O4.07 A NOVEL POLYCOMB FEED FORWARD LOOP IN GLIOBLASTOMA MULTIFORME

• Published in: Neuro-oncology (Charlottesville, Va.) Va.), 2014-09, Vol.16 (suppl 2), p.ii8-ii8
• Main Authors: Marino, S., Ceric, D., Ricci, B., Barnes, M.
• Format: Article
• Language: English
• ISSN: 1522-8517; 1523-5866
• DOI: 10.1093/neuonc/nou174.28

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. 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. Together, this convergent evidence points to increased trimethylation of H3K27 as a core mechanism mediating the functional outcome of Bmi1 upregulation. Bmi1 is overexpressed in a significant proportion of high grade gliomas and a wealth of suggestive evidence linking perturbations in H3K27 methylation to the development of these tumours exist, although it is still unclear how aberrant H3K27me3 contributes to gliomagenesis. Here, we used genetically engineered mouse models to study overexpression of PcG gene Bmi1 in NSC and GBM initiating cells (GBM-IC). ChIP followed by genome wide screening was carried out and the results analysed in combination with gene expression as assessed by RNASeq. We show that Bmi1-mediated regulation of the expression of Survivin was strikingly similar in GBM-IC as observed in NSC. 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. Similar to what observed in non-neoplastic NSC overexpressing Bmi1 a significant reduction of H3K27me3 was seen in these cells upon Bmi1 knockdown. Genome wide ChIPSeq analysis for H3K27me3 and RNASeq performed on NSC overexpressing Bmi1 and GBM-IC expressing similar level of Bmi1 allowed us to set these results in the wider context of the global epigenetic regulation of gene expression