PO42A NOVEL POLYCOMB FEED FORWARD LOOP IN GLIOBLASTOMA

Abstract

INTRODUCTION: Glioblastoma (GBM) is the most common malignant adult brain tumour. Polycomb group proteins (PcG) are chromatin modifiers that maintain heritable gene repression. We recently showed that overexpression of the PcG gene Bmi1 (Bmi1Over) in murine neural stem cells (NSC) increased their proliferation and self-renewal without inducing glioma formation. However, downregulation of Bmi1 expression in GBM initiating cells (GBM-IC) severely impairs their proliferation, raising the possibility that Bmi1 plays a role in tumour maintenance rather than initiation. At the mechanistic level, we observed accumulation of H3K27me3 at the promoter region of selected functionally relevant target genes in both non-neoplastic and neoplastic context. METHOD: H3K27me3 ChIPSeq and RNASeq were performed on GBM-IC as compared to Bmi1Over NSC and controls. System biology analysis (IPA) and functional validation with qRT-PCR were carried out. RESULTS: 180 genes were uniquely marked for H3K27me3 in GBM-IC and their expression was downregulated as compared to both Bmi1Over and wild type NSC. 121 of these genes had the peak in the extended promoter region. IPA analysis revealed significant enrichment in canonical pathways such as axonal guidance signalling, basal cell carcinoma signalling and Wnt signalling. Metaanalysis of a publicly available human GBM-IC ChIPSeq dataset confirmed similar deregulation of a proportion of the genes and pathways identified. CONCLUSION: Elucidating the molecular mechanisms of the epigenetic dysregulation observed in GBM is essential for the identification of novel biomarkers and also offers an opportunity to identify novel druggable targets or drug repositioning opportunities for more effective therapies.