CHARACTERIZING THE MIRNA IMPRINTOME IN ADULT NEURAL STEM CELLS AND GLIOBLASTOMA

Glioblastoma multiforme (GBM) is the most aggressive brain tumor in humans and has the poorest survival rate after diagnosis. Neural stem cells (NSCs) are responsible for neurogenesis in the subventricular zone (SVZ) of the adult brain, giving rise to neurons, astrocytes and oligodendrocytes. According to the cancer stem cell theory, GBM may originate from the transformation of NSCs into glioblastoma stem cells, which drive tumor initiation, progression and therapy resistance. MicroRNAs (miRNAs) are small non-coding RNA molecules that post-transcriptionally repress the expression of target mRNAs. Dysregulated miRNA expression, has been described in multiple cancers, including GBM, reporting that they can act both as oncogenes and tumor suppressors. Notably, DNA methylation regulates miRNA biogenesis and expression, linking monoallelic expression of imprinted miRNAs to the global genomic hypomethylation characteristic of GBM. This work explores the potential role of imprinted miRNAs in GBM initiation and progression using NSCs derived from the murine SVZ and a GBM cell line generated from NSCs carrying multiple mutations observed in human GBM. Whole transcriptome sequencing revealed a highly altered miRNome, with 16% of miRNAs differentially expressed in GBM cells compared to adult NSCs. More strikingly, most expressed miRNAs within imprinting clusters exhibited significant expression changes. Importantly, we identified miR-296-3p and miR-298-5p, located at the Gnas cluster, as candidates with a potential shared role in quiescence and activation of adult NSCs and GBM cells. These results provide insights into how imprinted miRNAs may contribute to GBM malignancy as key regulators of gene expression in the adult brain.