Abstract
Glioblastoma multiforme (GBM) exhibits considerable heterogeneity and associates with genome-wide alterations of the repressed chromatin marks DNA methylation and H3 lysine 27 trimethylation (H3K27me3). Tri-methylation on lysine 4 of histone H3 (H3K4me3) is an activating epigenetic mark that is enriched at promoter and promotes expression. It will be helpful in GBM diagnosis and treatment to identify the alteration of H3K4me3 between human GBM and GBM-surrounding tissues. Here, we performed an analysis using next-generation sequencing techniques to identify H3K4me3 modification in a case of GBM and the GBM-surrounding tissues. The results revealed a global decrease in H3K4me3 in GBM, especially at promoters and CpG islands. In GBM, homeobox genes gain H3K4me3, whereas the cell-cell adhesion-related cadherin genes lose H3K4me3. The products of the homeobox genes are highly connected with Ras-signalling and PI3K-Akt signalling pathways. Using The Cancer Genome Atlas (TCGA) data, we inferred the homeobox-regulated genes' expression is higher in 548 GBM cases than in 27 lower grade glioma cases giving that OLIG2 expression can be a reference. The results suggested that the H3K4me3 alteration is related to the formation and migration of GBM cells. We also found an extremely high reads count at epidermal growth factor receptor (EGFR) promoter, probably due to an amplification of copy number. Our analysis provides a case study about the change of H3K4me3 during shift to GBM.
Highlights
Glioblastoma multiforme (GBM) is an aggressive and lethal cancer
tri-methylation on lysine of histone H3 (H3K4me3) levels decrease in GBM compared with GBM-surrounding tissue We examined H3K4me3 profiles around specific genomic sites (Figure 1A)
We found that H3K4me3 levels decrease at promoters and CpG islands in GBM compared with the control (Figure 1A), which is in agreement with previous studies [1,7]
Summary
Sturm et al [1] suggested six subgroups for GBM: isocitrate dehydrogenase (IDH), K27, G34, RTK I and II, and MES [1]. The first three subgroups are associated with mutations IDH1 (R132H), H3F3A (K27) and H3F3A (G34); and the subgroups RTK I and II are associated with plateletderived growth factor receptor (PDGFRA) and epidermal growth factor receptor (EGFR) amplifications respectively and both with CDKN2A deletion [1]. Aberrant epigenetic alteration contributes to GBM [1,2]. IDH, K27 and G34 subgroups show alterations in both DNA methylation and tri-methylation on. IDH1 subgroup displays hypermethylation, whereas H3F3A (G34) subgroup shows hypomethylation [3,4]. Global reductions of H3K27me and H3K27me were found in H3F3A (K27M) subgroup [4]. In IDH1-mutated cells, it was thought that overproduction of 2-hydroxyglutarate inhibits the TET family of 5-methylcytosine hydroxylases and H3K27-specific demethylases, leading to a decrease in 5hydroxymethylcytosine and an increase in H3K27 methylation [5]
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