title: 3D hotspots of recurrent retroviral insertions reveal long-range interactions with cancer genes.
abstract: Genomically distal mutations can contribute to the deregulation of cancer genes by engaging in chromatin interactions. To study this, we overlay viral cancer-causing insertions obtained in a murine retroviral insertional mutagenesis screen with genome-wide chromatin conformation capture data. Here we find that insertions tend to cluster in 3D hotspots within the nucleus. 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. In addition, we observe a striking pattern of mutual exclusive integration. This is an indication that insertions in these loci target the same gene, either in their linear genomic vicinity or in their 3D spatial vicinity. Our findings shed new light on the repertoire of targets obtained from insertional mutagenesis screening and underline the importance of considering the genome as a 3D structure when studying effects of genomic perturbations.
authors.affiliation: Delft Bioinformatics Lab, Faculty of Electrical Engineering Mathematics and Computer Science, Delft University of Technology, Mekelweg 4, 2628 CD Delft, The Netherlands.
authors.forename: Sepideh
authors.initials: S
authors.lastname: Babaei
authors.affiliation: Division of Molecular Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Waseem
authors.initials: W
authors.lastname: Akhtar
authors.affiliation: Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Johann
authors.initials: J
authors.lastname: de Jong
authors.affiliation: Delft Bioinformatics Lab, Faculty of Electrical Engineering Mathematics and Computer Science, Delft University of Technology, Mekelweg 4, 2628 CD Delft, The Netherlands.
authors.forename: Marcel
authors.initials: M
authors.lastname: Reinders
authors.affiliation: Delft Bioinformatics Lab, Faculty of Electrical Engineering Mathematics and Computer Science, Delft University of Technology, Mekelweg 4, 2628 CD Delft, The Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: de Ridder
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000276:immunology; D002843:Chromatin / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000276:immunology*; D052138:Genes, Neoplasm / Q000235:genetics*; D051379:Mice; D016254:Mutagenesis, Insertional / Q000379:methods; D012192:Retroviridae Infections / Q000235:genetics / Q000821:virology*; D016662:Virus Integration / Q000235:genetics*
chemical_list: D002843:Chromatin