When TADs go bad: chromatin structure and nuclear organisation in human disease

Kaiser, Vera B.; Semple, Colin A.

doi:10.12688/f1000research.10792.1

Cited by 57 publications

(39 citation statements)

References 41 publications

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“…Using breakpoint data from all 1,672 ICGC donors and the set of 14,737 high confidence LAPs, we find that genes within the top 5% most disrupted chromatin loops (possessing 5 or more SV breakpoints in their LAPs) are indeed enriched for functional annotation terms associated with proliferation and the G1/S cell cycle transition(Table 2)(Bertoli et al 2013). The enrichments of such putatively cancer-associated terms are often only marginally significant given current sample sizes, but are broadly consistent with the previously reported oncogenic disruptions(Kaiser and Semple 2017). Subdividing the dataset into more refined categories of breakpoints and LAPs (e.g.…”

supporting

confidence: 85%

“…This excess in overlap is notably larger than that observed for the background set of all HMEC loops and GWAS hits (225 observed overlaps and a mean of 143.6 expected overlaps, based on 5000 permutations; p = 0.001), suggesting a possible causal relationship between LAP disruption and the breast cancer phenotype. However, in common with previous studies (Kaiser and Semple 2017), it is unclear to what extent this relationship is driven by the mutational biases that we have demonstrated at LAPs or selective processes in tumours.…”

Section: Brca1/2 Deficient Breast Tumours Suffer Higher Mutation Loadmentioning

confidence: 43%

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Chromatin loop anchors are associated with genome instability in cancer and recombination hotspots in the germline

Kaiser

Semple

2017

Preprint

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Chromatin loops form a basic unit of interphase nuclear organisation, providing contacts between regulatory regions and target promoters, and forming higher level patterns defining self interacting domains. Recent studies have shown that mutations predicted to alter chromatin loops and domains are frequently observed in tumours and can result in the upregulation of oncogenes, but the combinations of selection and mutational bias underlying these observations remains unknown. Here, we explore the unusual mutational landscape associated with chromatin loop anchor points (LAPs), which are located at the base of chromatin loops and form a kinetic trap for cohesin.We show that LAPs are strongly depleted for single nucleotide variants (SNVs) in tumours, which is consistent with their relatively early replication timing. However, despite low SNV rates, LAPs emerge as sites of evolutionary innovation showing enrichment for structural variants (SVs). They harbour an excess of SV breakpoints in cancers, are prone to double strand breaks in somatic cells, and are bound by DNA repair complex proteins. Recurrently disrupted LAPs are often associated with genes annotated with functions in cell cycle transitions. An unexpectedly large fraction of LAPs (16%) also overlap known meiotic recombination hotspot (HSs), and are enriched for the core PRDM9 binding motif, suggesting that LAPs have been foci for diversity generated during recent human evolution. We suggest that the unusual chromatin structure at LAPs underlies the elevated SV rates observed, marking LAPs as sites of regulatory importance but also genomic fragility.

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confidence: 85%

Section: Brca1/2 Deficient Breast Tumours Suffer Higher Mutation Loadmentioning

confidence: 43%

Chromatin loop anchors are associated with genome instability in cancer and recombination hotspots in the germline

Kaiser

Semple

2017

Preprint

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“…There are clear evidence that CTCF binding sites play a major role in the genome organization and they are very significantly enriched at that TAD boundaries [3,4]. Hence, the deletion of these binding sites has a higher chance of leading to the TAD structure disruption and TAD fusion [21,36,37,38]. Thus, we evaluate the number of predicted TAD fusions that contain at least a CTCF binding site (figure 2.b).…”

Section: Evaluating the Tad Fusion Scorementioning

confidence: 99%

Contribution of structural variation to genome structure: TAD fusion discovery and ranking

Huynh

Hormozdiari

2018

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The significant contribution of structural variants to function, disease, and evolution is widely reported. However, in many cases, the mechanism by which these variants contribute to the phenotype is not well understood. Recent studies reported structural variants that disrupted the three-dimensional genome structure by fusing two topologically associating domains (TADs), such that enhancers from one TAD interacted with genes from the other TAD, and could cause severe developmental disorders. However, no computational method exists for directly scoring and ranking structural variations based on their effect on the three-dimensional structure such as the TAD disruption to guide further studies of their biological function. In this paper, we formally define TAD fusion and provide a combinatorial approach for assigning a score to quantify the level of TAD fusion for each deletion denoted as TAD fusion score. We also show that our method outperforms the approaches which use predicted TADs and overlay the deletion on them to predict TAD fusion. Furthermore, we show that deletions that cause TAD fusion are rare and under negative selection in general population. Finally, we show that our method correctly gives higher scores to deletions reported to cause various disorders (developmental disorder and cancer) in comparison to the deletions reported in the 1000 genomes project.

