Transposable Element Dynamics in Glioblastoma Stem Cells: Insights from Locus-Specific Quantification

Background: Glioblastoma, the most common primary malignant brain tumor, has a median survival of less than two years. This is due in part to a subpopulation of cells called glioblastoma stem cells (GSCs), which drive tumor recurrence. Transposable elements (TEs) are expressed at higher levels in cancer stem cells, enhancing the oncogenic potential and plasticity of cells through changes in gene expression, fusion transcript generation, and genomic rearrangement. Results: Leveraging a large previously published dataset, we investigated the expression of TEs in bulk RNA sequencing data from 42 GSCs to identify subpopulations defined by their TE expression profile. Using telescope, a locus-specific approach to quantifying TE expression, we identified 858 TE loci that were expressed and defined two groups of GSCs using a consensus clustering approach. These TE-driven clusters displayed significant differences in both transcription factor (TF) and gene expression, with one group significantly enriched for a mesenchymal signature based on Gene Set Enrichment Analysis. Next, we extracted the locations and sequences of the TE regulatory domains and elucidated TF binding motifs within the TE sequences. This showed that the SOX11 consensus motif was enriched in the 5’ untranslated region of differentially expressed long interspersed nuclear elements (LINE). SOX11, a known inducer of LINE expression, was significantly under-expressed in the mesenchymal GSC cluster, which correlated with the concurrent decreased expression of LINE transcripts. These loci also overlapped with the enhancer elements of genes that were significantly downregulated, suggesting a potential link between TF binding to TE regulatory regions and gene expression. Conclusions: Although further mechanistic studies are required, the identified link between TE location, TE and TF expression, and corresponding gene expression suggests that TEs may play a regulatory role in GSC transcription regulation. The current findings highlight the need for further investigation into the role of TEs in defining the gene regulatory and expression landscapes of GSCs. Future studies in this area could have therapeutic implications, given that glioblastoma recurrence may be driven by these cells.