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Chromosomal translocations are guided by the spatial organization of the genome

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE35519 | GEO | 2012/02/16

SECONDARY ACCESSION(S): PRJNA152237

REPOSITORIES: GEO

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Chromosomal translocations are guided by the spatial organization of the genome

Project description: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. Hi-C interaction maps for WT and ATM -/- G1-arrested AMuLV-transformed pro-B cell lines.

2012-02-16 | E-GEOD-35519 | biostudies-arrayexpress

Total protein abundances upon Mcm6 knockdown in the murine CH12 cells

Project description:Chromosomal translocations result from joining of DNA double-strand breaks (DSBs) and frequently cause cancer. Yet, the steps linking DSB formation to DSB ligation remain undeciphered. We report that DNA replication timing (RT) directly regulates lymphomagenic Myc translocations during antibody maturation in B-cells downstream of DSBs and independently of DSB frequency. Depletion of minichromosome-maintenance (MCM) complexes alters replication origin activity, decreases translocations and abrogates global RT. Ablating a single origin at Myc causes an early-to-late RT switch, loss of translocations and reduced nuclear proximity with a translocation partner locus, phenotypes that were reversed by restoring early RT. Disruption of shared early RT also reduced tumorigenic translocations in human leukemic cells. Thus, RT constitutes a new, unprecedented mechanism in translocation biogenesis linking DSB formation to DSB ligation

2022-09-13 | PXD034446 | Pride

Genome-wide detection of DNA double-stranded breaks induced by engineered nucleases

Project description:We describe a robust linear amplification-mediated high-throughput genome-wide translocation sequencing (HTGTS) method that identifies endogenous or ectopic "prey" DNA double-stranded breaks (DSBs) across the human genome based on their translocation to "bait" DSBs generated by engineered nucleases. HTGTS with different Cas9:gRNA or TALEN-nuclease on-target baits revealed off-target hotspots for given nucleases that ranged from few or none to dozens or more, and greatly extended known off-target numbers for certain previously characterized engineered nucleases by more than 10-fold. Beyond various types of nuclease off-target collateral damage, we also identified collateral damage in the form of translocations between bona fide nuclease targets on homologous chromosomes. Based on frequent non-specific DSBs making any given human chromosome an HTGTS hotspot region for bait DSBs within it, we found that HTGTS also reveals wide-spread, low-level DSB-generating activities of engineered nucleases. Finally, HTGTS confirmed that the Cas9D10A paired nickase approach suppresses off-targets genome-wide and suggested other strategies to enhance desired nuclease activities.

2014-11-29 | GSE57283 | GEO

Genome wide mapping of long range contacts unveils DNA Double Strand Breaks clustering at damaged active genes.

Project description:Translocations, that occur when two DNA Double Strand breaks (DSBs) are abnormally rejoined, represent highly deleterious genome rearrangements favoring cancer apparition and progression. However, the mechanisms that drive their formation are yet poorly deciphered. One prerequisite for translocation is the juxtaposition of two distant DSBs, an event that would be favored if DSB cluster, i.e. are brought together in close spatial proximity within the nucleus. Whether DSB cluster in higher eukaryotes has been subjected to a strong controversy over the past decade, due to conflicting results obtained using microscopy based methods1-9. Here we used for the first time a high throughput chromosome conformation capture assay (Capture Hi-C10) to investigate DSB clustering. We unambiguously found that DSBs do cluster in human nuclei but only when induced in transcriptionally active genes. Clustering of damaged genes mainly occur during the G1 cell cycle phase and coincide with delayed repair. Moreover DSB clustering depends on the MRN complex, as well as the Formin 2 (FMN2) nuclear actin organizer and the LINC (LInker of Nuclear and Cytoplasmic skeleton) complex, suggesting that active mechanisms promote DSB clustering. This work reveals that when damaged, active genes exhibit a very peculiar behavior compared to the rest of the genome, being mostly left unrepaired and clustered in G1 while being repaired by homologous recombination in post-replicative cells.

2017-04-19 | E-MTAB-4846 | biostudies-arrayexpress

High-throughput sequencing of genome-wide translocations from stimulated wild-type or ATM-deficient B cells

Project description:High-throughput genome-wide translocation sequencing (HTGTS) is a robust approach to identify genome-wide translocation junctions. We performed HTGTS to study the fate of introduced c-myc DSBs in mouse splenic B cells activated for activation cytidine deaminase (AID)-dependent class switch recombination (CSR). We found frequent translocations of c-myc DSBs to AID-initiated DSBs in IgH switch regions in wild-type (WT) and ATM-deficient B cells. However, c-myc also translocated frequently to newly generated DSBs within a 35-megabase region downstream of IgH in ATM-deficient, but not WT, CSR-activated B cells. Moreover, we found such DSBs and translocations in activated B cells that did not express AID or undergo CSR. These findings indicate that ATM deficiency leads to formation of chromosome 12 dicentrics via RAG-initiated IgH DSBs in progenitor B cells and that these dicentrics can be propagated developmentally into mature B cells where they generate new DSBs downstream of IgH via breakage-fusion-bridge cycles. Preparation of libraries from WT or ATM-deficient activated by a-CD40/IL4 or RP105.

