Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Circular extrachromosomal DNA promotes tumor heterogeneity in high-risk medulloblastomas [scRNA+ATAC-seq]

ABSTRACT: Circular extrachromosomal DNA (ecDNA) in patient tumor genomes is an important driver of oncogenic gene expression, evolution of drug resistance, and poor patient outcomes. Applying computational methods for detection and reconstruction of ecDNA across a retrospective cohort of 481 medulloblastoma (MB) tumors from 465 patients, we identify circular ecDNA in 82 patients (18%). Patients with ecDNA+ MB were more than twice as likely to relapse and three times as likely to die within 5 years of diagnosis. Individual tumors harbor multiple ecDNA lineages, each containing distinct amplified oncogenes. Multimodal sequencing, imaging, and CRISPR inhibition experiments in MB models reveal intratumoral heterogeneity of ecDNA copy number per cell and frequent putative "enhancer rewiring" events on ecDNA. This study reveals the frequency and diversity of ecDNA in a subset of highly aggressive MB tumors, and suggests copy number heterogeneity and enhancer rewiring as clinically relevant features of ecDNA in MB.

ORGANISM(S): Homo sapiens

PROVIDER: GSE240984 | GEO | 2023/09/15

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Circular extrachromosomal DNA promotes tumor heterogeneity in high-risk medulloblastomas [Hi-C]

Project description:Circular extrachromosomal DNA (ecDNA) in patient tumor genomes is an important driver of oncogenic gene expression, evolution of drug resistance, and poor patient outcomes. Applying computational methods for detection and reconstruction of ecDNA across a retrospective cohort of 481 medulloblastoma (MB) tumors from 465 patients, we identify circular ecDNA in 82 patients (18%). Patients with ecDNA+ MB were more than twice as likely to relapse and three times as likely to die within 5 years of diagnosis. Individual tumors harbor multiple ecDNA lineages, each containing distinct amplified oncogenes. Multimodal sequencing, imaging, and CRISPR inhibition experiments in MB models reveal intratumoral heterogeneity of ecDNA copy number per cell and frequent putative "enhancer rewiring" events on ecDNA. This study reveals the frequency and diversity of ecDNA in a subset of highly aggressive MB tumors, and suggests copy number heterogeneity and enhancer rewiring as clinically relevant features of ecDNA in MB.

2023-09-14 | GSE240410 | GEO

Circular extrachromosomal DNA promotes tumor heterogeneity in high-risk medulloblastomas [ATAC-seq]

2023-09-15 | GSE240830 | GEO

Circular extrachromosomal DNA promotes tumor heterogeneity in high-risk medulloblastomas [pooled CRISPRi]

2023-09-15 | GSE240823 | GEO

Circular extrachromosomal DNA drives massive oncogene expression and chromatin accessibility

Project description:Oncogenes are commonly amplified on extrachromosomal DNA particles (ecDNA) in cancer, but our understanding of the structure of ecDNA and its impact on gene regulation is limited. We integrated ultrastructural imaging, long range-optical mapping, and computational analysis of whole genome sequencing to demonstrate unequivocally that ecDNA is circular. Pan-cancer analyses reveal that the oncogenes encoded on ecDNA are among the most highly expressed genes in the transcriptome of tumours, linking elevated copy with very high levels of transcription. Quantitative assessment of the chromatin state, including ATAC-seq to map the accessible genome and ATAC-see to examine spatial distribution of open chromatin, reveal that while ecDNA is chromatinized, it lacks higher order compaction typical of chromosomes. In fact, ecDNA contains the most accessible DNA in the tumour genome. Using chromosome conformation capture technologies and CRISPR interference, we reveal the differential organization of active chromatin in cancer that is dictated by the circular shape of ecDNA. Lastly, we develop comprehensive maps that provide new insight into how circular ecDNA structure determines oncogene function, bridging ecDNA biology with modern cancer genomics and epigenetics.

2019-12-31 | GSE131956 | GEO

TBC1D3 suppression of the Histone Lysine N-methyltransferase G9a promotes the generation of neural progenitors and cortical expansion [ChIP-seq]

Project description:we conducted chromotin Immunoprecipitation sequencing (ChIP-seq) using human cerebral organoids treated with TAT-Scrambled (Short for TAT-Scr) with the sequence of YGRKKRRQRRR-FRVRYWFQGCHSEDPWR and TAT-465-481, a special peoptide designed for inhibition of TBC1D3, with the sequence of YGRKKRRQRRR-EGPWFRHYDFRQSCWVR.

2021-02-08 | GSE136281 | GEO

Oncogene expression from extrachromosomal DNA is driven by copy number amplification and does not require spatial clustering in glioblastoma stem cells

Project description:Extrachromosomal DNA (ecDNA) are frequently observed in human cancers and are responsible for high levels of oncogene expression. In glioblastoma (GBM), ecDNA copy number correlates with poor prognosis. It is hypothesized that their copy number, size and chromatin accessibility facilitate clustering of ecDNA and colocalization with transcriptional hubs, and that this underpins their elevated transcriptional activity. Here, we use super-resolution imaging and quantitative image analysis to evaluate GBM stem cells harboring distinct ecDNA species (EGFR, CDK4, PDGFR). We found no evidence that ecDNA routinely cluster with one another or closely interact with transcriptional hubs. Cells with EGFR-containing ecDNA have increased EGFR transcriptional output, but transcription per gene copy was similar in ecDNA compared to the endogenous chromosomal locus. These data suggest that it is the increased copy number of oncogene-harboring ecDNA that primarily drives high levels of oncogene transcription, rather than specific interactions of ecDNA with each other or with high concentrations of the transcriptional machinery.

