Dataset Information

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

ABSTRACT: Extrachromosomal circular DNAs (eccDNAs) are somatically mosaic and contribute to intercellular heterogeneity in normal and tumor cells. Because short eccDNAs are poorly chromatinized, we hypothesized that they are sequenced by tagmentation in ATAC-seq experiments without any enrichment of circular DNA. Indeed, ATAC-seq identified thousands of eccDNAs in cell lines that were validated by inverse PCR and by metaphase FISH. ATAC-seq in gliomas and glioblastomas identify hundreds of eccDNAs, including one containing the well-known EGFR gene amplicon from chr7. More than 18,000 eccDNAs, many carrying known cancer driver genes, are identified in a pan-cancer analysis of ATAC-seq libraries from 23 tumor types. Somatically mosaic eccDNAs are identified by ATAC-seq even before amplification is recognized by genome-wide copy number variation measurements. Thus, ATAC-seq is a sensitive method to detect eccDNA present in a tumor at the pre-amplification stage and can be used to predict resistance to therapy.

SUBMITTER: Kumar P

PROVIDER: S-EPMC7228742 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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

Kumar Pankaj P Kiran Shashi S Saha Shekhar S Su Zhangli Z Paulsen Teressa T Chatrath Ajay A Shibata Yoshiyuki Y Shibata Etsuko E Dutta Anindya A

Science advances 20200515 20

Extrachromosomal circular DNAs (eccDNAs) are somatically mosaic and contribute to intercellular heterogeneity in normal and tumor cells. Because short eccDNAs are poorly chromatinized, we hypothesized that they are sequenced by tagmentation in ATAC-seq experiments without any enrichment of circular DNA. Indeed, ATAC-seq identified thousands of eccDNAs in cell lines that were validated by inverse PCR and by metaphase FISH. ATAC-seq in gliomas and glioblastomas identify hundreds of eccDNAs, includ ...[more]

PMID: 32440553

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Project description:Although glucagon-secreting ?-cells and insulin-secreting ?-cells have opposing functions in regulating plasma glucose levels, the two cell types share a common developmental origin and exhibit overlapping transcriptomes and epigenomes. Notably, destruction of ?-cells can stimulate repopulation via transdifferentiation of ?-cells, at least in mice, suggesting plasticity between these cell fates. Furthermore, dysfunction of both ?- and ?-cells contributes to the pathophysiology of type 1 and type 2 diabetes, and ?-cell de-differentiation has been proposed to contribute to type 2 diabetes. Our objective was to delineate the molecular properties that maintain islet cell type specification yet allow for cellular plasticity. We hypothesized that correlating cell type-specific transcriptomes with an atlas of open chromatin will identify novel genes and transcriptional regulatory elements such as enhancers involved in ?- and ?-cell specification and plasticity.We sorted human ?- and ?-cells and performed the "Assay for Transposase-Accessible Chromatin with high throughput sequencing" (ATAC-seq) and mRNA-seq, followed by integrative analysis to identify cell type-selective gene regulatory regions.We identified numerous transcripts with either ?-cell- or ?-cell-selective expression and discovered the cell type-selective open chromatin regions that correlate with these gene activation patterns. We confirmed cell type-selective expression on the protein level for two of the top hits from our screen. The "group specific protein" (GC; or vitamin D binding protein) was restricted to ?-cells, while CHODL (chondrolectin) immunoreactivity was only present in ?-cells. Furthermore, ?-cell- and ?-cell-selective ATAC-seq peaks were identified to overlap with known binding sites for islet transcription factors, as well as with single nucleotide polymorphisms (SNPs) previously identified as risk loci for type 2 diabetes.We have determined the genetic landscape of human ?- and ?-cells based on chromatin accessibility and transcript levels, which allowed for detection of novel ?- and ?-cell signature genes not previously known to be expressed in islets. Using fine-mapping of open chromatin, we have identified thousands of potential cis-regulatory elements that operate in an endocrine cell type-specific fashion.

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

Publications

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

Similar Datasets

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