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Genome Organization Drives Chromosome Fragility [END-seq]

ABSTRACT: In this study, we show that evolutionarily conserved chromosome loop anchors bound by CTCF and cohesin are vulnerable to DNA double strand breaks (DSBs) mediated by topoisomerase 2B (TOP2B). Polymorphisms in the genome that redistribute CTCF/cohesin occupancy concomitantly rewire DNA cleavage sites to novel contact domain boundaries. While transcription and replication coupled genomic rearrangements have been well documented, we demonstrate that DSBs at loop anchors are transcription-, replication-, and cell type- independent. DSBs are continuously formed throughout interphase, are enriched on both sides of strong topological domain borders, and frequently occur at breakpoint clusters commonly translocated in acute leukemias and prostate cancers. Thus, loop anchors serve as preferred and promiscuous fragile sites that generate DSBs and chromosomal rearrangements.

ORGANISM(S): Mus musculus Mus spretus Homo sapiens

PROVIDER: GSE99194 | GEO | 2017/06/28

SECONDARY ACCESSION(S): PRJNA387545

REPOSITORIES: GEO

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Genome Organization Drives Chromosome Fragility [nsRNA-seq]

Project description:In this study, we show that evolutionarily conserved chromosome loop anchors bound by CTCF and cohesin are vulnerable to DNA double strand breaks (DSBs) mediated by topoisomerase 2B (TOP2B). Polymorphisms in the genome that redistribute CTCF/cohesin occupancy concomitantly rewire DNA cleavage sites to novel contact domain boundaries. While transcription and replication coupled genomic rearrangements have been well documented, we demonstrate that DSBs at loop anchors are transcription-, replication-, and cell type- independent. DSBs are continuously formed throughout interphase, are enriched on both sides of strong topological domain borders, and frequently occur at breakpoint clusters commonly translocated in acute leukemias and prostate cancers. Thus, loop anchors serve as preferred and promiscuous fragile sites that generate DSBs and chromosomal rearrangements.

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Project description:In this assay, we aimed to investigate the occupancy of ZFP661 in the mouse genome and its possible role in regulating the occupancies of CTCF and cohesin, which are two key factors in establishing 3D chromatin structures. To achieve this, we performed ChIP-seq in ZFP661-3HA endogenously tagged mESCs (for ZFP661), Zfp661 knockout (KO) mESCs (for CTCF and RAD21), and ZFP661-3HA overexpressing (OE) mESCs (for ZFP661, CTCF, RAD21, KAP1, and H3K9me3). Our results reveal that 1) ZFP661 binding peaks were co-occupied with those of CTCF; 2) ZFP661 binds exclusively inside the CTCF loop anchors; and 3) ZFP661 can suppress cohesin binding at CTCF barriers without altering CTCF binding.

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Project description:This SuperSeries is composed of the SubSeries listed below, and presents the high throuput sequencing datasets that were generated as part of a larger study that investigates the role of CTCF and cohesin as key drivers of 3D-nuclear organization, anchoring the megabase-scale Topologically Associating Domains (TADs) that segment the genome. This study presents and validates a computational method to predict cohesin-and-CTCF binding sites that form intra-TAD DNA loops. The intra-TAD loop anchors identified are structurally indistinguishable from TAD anchors regarding binding partners, sequence conservation, and resistance to cohesin knockdown; further, the intra-TAD loops retain key functional features of TADs, including chromatin contact insulation, blockage of repressive histone mark spread, and ubiquity across tissues. The intra-TAD loops are proposed to be formed by the same loop extrusion mechanism as the larger TAD loops; their shorter length enables finer regulatory control in restricting enhancer-promoter interactions, which enables selective, high-level expression of gene targets of super-enhancers and genes located within repressive nuclear compartments. These findings elucidate the role of intra-TAD cohesin-and-CTCF binding in nuclear organization associated with widespread insulation of distal enhancer activity.

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