Nuclear exclusion of TET1 is associated with loss of 5-hydroxymethylcytosine in IDH1 wildtype gliomas

IDH1 mutations are associated with a CpG island methylator phenotype in glioblastomas. Cells harboring IDH1 mutations produce 2-hydroxyglutarate inhibiting TET enzymes involved in the oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). Glioma tissues and cell lines were investigated by RT-PCR, immunohistochemistry and pyrosequencing for the expression of TET enzymes, 5hmC content and IDH1 status respectively. 61% of gliomas revealed no immunoreactivity for 5-hmC and no correlation was observed between IDH1 mutations and loss of 5hmC. The subcellular localization of TET1 showed remarkable differences. IDH1 mutations were significantly correlated with nuclear accumulation of TET1. 70% of 5-hmC negative gliomas showed either exclusive or dominant cytoplasmic expression of TET1 suggesting that its nuclear exclusion may influence the 5hmC content of cells.