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BACKGROUND: Dysregulation of epigenetic mechanisms, together with genetic mutations, is an essential driver in the progression of malignant gliomas. Polycomb group proteins (PcG) are chromatin associated proteins that play an essential role in epigenetic regulation of gene expression by maintaining heritable gene repression through histone modification and chromatin compaction. We have recently demonstrated that conditional overexpression of Bmi1 in neural stem cells (NSC) increased their proliferation and self-renewal while overexpression of Bmi1 in intermediate progenitors committed toward the neuronal lineage triggered apoptosis. At the mechanistic level, in Bmi1-overexpressing NSC we observed downregulation of both the p21/Foxg1 and the ink4a/arf pathways, the latter of which coincided with the accumulation of H3K27me3 at the promoter region of the p16ink4a gene, thus indicating the key role of this modification as downstream effector of Bmi1-induced silencing. Moreover, we have shown that a similar mechanism is also responsible for silencing expression of Survivin, a key antiapoptotic factor, in committed neuronal progenitors, thereby leading to their apoptosis. H3K27me3 serves as a docking site to recruit PRC1; consistently we found increased binding of Bmi1 to the promoter region of Survivin upon Bmi1 overexpression. Together, this convergent evidence points to increased trimethylation of H3K27 as a core mechanism mediating the functional outcome of Bmi1 upregulation. Despite the wealth of suggestive evidence linking perturbations in H3K27 methylation to the development of malignant gliomas, it is still unclear how aberrant H3K27me3 contributes to gliomagenesis. METHODS: Genetically engineered mouse models of high grade gliomas and tumour initiating cells derived thereof as well as chromatin immunoprecipitation followed by target specific or genome wide screening and functional validation assays were used. RESULTS: Interestingly, we show that Bmi1-mediated regulation of the expression of Survivin was strikingly similar in GBM-IC as observed in NSC. Our data show that mGBM-IC isolated from a mouse model of glioblastoma express similar level of Bmi1 as detected in NSC isolated from NestinCre;STOPFloxBmi1 and knock down of Bmi1 significantly hampers proliferation of mGBM-IC. The epigenetic regulation of the expression of Bmi1 target genes in these cells was very similar to non-neoplastic NSC overexpressing Bmi1 and significant reduction of H3K27me3 was seen in these cells upon Bmi1 knockdown. CONCLUSIONS: Elucidating the molecular mechanisms of the epigenetic dysregulation observed in high grade gliomas is essential for the identification of novel biomarkers of early stage tumours and of novel druggable targets for more effective therapeutic interventions. SECONDARY CATEGORY: n/a.

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