Spatial Organization of the Mouse Genome and Its Role in Recurrent Chromosomal Translocations

Abstract

SUMMARY The extent to which the three dimensional organization of the genome contributes to chromosomal translocations is an important question in cancer genomics. We now have generated a high resolution Hi-C spatial organization map of the G1-arrested mouse pro-B cell genome and mapped translocations from target DNA double strand breaks (DSBs) within it via high throughput genome-wide translocation sequencing. 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 co-localization 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 sub-chromosomal domains in a manner directly related to pre-existing spatial proximity. Our studies reveal the power of combining two high-throughput genomic methods to address long-standing questions in cancer biology.

Long-distance interaction of the integrated HPV fragment with MYC gene and 8q24.22 region upregulating the allele-specific MYC expression in HeLa cells

“…6). In supporting our notion, several studies have showed that distal regulatory elements can interact with not only their target genes but also other elements, and the formation of intricate three‐dimensional patterns involves genes and their regulatory elements hundreds of kb distant from each other in linear relationship 24, 25, 26…”

Iteratively improving Hi-C experiments one step at a time

“…The ability to represent 3D genome organization in terms of matrices of contact frequencies allows the characterization of structures across a variety of length scales, from the positioning of whole chromosome territories to the folding of small-scale enhancer-promoter loops [3,16,17]. Even when more focused resolution is desired, many techniques begin with an approach similar to Hi-C and then isolate a subpopulation of interactions of interest.…”

“…The billions of DNA bases in the eukaryotic genome must be efficiently packed to fit inside the micronsized nucleus and to perform necessary cellular functions including gene expression as well as DNA replication and repair [1][2][3]. Abnormal 3D packaging of chromatin may disrupt cellular homeostasis and lead to diseases [4,5].…”

Lechromothripsis

“…Ces séquences peuvent servir de zones de micro-homologie et, ainsi, faciliter le changement de matrice dans la réparation réplicative. La juxtaposition des territoires chromosomiques au sein du noyau, le regroupement de différents locus ou de motifs particuliers dans ces territoires spécifiques [43], ou encore leur proximité avec des zones de rétention des éléments de la machinerie de réparation ou de réplication (bulle de réplication) [44], sont autant d'éléments qui peuvent constituer le fondement structural de la survenue d'un si grand nombre de remaniements dans des régions chromosomiques distinctes et du regroupement des points de cassure en cluster. der (1) der (3) chr 1 chr 2…”