ATAC-seq identifies thousands of extrachromosomal circular DNA in cancer and cell lines

Kumar, Pankaj; Kiran, Shashi; Saha, Shekhar; Su, Zhangli; Paulsen, Teressa; Chatrath, Ajay; Shibata, Yoshiyuki; Shibata, Etsuko; Dutta, Anindya

doi:10.1126/sciadv.aba2489

Cited by 133 publications

(120 citation statements)

References 26 publications

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“…This suggests that large disruptions to topology may not be necessary for transformation or divergent subtyping of prostate tumours, corroborating previous observations of conserved TADs across cell types 5,45 . These findings stand in contrast with how extrachromosomal circular DNA acquired during oncogenesis engage sequences that would otherwise be constrained by the chromatin and topology 22,46,47 . However, the stable genome topology we observe is consistent with the conserved topologies seen between homologous regions in separate species 5,48 , suggesting that TADs do not necessarily need to split or merge with neighbouring TADs to facilitate changes in gene regulation.…”

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confidence: 59%

“…CC-BY-NC 4.0 International license made available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is The copyright holder for this preprint this version posted January 6, 2021. ; https://doi.org/10.1101/2021.01.05.425333 doi: bioRxiv preprint otherwise be constrained by the chromatin and topology 22,46,47 . However, the stable genome topology we observe is consistent with the conserved topologies seen between homologous regions in separate species 5,48 , suggesting that TADs do not necessarily need to split or merge with neighbouring TADs to facilitate changes in gene regulation.…”

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confidence: 99%

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Cis-regulatory Element Hijacking by Structural Variants Overshadows Higher-Order Topological Changes in Prostate Cancer

Hawley

Zhou

Arlidge

et al. 2021

Preprint

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Prostate cancer is a heterogeneous disease whose progression is linked to genome instability 1. Despite large-scale tumour sequencing efforts, the impact of mutations on the genetic architecture in cancer remains ill-defined due to limited integration of genomics data across dimensions 2. We addressed this limitation by assessing the impact of structural variants on the chromatin states and the three-dimensional organization across benign and malignant primary prostate genomes. We find high concordance in the three-dimensional genome organization between malignant and benign prostate tissues, arguing for constraints to the three-dimensional genome of prostate tumours. Moreover, we identify structural variants as effectors of changes to focal chromatin interactions, guiding cis-regulatory element hijacking 2,3 that imposes opposing expression changes on genes found at antipodes of a rearrangement. This leads to the repression of tumour suppressor gene expression and up-regulation of oncogenes, such as at the TMPRSS2-ERG and PMEPA1-ZNF156 loci. Collectively, our results argue that cis-regulatory element hijacking by structural variants overshadows large-scale topological changes to alter gene regulation and promote oncogenesis.

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confidence: 59%

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confidence: 99%

Cis-regulatory Element Hijacking by Structural Variants Overshadows Higher-Order Topological Changes in Prostate Cancer

Hawley

Zhou

Arlidge

et al. 2021

Preprint

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“…ecDNAs can evolve over time from submicroscopic episomes to large double minutes, and that these extrachromosomal elements can re-integrate into chromosomes and form tandem repeats termed homogeneously staining regions (HSRs) [15][16][17][18][19] . ecDNA possess increased chromatin accessibility and lack higher order chromatin compaction 1,20 , and encompass the endogenous oncogene enhancer elements 21 . ecDNA exists outside the normal chromosomal context by definition, and its spatial organization in the nucleus is poorly understood.…”

Section: Introductionmentioning

confidence: 99%

EcDNA hubs drive cooperative intermolecular oncogene expression

Hung

Yost

Xie

et al. 2020

Preprint

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Extrachromosomal DNAs (ecDNAs) are prevalent in human cancers and mediate high oncogene expression through elevated copy number and altered gene regulation1. Gene expression typically involves distal enhancer DNA elements that contact and activate genes on the same chromosome2,3. Here we show that ecDNA hubs, comprised of ~10-100 ecDNAs clustered in the nucleus of interphase cells, drive intermolecular enhancer input for amplified oncogene expression. Single-molecule sequencing, single-cell multiome, and 3D enhancer connectome reveal subspecies of MYC-PVT1 ecDNAs lacking enhancers that access intermolecular and ectopic enhancer-promoter interactions in ecDNA hubs. ecDNA hubs persist without transcription and are tethered by BET protein BRD4. BET inhibitor JQ1 disperses ecDNA hubs, preferentially inhibits ecDNA oncogene transcription, and kills ecDNA+ cancer cells. Two amplified oncogenes MYC and FGFR2 intermix in ecDNA hubs, engage in intermolecular enhancer-promoter interactions, and transcription is uniformly sensitive to JQ1. Thus, ecDNA hubs are nuclear bodies of many ecDNAs tethered by proteins and platforms for cooperative transcription, leveraging the power of oncogene diversification and combinatorial DNA interactions. We suggest ecDNA hubs, rather than individual ecDNAs, as units of oncogene function, cooperative evolution, and new targets for cancer therapy.

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“…Gontarz et al compared the sensitivity and specificity of six different accessibility analysis strategies for ATAC-seq data (10). In addition to chromosomal DNA, scientists can now use ATAC-seq to identify thousands of extrachromosomal circular DNA present in normal and tumor cells (11).…”

Section: Introductionmentioning

confidence: 99%

Bibliometric Analysis of ATAC-Seq and Its Use in Cancer Biology via Nucleic Acid Detection

et al. 2020

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Assay for transposase-accessible chromatin using sequencing (ATAC-seq) is associated with significant progress in biological research and has attracted increasing attention. However, the impact of ATAC-seq on cancer biology has not been objectively analyzed. We categorized 440 ATAC-seq publications according to the publication date, type, field, and country. R 3.6.2 was used to analyze the distribution of research fields. VOSviewer was used for country co-authorship and author co-authorship analyses, and GraphPad Prism 8 was used for correlation analyses of the factors that may affect the number of articles published in different countries. We found that ATAC-seq plays roles in carcinogenesis, anticancer immunity, targeted therapy, and metastasis risk predictions and is most frequently used in studies of leukemia among all types of cancer. We found a significantly strong correlation between the top 10 countries in terms of the number of publications and the gross expenditure on research and development (R&D), the number of universities, and the number of researchers. At present, ATAC-seq technology is undergoing a period of rapid development, making it inseparable from the emphasis and investment in scientific research by many countries. Collectively, ATAC-seq has advantages in the study of the cancer mechanisms because it can detect nucleic acids and thus has good application prospects in the field of cancer, especially in leukemia studies. As a country's economic strength increases and the emphasis on scientific research deepens, ATAC-seq will definitely play a more significant role in the field of cancer biology.

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ATAC-seq identifies thousands of extrachromosomal circular DNA in cancer and cell lines

Cited by 133 publications

References 26 publications

Cis-regulatory Element Hijacking by Structural Variants Overshadows Higher-Order Topological Changes in Prostate Cancer

Cis-regulatory Element Hijacking by Structural Variants Overshadows Higher-Order Topological Changes in Prostate Cancer

EcDNA hubs drive cooperative intermolecular oncogene expression

Bibliometric Analysis of ATAC-Seq and Its Use in Cancer Biology via Nucleic Acid Detection

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