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“…CTCF binding also appears to be an informative variable, genome-wide in all models, though it binds at sites constituting a very small fraction of the genome. Given the critical roles of CTCF in chromatin architecture and regulation (32), there has been intense interest in the causes and effects of structural variants disrupting CTCF binding sites (35,36).…”

Section: Accurate Models Of Genome-wide Dsb Frequency Across Cell Typesmentioning

confidence: 99%

Modelling double strand break susceptibility to interrogate structural variation in cancer

Ballinger

Bouwman

Mirzazadeh

et al. 2018

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26Background: Structural variants (SVs) are known to play important roles in a 27 variety of cancers, but their origins and functional consequences are still poorly 28 understood. Many SVs are thought to emerge via errors in the repair processes 29 following DNA double strand breaks (DSBs) and previous studies have 30 experimentally measured DSB frequencies across the genome in cell lines. 31Results: Using these data we derive the first quantitative genome-wide models 32 of DSB susceptibility, based upon underlying chromatin and sequence features. 33These models are accurate and provide novel insights into the mutational 34 mechanisms generating DSBs. Models trained in one cell type can be successfully 35 applied to others, but a substantial proportion of DSBs appear to reflect cell type 36 specific processes. Using model predictions as a proxy for susceptibility to DSBs 37 in tumours, many SV enriched regions appear to be poorly explained by 38 selectively neutral mutational bias alone. A substantial number of these regions 39show unexpectedly high SV breakpoint frequencies given their predicted 40 susceptibility to mutation, and are therefore credible targets of positive selection 41 in tumours. These putatively positively selected SV hotspots are enriched for 42 3 genes previously shown to be oncogenic. In contrast, several hundred regions 43 across the genome show unexpectedly low levels of SVs, given their relatively 44 high susceptibility to mutation. These novel 'coldspot' regions appear to be 45 subject to purifying selection in tumours and are enriched for active promoters 46 and enhancers. 47 Conclusions:We conclude that models of DSB susceptibility offer a rigorous 48 approach to the inference of SVs putatively subject to selection in tumours. 49 50 Keywords: Double strand break, cancer, structural variaton, chromatin, 51 modelling 52 53 Background 54 55 Structural variation (SV) in tumour genomes is known to play important roles in 56 disease progression and may be critical in driving the development of certain 57cancer types (1-3). However, challenges remain not only in ascertaining accurate 58 SV calls, as evidenced by the compendium of SV calling algorithms used in many 59 projects (4-6), but also in predicting their functional impact. Some SVs have 60 apparently direct consequences; for example, amplification of oncogenes leading 61 to overexpression, deletion of tumor suppressors leading to dysfunction, and 62 translocations generating oncogenic fusion proteins (4). Reportedly indirect 63 consequences of SVs include changes in enhancer targeting, affecting the 64 expression of nearby genes, or "enhancer hijacking" (7). However, it remains 65 Project (30) and others, allowing well-matched models to be constructed for all 131 datasets. We demonstrate that these models provide accurate estimates for the 132 expected rate of DSBs in a given region and can be cross applied between DSB 133 datasets. In addition the models can be used to explore tumour SV breakpoint 134 data, to nominate novel regions p...

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When TADs go bad: chromatin structure and nuclear organisation in human disease

Cited by 57 publications

References 41 publications

Chromatin loop anchors are associated with genome instability in cancer and recombination hotspots in the germline

Chromatin loop anchors are associated with genome instability in cancer and recombination hotspots in the germline

Contribution of structural variation to genome structure: TAD fusion discovery and ranking

Modelling double strand break susceptibility to interrogate structural variation in cancer

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