2014-06-18 | E-GEOD-58599 | biostudies-arrayexpress

Transcription profiling of human lymphoblastoid cell line GM06690 in conjunction with Hi-C to determine the three-dimensional architecture of the genome

Project description:We describe Hi-C, a method that probes the three-dimensional architecture of whole genomes by coupling proximity-based ligation with massively parallel sequencing. We constructed spatial proximity maps of the human genome with Hi-C at a resolution of 1Mb. These maps confirm the presence of chromosome territories and the spatial proximity of small, gene-rich chromosomes. We identified an additional level of genome organization that is characterized by the spatial segregation of open and closed chromatin to form two genome-wide compartments. At the megabase scale, the chromatin conformation is consistent with a fractal globule, a knot-free conformation that enables maximally dense packing while preserving the ability to easily fold and unfold any genomic locus. The fractal globule is distinct from the more commonly used globular equilibrium model. Our results demonstrate the power of Hi-C to map the dynamic conformations of whole genomes. These expression data are used in the paper to show that there are marked differences in mRNA expression between loci in the open and closed chromatin compartments. Experiment Overall Design: Affy Expression array for GM06690 cells

2009-10-10 | E-GEOD-18350 | biostudies-arrayexpress

DNA replication timing directly regulates the frequency of oncogenic chromosomal translocations

Project description:Chromosomal translocations result from the joining of DNA double-strand breaks (DSBs) and frequentlycause cancer. However, the steps linking DSB formation to DSB ligation remain undeciphered. Wereport that DNA replication timing (RT) directly regulates lymphomagenicMyctranslocations duringantibody maturation in B cells downstream of DSBs and independently of DSB frequency. Depletion ofminichromosome maintenance complexes alters replication origin activity, decreases translocations,and deregulates global RT. Ablating a single origin atMyccauses an early-to-late RT switch, loss oftranslocations, and reduced proximity with the immunoglobulin heavy chain (Igh) gene, its majortranslocation partner. These phenotypes were reversed by restoring early RT. Disruption of early RT alsoreduced tumorigenic translocations in human leukemic cells. Thus, RT constitutes a general mechanismin translocation biogenesis linking DSB formation to DSB ligation.

2022-09-15 | GSE161818 | GEO

Chromosome positioning and the clustering of functionally related loci in yeast is driven by chromosomal interactions

Project description:In recent years there has been considerable and growing interest in the 3-dimensional organization of genomes. In yeast this has included detailed FISH studies that show a surprising degree of spatial clustering of the tRNA genes, the localization of telomeres, centromere positioning, and global studies of chromosomal interactions.M-BM- In this study we performed an integrated biophysical M-bM-^@M-^S molecular study to produce the first high-resolution 3-dimensional reconstruction of a eukaryotic genome from first principles. Our conformations were produced using a using a molecular dynamics simulator to model the 16 yeast chromosomes as individual polymers. Critically, the compaction, folding and spatial organization of these chromosomes was informed by empirical data determined using proximity-based ligation. Our models allow us to investigate the structural organization and functional spatial clustering of the yeast nucleus at a resolution that has not previously been possible. We clearly show that yeast chromosomes have preferred yet non-exclusive positions. Surprisingly, while there are general trends relating chromosome position along the spindle pole body M-bM-^@M-^S nucleolus axis and chromosome size, some chromosomes have territories that contain two linked domains. Similarly, there is clear evidence for functional clustering of tRNAs and Gal4 protein binding sites. Intriguingly, these functional clusters are dynamic and the identity of the component elements alters in different model solutions. Genome Conformation Capture has been performed on exponentially growing Saccharomyces cerevisiae in media containing Glucose

2012-07-18 | E-GEOD-33018 | biostudies-arrayexpress

High-throughput sequencing of genome-wide translocations from stimulated wild-type or ATM-deficient B cells

2014-06-18 | GSE58599 | GEO

DNA replication timing directly regulates the frequency of oncogenic chromosomal translocations [SNS-seq]

Project description:Many cancers originate from misregulation of gene expression caused by chromosomal translocations which result from ligation of DNA double-strand breaks (DSBs). Indeed, translocations may be causal in ~20% of human cancer morbidity 1. Although the sources of DSBs are numerous2-5, we have virtually no knowledge of the steps linking DSB formation to DSB ligation. Here, we show that early replication timing of translocation partner loci, mediated by the activity of replication origins, is a critical regulator of lymphomagenic Myc translocations generated by activation-induced deaminase (AID) during antibody maturation in B-cells. Reduced levels of the replicative helicase, the minichromosome maintenance (MCM) complex6, impairs translocation genesis, decreases firing of replication origins at AID target genes and globally abrogates the replication timing program without altering cell proliferation, gene expression or genome architecture. Strikingly, deleting a single origin of replication at Myc induces a switch from early-to-late replication at Myc with concomitantly impaired translocation frequency. This phenotype is reversed by restoring early replication at Myc thereby demonstrating a direct, causal role of replication origin activity and replication timing in translocation genesis. Finally, this replication timing-mediated step acts downstream of DSBs and is independent of DSB frequency, constituting a novel regulatory step in translocation biogenesis.

2022-09-15 | GSE161821 | GEO

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