Jeroen de Ridder, Bioinformatics Lab, EWI, TU Delft

3D hotspots of recurrent retroviral insertions reveal long-range interactions with cancer genes

In this talk, I will present our finding that cancer-causing DNA integrations are clustered in the 3D genome. This is a strong indication that these integrations can target cancer genes through long-range DNA interactions and shed new light on the repertoire of cancer genes identified with insertional mutagenesis screening.

Evidence is mounting that the organization of the genome in the cell nucleus is extremely important for gene regulation. This finding is facilitated by recent technological advances (i.e. Hi-C) that enabled researchers to accurately capture the 3D conformation of chromosomes in the cellular nucleus at a high resolution. In this work, we have exploited a large existing Hi-C dataset to take 3D chromosome conformation into account while determining hotspots of viral cancer-causing mutations. I will show that the identified hotspots are significantly enriched for known cancer genes, and bear the expected characteristics of bona-fide regulatory interactions, such as enrichment for transcription factor binding sites. Additionally, we observe a striking pattern of mutual exclusive integration. This is an indication that insertions in these loci target the same gene through long-range interactions.

In my talk, I will focus on the computational and statistical methods that are required to make an insightful overlay of ~20.000 cancer-causing retroviral mutations with high-resolution conformation maps obtained using Hi-C. Moreover, I will share the results of a similar analysis  that shows a striking relation between genome conformation and expression correlation in the brain, obtained from the Allan Brain Atlas.