2022-11-11 | GSE215420 | GEO

Disparate pathways for extrachromosomal DNA biogenesis and genomic DNA repair

Project description:Oncogene amplification on extrachromosomal DNA (ecDNA) is a pervasive driver event in cancer, yet our understanding of how ecDNA forms is limited. Here, we couple a CRISPR-based method for ecDNA induction with extensive characterization of newly formed ecDNA to examine their biogenesis. We find that DNA circularization is efficient, irrespective of 3D genome context, with formation of 800kb, 1 Mb, and 1.8 Mb ecDNAs reaching or exceeding 15%. We show non-homologous end joining and microhomology-mediated end joining both contribute to ecDNA formation, while inhibition of DNA-PKcs and ATM have opposing impacts on ecDNA formation. EcDNA and the corresponding chromosomal excision scar can form at significantly different rates and respond differently to DNA-PKcs and ATM inhibition. Taken together, our results support a model of ecDNA formation in which double strand break ends dissociate from their legitimate ligation partners prior to joining of illegitimate ends to form the ecDNA and excision scar.

2024-07-25 | GSE273081 | GEO

Parallel sequencing of extrachromosomal circular DNAs and transcriptomes in single cancer cells

Project description:Oncogenic extrachromosomal DNAs (ecDNA) are common in cancers, but many questions about their origin, structural dynamics and impact on intratumor heterogeneity are still unresolved. Here we describe scEC&T-seq, a method for parallel isolation and sequencing of extrachromosomal circular DNAs and full-length mRNA from single human cells. By applying scEC&T-seq to cancer cells, we not only describe intercellular differences in ecDNA content, but also investigate their structural heterogeneity and transcriptional impact. We reveal that whereas oncogene-containing ecDNA elements are clonally present in cancer cells and drive intercellular oncogene expression differences, other small circular DNAs also captured by scEC&T-seq are mostly private to individual cancer cells, indicating differences in selection and propagation. Moreover, scEC&T-seq uncovers intercellular differences in ecDNA structure, which allowed the inference of ecDNA structural dynamics and point to circular recombination as a potential mechanism of ecDNA evolution. We envision that our method may enable the analysis of yet unknown prerequisites for the maintenance of both small and large circular DNA in cancers, but also in the context of other diseases and normal cellular development.

| EGAS00001007026 | EGA

DOCK1 gene derived hsa_circ_0020397 RNA is over-expressed in luminal mammary tumors and it is involved in the epithelial differentiation, growth and motility of the neoplastic cell

Project description:Circular-RNAs are an emerging group of regulatory molecules involved in the control of numerous cellular processes and may play a role in the growth and diffusion of various types of tumors. In the present study, we define the expression of 15 selected circular-RNAs, which may be involved in the process of epithelial-to-mesenchymal-transition, using a panel of 18 breast cancer cell-lines recapitulating the heterogeneity of the tumor and consisting of three distinct groups according to the mesenchymal/epithelial phenotype. The circular RNA deriving from the DOCK1 gene (hsa_circ_0020397) is characterized by the most interesting expression profile, as it is undetectable in triple-negative mesenchymal cell-lines, while it is easily measurable in epithelial cell-lines independent of their positivity to estrogen receptor or the HER2 membrane receptor. Whole-genome RNA-sequencing experiments performed on the triple-negative/mesenchymal MDA-MB-231 and MDA-MB-157 cell-lines engineered to over-express hsa_circ_0020397 demonstrate that the circular-RNA controls the expression of 110 common genes. Pathway analysis of these genes indicate that over-expression of the circular-RNA differentiates the two mesenchymal cell-lines along the epithelial pathway and increase cell-to-cell adhesion. This is accompanied by a growth inhibitory effect and a reduction in the random/directional motility of the two cell-lines. The up-regulated AGR2, ENPP1 and PPP1R9A genes as well as the down-regulated APOE, AQP3, CD99L2 and IGFBP4 genes show an opposite regulation by circDOCK1 silencing in CAMA1 luminal cells.

2022-06-15 | E-MTAB-10819 | biostudies-arrayexpress

Oncogenic extrachromosomal DNA functions as mobile enhancers to globally amplify chromosomal transcription

Project description:Extrachromosomal, circular DNA (ecDNA) is emerging as a prevalent yet less characterized oncogenic alteration in cancer genomes. We leverage ChIA-PET and ChIA-Drop chromatin interaction assays to characterize genome-wide ecDNA-mediated chromatin contacts that impact transcriptional programs in cancers. ecDNAs in glioblastoma patient-derived neurosphere and prostate cancer cell cultures are marked by widespread intra-ecDNA and genome-wide chromosomal interactions. ecDNA-chromatin contact foci are characterized by broad and high-level H3K27ac signals converging predominantly on chromosomal genes of increased expression levels. Prostate cancer cells harboring synthetic ecDNA circles composed of characterized enhancers result in the genome-wide activation of chromosomal gene transcription. Deciphering the chromosomal targets of ecDNAs at single-molecule resolution reveals an association with actively expressed oncogenes spatially clustered within ecDNA-directed interaction networks. Our results suggest that ecDNA can function as mobile transcriptional enhancers to promote tumor progression and manifest a potential synthetic aneuploidy mechanism of transcription control in cancer.

2021-04-08 | GSE124769 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data