the direct transfer of TET by exosomes, its alterations in the cell targeted by exosomes and the effect of TET alterations on exosome secretion.
Ten eleven translocation (TET) enzymes are composed of three representatives: TET1/2/3 which are involved in the hydroxymethylation of methylated cytosines. This not only initiates the process of demethylation, but also determines the generation of another epigenetic mark, 5-hydroxymethylcytosine (
Thus, we will further discuss the direct transfer of TET by exosomes, its alterations in target cells and the effect of TET alterations on exosome secretion (
One manner through which exosomes can alter the target cell is through the direct transfer of proteins and increase in their level within the target cell. In this context, it has been shown that CD137 activation reduces the loading of TET2 within exosomes secreted by endothelial cells, thus reducing the TET2 that would normally be transferred to smooth muscle cells. Normally, the physiological transfer of TET2 from endothelial cells protects smooth muscle cells from phenotype switch, inducing an anti atherosclerotic effect. The reduction of TET2 transfer is associated with an increased phenotype switch in smooth muscle cells and atherosclerosis promotion (
Current studies have shown that TET activity in the target cell can be altered either through the influence of microRNAs or through certain metabolites shuttled via exosomes. Nonetheless, because of the small number of studies currently present in the literature, there might also be other manners through which TET enzymes within the target cell might be affected by exosomes.
In the case of hepatocellular carcinoma, exosomes secreted from the malignant clone were shown to have a higher miR-21 content, which can alter the level of TET1/2/3 in the target cell. This, indirectly activates the PI3K/AKT pathway
Added to this, certain metabolites that influence the activity of TET in the target cell can be transferred
Alteration of TET enzymes activity can also affect both exosome loading and secretion. TET1/2 knock-out experiments in bone marrow mesenchymal stem cells showed that exosome secretion is reduced, which further leads to the intracellular accumulation of miR-297a/b/c. This is important as these reduce the activity of RUNX2, thus inhibiting the role of bone marrow mesenchymal stem cells in bone formation, and further explaining the osteopenic phenotype a TET1/2 knock-out mice model presents (
In the future it is possible that more studies showing the interdependence between exosomes and TET signaling will be made. Considering the wide range of processes in which TET signaling is a key component of (