Long-range gene regulation and 3D organisation of the Glioblastoma Genome: mechanisms underlying tumor heterogeneity and high invasiveness
Rearrangements in non-coding regulatory regions (e.g enhancers) has a high impact in gene expression in cancer. In this project, we are establishing a high-resolution map of the enhancer landscape and the 3D organisation of the glioblastoma genome. Studying this interplay between the regulatory and topological organisation of the genome is helping us understand how changes in the enhancer landscape contribute to malignancy in glioblastoma.
Glioblastoma (GBM) is the most lethal and aggressive, but also the most common, of all primary brain tumors. Most genetic variants that predispose to cancer are located in non-coding regions enriched in putative enhancers, whose systematic rearrangements have a high impact on gene expression in cancer. Despite the number of susceptibility loci identified in glioblastoma, a functional understanding of how the non-coding regulatory genome contributes to the pathogenesis is missing. In this study, we investigate how reprogramming of regulatory regions and topological changes in 3D chromatin organization determine gene dysregulation in glioblastoma, and how this subsequently contributes to malignancy, heterogeneity and invasiveness. To this end, we employ next generation sequencing approaches and bioinformatics analysis to map the enhancer landscape and topological organization of the glioblastoma genome in patient-derived human glioblastoma cell lines. By genome editing and live-cell imaging in both glioblastoma mouse models and human glioblastoma cell lines, we functionally validate the impact of the changes in the enhancer landscape in the malignancy of such tumor cells. The planned research will shed light on how the regulatory and topological architecture of the genome influences malignancy and integrates cues from the neurons in the tumor microenvironment to orchestrate gene expression in glioblastoma. The expected outcome will open up for new therapeutic opportunities in the field of glioblastoma by modulating the regulation of certain genes or the neuron-glioblastoma cell interaction.