Oncogenic extrachromosomal DNA functions as mobile enhancers to globally amplify chromosomal transcription
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE124769 | GEO | 2021/04/08
REPOSITORIES: GEO
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Project description:Extrachromosomal DNA (ecDNA) is prevalent in human cancers and mediates high oncogene expression through gene amplification and altered gene regulation. Gene induction typically involves cis regulatory elements that contact and activate genes on the same chromosome. Here we show that ecDNA hubs, clusters of ~10-100 ecDNAs within the nucleus, enable intermolecular enhancer-gene interactions to promote oncogene overexpression in trans. ecDNAs encoding multiple distinct oncogenes form hubs in diverse cancer cell types and primary tumors. Each ecDNA is more likely to transcribe the oncogene when spatially clustered with additional ecDNAs. ecDNA hubs are tethered by the BET protein BRD4 in a MYC-amplified colorectal cancer cell line. BET inhibitor JQ1 disperses ecDNA hubs and preferentially inhibits ecDNA-based oncogene transcription. A BRD4-bound promoter in PVT1 is ectopically fused to MYC and duplicated in ecDNA, receiving promiscuous enhancer input to drive potent MYC expression. PVT1 promoter on a heterologous episome suffices to mediate gene activation in trans by ecDNA hubs in a JQ1-sensitive manner. Systematic CRISPRi silencing of ecDNA enhancers reveal intermolecular enhancer-gene activation among multiple oncogene loci amplified on distinct ecDNAs. Together, these results demonstrate that ecDNA hubs are protein-tethered clusters of ecDNAs which enable intermolecular transcriptional regulation. ecDNA hubs may act as units of oncogene function, cooperative evolution, and potential targets for cancer therapy.
2021-05-24 | GSE175452 | GEO
Project description:Extrachromosomal DNA (ecDNA) is prevalent in human cancers and mediates high oncogene expression through gene amplification and altered gene regulation. Gene induction typically involves cis regulatory elements that contact and activate genes on the same chromosome. Here we show that ecDNA hubs, clusters of ~10-100 ecDNAs within the nucleus, enable intermolecular enhancer-gene interactions to promote oncogene overexpression in trans. ecDNAs encoding multiple distinct oncogenes form hubs in diverse cancer cell types and primary tumors. Each ecDNA is more likely to transcribe the oncogene when spatially clustered with additional ecDNAs. ecDNA hubs are tethered by the BET protein BRD4 in a MYC-amplified colorectal cancer cell line. BET inhibitor JQ1 disperses ecDNA hubs and preferentially inhibits ecDNA-based oncogene transcription. A BRD4-bound promoter in PVT1 is ectopically fused to MYC and duplicated in ecDNA, receiving promiscuous enhancer input to drive potent MYC expression. PVT1 promoter on a heterologous episome suffices to mediate gene activation in trans by ecDNA hubs in a JQ1-sensitive manner. Systematic CRISPRi silencing of ecDNA enhancers reveal intermolecular enhancer-gene activation among multiple oncogene loci amplified on distinct ecDNAs. Together, these results demonstrate that ecDNA hubs are protein-tethered clusters of ecDNAs which enable intermolecular transcriptional regulation. ecDNA hubs may act as units of oncogene function, cooperative evolution, and potential targets for cancer therapy.
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Project description:Extrachromosomal DNA (ecDNA) is prevalent in human cancers and mediates high oncogene expression through gene amplification and altered gene regulation. Gene induction typically involves cis regulatory elements that contact and activate genes on the same chromosome. Here we show that ecDNA hubs, clusters of ~10-100 ecDNAs within the nucleus, enable intermolecular enhancer-gene interactions to promote oncogene overexpression in trans. ecDNAs encoding multiple distinct oncogenes form hubs in diverse cancer cell types and primary tumors. Each ecDNA is more likely to transcribe the oncogene when spatially clustered with additional ecDNAs. ecDNA hubs are tethered by the BET protein BRD4 in a MYC-amplified colorectal cancer cell line. BET inhibitor JQ1 disperses ecDNA hubs and preferentially inhibits ecDNA-based oncogene transcription. A BRD4-bound promoter in PVT1 is ectopically fused to MYC and duplicated in ecDNA, receiving promiscuous enhancer input to drive potent MYC expression. PVT1 promoter on a heterologous episome suffices to mediate gene activation in trans by ecDNA hubs in a JQ1-sensitive manner. Systematic CRISPRi silencing of ecDNA enhancers reveal intermolecular enhancer-gene activation among multiple oncogene loci amplified on distinct ecDNAs. Together, these results demonstrate that ecDNA hubs are protein-tethered clusters of ecDNAs which enable intermolecular transcriptional regulation. ecDNA hubs may act as units of oncogene function, cooperative evolution, and potential targets for cancer therapy.
