Depletion of 5-hydroxymethylcytosine in aggressive G-CIMP subtype

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5-hydroxymethylcytosine (5hmC) is an oxidation product of 5-methylcytosine, a reaction potentially mediated by the Tet family of enzymes. Levels of 5hmC were reported to be lower in glioblastoma and because gliomas carrying an IDH1/2 mutation (high or low grade) manifest a CpG island methylator phenotype (G-CIMP), we decided to investigate 5hmC levels in G-CIMP subtypes, G-CIMP-high and G-CIMP-low, due to their distinct clinical outcome, independent of histological grade. We generated genome-wide maps of 5hmC for G-CIMP-low (n=4) and G-CIMP-high (n=6) samples by hMeDIP-seq (∼ 46M reads per sample). We also have additional whole-genome bisulfite sequencing (WGBS) data for G-CIMPlow (n=1), G-CIMP-high (n=2) and non-tumor brain (n=2) samples. When we compared hMeDIP-seq with WGBS, we found a positive correlation between DNA hypomethylation and depletion of 5hmC in G-CIMPlow. As reported in previous studies, the highest concentration of 5hmC is within gene bodies (75% vs. 25% in intergenic regions). However, we observed an unbalanced level of 5hmC in G-CIMP subtypes (68,397 5hmC peaks lost in G-CIMP-low vs. 2,554 gained, FDR < 0.05). G-CIMP-high has an abundant number of 5hmC peaks, whereas G-CIMP-low seems to have poor 5hmC density in the same regions. We observed G-CIMP-low may arise from G-CIMP-high during tumor recurrence, and we suggest that loss of 5hmC within G-CIMP tumors lead to a more aggressive phenotype. Interestly, 85% of peaks associated with loss of 5hmC overlap regions with loss of intergenic enhancer activity in G-CIMP-low, as defined by H3K27ac peaks. Furthermore, 22% of genes with intronic loss of 5hmC in G-CIMP-low samples are downregulated (FDR < 0.05). We did not find any distinct genomic alterations associated with G-CIMP-low nor did we observe differential expression of genes from the Tet family, we suggest that a yet to be determined alternative mechanism may be driving an aberrant loss of 5hmC in G-CIMP-low.




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