The Profiles of Tet-Mediated DNA Hydroxymethylation in Human Gliomas

Abstract

Gliomas are the most common primary malignant intracranial brain tumors. Their proliferative and invasive behavior is controlled by various epigenetic mechanisms. 5-hydroxymethylcytosine (5-hmC) is one of the epigenetic DNA modifications that employs ten-eleven translocation (TET) enzymes to its oxidation. Previous studies demonstrated altered expression of 5-hmC across gliomagenesis. However, its contribution to the initiation and progression of human gliomas still remains unknown. To characterize the expression profiles of 5-hmC and TET in human glioma samples we used the EpiJET 5-hmC and 5-mC Analysis Kit, quantitative real-time PCR, and Western blot analysis. A continuous decline of 5-hmC levels was observed in solid tissue across glioma grades. However, in glioblastoma (GBM), we documented uncommon heterogeneity in 5-hmC expression. Further analysis showed that the levels of TET proteins, but not their transcripts, may influence the 5-hmC abundance in GBM. Early tumor-related biomarkers may also be provided by the study of aberrant DNA hydroxymethylation in the blood of glioma patients. Therefore, we explored the patterns of TET transcripts in plasma samples and we found that their profiles were variously regulated, with significant value for TET2. The results of our study confirmed that DNA hydroxymethylation is an important mechanism involved in the pathogenesis of gliomas, with particular reference to glioblastoma. Heterogeneity of 5-hmC and TET proteins expression across GBM may provide novel insight into define subtype-specific patterns of hydroxymethylome, and thus help to interpret the heterogeneous outcomes of patients with the same disease.

The Spectrum of Molecular Pathways in Gliomas—An Up-to-Date Review

“…Demethylation is the process of oxidative conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) by the so-called ten-eleven translocase enzymes (TETs). Reduced expression of TET enzymes and a decrease in 5hmC levels have been described in gliomas, with the reduction being much more pronounced in glioblastomas than in gliomas with a lower tumor grade [ 172 , 173 ]. Ascorbate, a cofactor of TET enzymes, was also significantly reduced in gliomas, with significantly lower levels in glioblastomas [ 173 ].…”

Novel insights on genetics and epigenetics as clinical targets for paediatric astrocytoma

“…In pHGG such as GBM, an oncometabolite, 2‐hydroxy glutarate which accumulates due to the mutation of IDH gene, affects the structure of chromatin by altering epigenetic variables such as histone post‐translational modification and global DNA methylation. This impairment leads to the inhibition of ten‐eleven translocation ( TET )‐mediated demethylation leading to hypermethylation in the cells and as a result, a drop in patient survival was observed 118 . Other non‐recurrent epigenetic mutations found in pA include chromodomain helicase DNA‐binding proteins, lysine‐specific demethylase, polycomb repressive complex 2, histone deacetylase 2, histone‐lysine N‐methyltransferase enzyme ( EZH2 and SET2 ), histone demethylase ( JARID1C ) and H3 K4 mono‐methyltransferase ( MLL2 ) 114 .…”

“…This impairment leads to the inhibition of ten‐eleven translocation ( TET )‐mediated demethylation leading to hypermethylation in the cells and as a result, a drop in patient survival was observed. 118 Other non‐recurrent epigenetic mutations found in pA include chromodomain helicase DNA‐binding proteins, lysine‐specific demethylase, polycomb repressive complex 2, histone deacetylase 2, histone‐lysine N‐methyltransferase enzyme ( EZH2 and SET2 ), histone demethylase ( JARID1C ) and H3 K4 mono‐methyltransferase ( MLL2 ). 114 In addition, other methylation markers in pA include genes involved in WNT signalling pathway such as secreted frizzled related protein (SFRP) group of proteins, those involved in STAT signalling pathway such as RASSF (Ras association domain family member), those involved in cell migration, proliferation and apoptosis such as slit guidance ligand 2 ( SLIT2 ), epithelial membrane protein 3 ( EMP3 ) and receptor for RANK‐ligand ( RANK ), respectively.…”

MiR-10b-5p Impairs TET2-Mediated Inhibition of PD-L1 Transcription Thus Promoting Immune Evasion and Tumor Progression in Glioblastoma

“…the pathogenesis of gliomas(Bragiel-Pieczonka et al 2022).Chen et al showed the glioma grade advanced as the TET2 expression decreased partially due to Zinc finger E-box-binding homeobox 1 in non-stem-like cell GBM models(Chen et al 2017). When concerning TET2 involvement in lymphoid and myeloid cell development and its functional roles, we discussed how TET2 activities are modulated by microRNAs.…”