Spatial organization of the mouse genome and its role in recurrent chromosomal translocations
Program in Gene Function and Expression; Program in Systems Biology; Department of Biochemistry and Molecular Pharmacology
Medical Subject Headings
Animals; DNA Breaks, Double-Stranded; G1 Phase; *Genome; High-Throughput Nucleotide Sequencing; Mice; Mice, 129 Strain; Mice, Inbred BALB C; Neoplasms; Precursor Cells, B-Lymphoid; Receptors, Antigen; *Translocation, Genetic
Biochemistry, Biophysics, and Structural Biology | Genetics and Genomics | Systems Biology
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.
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Citation: Cell. 2012 Mar 2;148(5):908-21. Epub 2012 Feb 16. Link to article on publisher's site