2020-11-25 | GSE159985 | GEO
Project description:Extrachromosomal DNA (ecDNA) is prevalent in human cancers and mediates high oncogene expression through gene amplification and altered gene regulation. Gene induction typically involves cis regulatory elements that contact and activate genes on the same chromosome. Here we show that ecDNA hubs, clusters of ~10-100 ecDNAs within the nucleus, enable intermolecular enhancer-gene interactions to promote oncogene overexpression in trans. ecDNAs encoding multiple distinct oncogenes form hubs in diverse cancer cell types and primary tumors. Each ecDNA is more likely to transcribe the oncogene when spatially clustered with additional ecDNAs. ecDNA hubs are tethered by the BET protein BRD4 in a MYC-amplified colorectal cancer cell line. BET inhibitor JQ1 disperses ecDNA hubs and preferentially inhibits ecDNA-based oncogene transcription. A BRD4-bound promoter in PVT1 is ectopically fused to MYC and duplicated in ecDNA, receiving promiscuous enhancer input to drive potent MYC expression. PVT1 promoter on a heterologous episome suffices to mediate gene activation in trans by ecDNA hubs in a JQ1-sensitive manner. Systematic CRISPRi silencing of ecDNA enhancers reveal intermolecular enhancer-gene activation among multiple oncogene loci amplified on distinct ecDNAs. Together, these results demonstrate that ecDNA hubs are protein-tethered clusters of ecDNAs which enable intermolecular transcriptional regulation. ecDNA hubs may act as units of oncogene function, cooperative evolution, and potential targets for cancer therapy.
2021-09-22 | GSE184566 | GEO
Project description:Extrachromosomal DNA (ecDNA) is prevalent in human cancers and mediates high oncogene expression through gene amplification and altered gene regulation. Gene induction typically involves cis regulatory elements that contact and activate genes on the same chromosome. Here we show that ecDNA hubs, clusters of ~10-100 ecDNAs within the nucleus, enable intermolecular enhancer-gene interactions to promote oncogene overexpression in trans. ecDNAs encoding multiple distinct oncogenes form hubs in diverse cancer cell types and primary tumors. Each ecDNA is more likely to transcribe the oncogene when spatially clustered with additional ecDNAs. ecDNA hubs are tethered by the BET protein BRD4 in a MYC-amplified colorectal cancer cell line. BET inhibitor JQ1 disperses ecDNA hubs and preferentially inhibits ecDNA-based oncogene transcription. A BRD4-bound promoter in PVT1 is ectopically fused to MYC and duplicated in ecDNA, receiving promiscuous enhancer input to drive potent MYC expression. PVT1 promoter on a heterologous episome suffices to mediate gene activation in trans by ecDNA hubs in a JQ1-sensitive manner. Systematic CRISPRi silencing of ecDNA enhancers reveal intermolecular enhancer-gene activation among multiple oncogene loci amplified on distinct ecDNAs. Together, these results demonstrate that ecDNA hubs are protein-tethered clusters of ecDNAs which enable intermolecular transcriptional regulation. ecDNA hubs may act as units of oncogene function, cooperative evolution, and potential targets for cancer therapy.
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Project description:Extrachromsomal DNA (ecDNA) are prevalent in human cancers and are associated with high oncogene expression as well as altered chromatin. Here we show that multiple ecDNAs cluster in the nucleus during interphase to form ecDNA hubs, where oncogene transcription preferentially occurs. Single-cell multiomics, single-molecule sequencing, and 3D enhancer connectome reveal MYC ecDNAs are heterogenous in primary sequence and that ecDNA hubs support ectopic and intermolecular enhancer-promoter interactions. Bromodomain-containing protein 4 (BRD4) extensively occupies ecDNA regulatory elements, and inhibition by JQ1 disperses ecDNA hubs and preferentially reduces ecDNA oncogene transcription. Two amplified oncogenes can intermix in ecDNA hubs, engage in intermolecular enhancer-promoter interactions, and transcription is uniformly sensitive to JQ1. Thus, ecDNA hubs – nuclear bodies of many ecDNAs tethered by proteins – are platforms for cooperative oncogene transcription. The recognition of ecDNA hubs as units of oncogene function and diversification has potentially broad implications for cancer cell evolution and therapy.
2020-11-25 | GSE160148 | GEO
Project description:Enhancer hijacking, caused by structural alterations, is a common cancer driver event that causes aberrant expression of oncogenes. Unfortunately, enhancer hijacking is difficult to detect due to the complexity of the cancer genome. Here we propose a simple yet robust strategy HAPI (Highly Active Promoter Interactions) to identify and characterize such events by following two rules: 1) oncogenes subject to enhancer hijacking should be potentially highly regulated by enhancers, 2) the hijacked enhancers should contribute an appreciable proportion of an oncogene’s overall enhancer activity. Applying this strategy to HiChIP data we and others generated in 34 cancer cell lines, we identified known enhancer hijacking events and uncovered novel enhancers hijacked by known or potentially novel oncogenes such as CCND1, ETV1, ID4, and NKX2-5, which we validated using CRISPRi assays and RNA-seq analysis. Furthermore, we found that complex enhancer hijacking events connecting genes and enhancers from multiple chromosomal segments are often caused by the formation of extrachromosomal circular DNA (ecDNA). Focusing on ecDNAs harboring the MYC oncogene, one of the most common gene targets of ecDNA, we found that these ecDNAs often stitch additional genes such as CDX2, ERBB2, and NFIB from other chromosomes to the MYC locus. These genes heavily hijack MYC enhancers for their activation, a novel insight into ecDNA biology, suggesting alternative therapeutic targets for MYC ecDNAs. Our study provides an efficient strategy to detect enhancer hijacking events, and more importantly reveals novel mechanisms underlying oncogene activation caused by simple or complex structural alterations.
