title: Spatial organization of the mouse genome and its role in recurrent chromosomal translocations.
abstract: The extent to which the three-dimensional organization of the genome contributes to chromosomal translocations is an important question in cancer genomics. We generated a high-resolution Hi-C spatial organization map of the G1-arrested mouse pro-B cell genome and used high-throughput genome-wide translocation sequencing to map translocations from target DNA double-strand breaks (DSBs) within it. RAG endonuclease-cleaved antigen-receptor loci are dominant translocation partners for target DSBs regardless of genomic position, reflecting high-frequency DSBs at these loci and their colocalization in a fraction of cells. To directly assess spatial proximity contributions, we normalized genomic DSBs via ionizing radiation. Under these conditions, translocations were highly enriched in cis along single chromosomes containing target DSBs and within other chromosomes and subchromosomal domains in a manner directly related to pre-existing spatial proximity. By combining two high-throughput genomic methods in a genetically tractable system, we provide a new lens for viewing cancer genomes.
authors.affiliation: Howard Hughes Medical Institute, Children's Hospital Boston and Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Rachel Patton
authors.initials: RP
authors.lastname: McCord
authors.forename: Yu-Jui
authors.initials: YJ
authors.lastname: Ho
authors.forename: Bryan R
authors.initials: BR
authors.lastname: Lajoie
authors.forename: Dominic G
authors.initials: DG
authors.lastname: Hildebrand
authors.forename: Aline C
authors.initials: AC
authors.lastname: Simon
authors.forename: Michael S
authors.initials: MS
authors.lastname: Becker
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Alt
authors.forename: Job
authors.initials: J
authors.lastname: Dekker
mesh_terms: D000818:Animals; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D016193:G1 Phase; D016678:Genome; D059014:High-Throughput Nucleotide Sequencing; D051379:Mice; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology; D011946:Receptors, Antigen / Q000235:genetics; D014178:Translocation, Genetic
chemical_list: D011946:Receptors, Antigen