2024-04-02 | GSE228246 | GEO
Project description:Enhancer hijacking, caused by structural alterations, is a common cancer driver event that causes aberrant expression of oncogenes. Unfortunately, enhancer hijacking is difficult to detect due to the complexity of the cancer genome. Here we propose a simple yet robust strategy HAPI (Highly Active Promoter Interactions) to identify and characterize such events by following two rules: 1) oncogenes subject to enhancer hijacking should be potentially highly regulated by enhancers, 2) the hijacked enhancers should contribute an appreciable proportion of an oncogene’s overall enhancer activity. Applying this strategy to HiChIP data we and others generated in 34 cancer cell lines, we identified known enhancer hijacking events and uncovered novel enhancers hijacked by known or potentially novel oncogenes such as CCND1, ETV1, ID4, and NKX2-5, which we validated using CRISPRi assays and RNA-seq analysis. Furthermore, we found that complex enhancer hijacking events connecting genes and enhancers from multiple chromosomal segments are often caused by the formation of extrachromosomal circular DNA (ecDNA). Focusing on ecDNAs harboring the MYC oncogene, one of the most common gene targets of ecDNA, we found that these ecDNAs often stitch additional genes such as CDX2, ERBB2, and NFIB from other chromosomes to the MYC locus. These genes heavily hijack MYC enhancers for their activation, a novel insight into ecDNA biology, suggesting alternative therapeutic targets for MYC ecDNAs. Our study provides an efficient strategy to detect enhancer hijacking events, and more importantly reveals novel mechanisms underlying oncogene activation caused by simple or complex structural alterations.
2024-04-02 | GSE228166 | GEO
Project description:Enhancer hijacking, caused by structural alterations, is a common cancer driver event that causes aberrant expression of oncogenes. Unfortunately, enhancer hijacking is difficult to detect due to the complexity of the cancer genome. Here we propose a simple yet robust strategy HAPI (Highly Active Promoter Interactions) to identify and characterize such events by following two rules: 1) oncogenes subject to enhancer hijacking should be potentially highly regulated by enhancers, 2) the hijacked enhancers should contribute an appreciable proportion of an oncogene’s overall enhancer activity. Applying this strategy to HiChIP data we and others generated in 34 cancer cell lines, we identified known enhancer hijacking events and uncovered novel enhancers hijacked by known or potentially novel oncogenes such as CCND1, ETV1, ID4, and NKX2-5, which we validated using CRISPRi assays and RNA-seq analysis. Furthermore, we found that complex enhancer hijacking events connecting genes and enhancers from multiple chromosomal segments are often caused by the formation of extrachromosomal circular DNA (ecDNA). Focusing on ecDNAs harboring the MYC oncogene, one of the most common gene targets of ecDNA, we found that these ecDNAs often stitch additional genes such as CDX2, ERBB2, and NFIB from other chromosomes to the MYC locus. These genes heavily hijack MYC enhancers for their activation, a novel insight into ecDNA biology, suggesting alternative therapeutic targets for MYC ecDNAs. Our study provides an efficient strategy to detect enhancer hijacking events, and more importantly reveals novel mechanisms underlying oncogene activation caused by simple or complex structural alterations.
2024-04-02 | GSE247056 | GEO
Project description:It has been verified that extrachromosomal circular DNA (ecDNA) has important clinical significance, and the formation process of ecDNA, its immunogenicity, and its other functions have also been described. However, the balancing mechanism by which cells respond to ecDNA, i.e., how ecDNA degrades within cells, is unclear. Here, by using Circle-Seq method conducted on PLC-PRF-5 HCC Cells, ecDNA was purified and the samples were used for DNA Library Preparation and Next Generation Paired-End Sequencing using Illumina MiSeq Technology, We found that some ecDNAs disappeared after VD treatment compared with the DMSO group, and these disappearing ecDNA were related to EMT, proliferation, cell cycle, focal adhesion and other malignant behaviors. Moreover, Circle-seq peaks narrowed after VD treatment, and the coverage over the whole gene was significantly reduced, suggesting that ecDNA after VD treatment carried smaller DNA fragments, which may cause them not to function as a whole gene. Importantly, we demonstrate that VD can cause a continuous and steady decrease in ecDNA in HCC cells.
2023-02-01 | GSE221428 | GEO