Circular ecDNA promotes accessible chromatin and high oncogene expression

Wu, Sihan; Turner, Kristen M.; Nguyen, Nam; Raviram, Ramya; Erb, Marcella L.; Santini, Jennifer; Luebeck, Jens; Rajkumar, Utkrisht; Diao, Yarui; Li, Bin; Zhang, Wenjing; Jameson, Nathan M.; Corces, M. Ryan; Granja, Jeffrey M.; Chen, Xingqi; Çoruh, Ceyda; Abnousi, Armen; Houston, Jack; Ye, Zhen; Hu, Rong; Yu, Miao; Kim, Hoon; Law, Julie A.; Verhaak, Roel G.W.; Hu, Ming; Furnari, Frank B.; Chang, Howard Y.; Ren, Bing; Bafna, Vineet; Mischel, Paul S.

doi:10.1038/s41586-019-1763-5

Cited by 427 publications

(631 citation statements)

References 35 publications

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“…In line with our observation of local enhancer co-amplification, Morton et al recently described that local enhancers are significantly co-amplified with other proto-oncogenes in other cancer entities 19 . They showed that experimentally interfering with local EGFR enhancers in EGFR- More generally, we show that TADs also form in ecDNA, in line with recent findings by Wu et al 24 . We extend this observation to homogeneously staining regions, which form extremely expanded stretches of chromatin in interphase nuclei and lose chromosomal territoriality 25 Reconstruction of amplicons has previously relied on combining structural breakpoint coordinates to infer the underlying structure.…”

Section: Discussionsupporting

confidence: 93%

Enhancer hijacking determines intra- and extrachromosomal circularMYCNamplicon architecture in neuroblastoma

Helmsauer

Валиева

Ali

et al. 2019

Preprint

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MYCN amplification drives one in six cases of neuroblastoma. The supernumerary gene copies are commonly found on highly rearranged, extrachromosomal circular DNA. The exact amplicon structure has not been described thus far and the functional relevance of its rearrangements is unknown. Here, we analyzed the MYCN amplicon structure and its chromatin landscape. This revealed two distinct classes of amplicons which explain the regulatory requirements for MYCN overexpression. The first class always co-amplified a proximal enhancer driven by the noradrenergic core regulatory circuit (CRC). The second class of MYCN amplicons was characterized by high structural complexity, lacked key local enhancers, and instead contained distal chromosomal fragments, which harbored CRC-driven enhancers. Thus, ectopic enhancer hijacking can compensate for the loss of local gene regulatory elements and explains a large component of the structural diversity observed in MYCN amplification.

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Section: Discussionsupporting

confidence: 93%

Enhancer hijacking determines intra- and extrachromosomal circularMYCNamplicon architecture in neuroblastoma

Helmsauer

Валиева

Ali

et al. 2019

Preprint

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“…Our analysis points to a very high fitness advantage (300%) of the EGFRvI I I amplification in the GBM39 cell line. This is consistent with recent functional evidence of the EGFRvI I I amplification [1,9], as well as clinical evidence of poor survival of patients with ecDNA amplifications [38]. It will be highly interesting to quantify evolutionary histories of ecDNA in individual patients in future studies.…”

Section: Discussionsupporting

confidence: 85%

“…In the following, we integrate a mathematical analysis of the ecDNA somatic evolutionary process, individual based stochastic computer simulations and in vitro ecDNA heterogeneity patterns from growth experiments of the glioblastoma cell line GBM39 with the known circular extra-chromosomal EGFRvI I I amplification [1,9]. For a better grasp on some of the peculiar properties of ecDNA evolution, we first discuss deterministic ecDNA dynamics.…”

Section: Resultsmentioning

confidence: 99%

“…Recent genome profiling studies of both healthy and cancerous human tissues found a high prevalence of nuclear extra-chromosomal DNA (ecDNA) [1,2,3,4]. ecDNA occurs during episodes of chromosomal instability and contributes to cancer initiation and treatment resistance [5,6,7,8,9]. Double minute oncogene amplifications exist in 31.7% of all neuroblastoma and highly amplified extra-chromosomal KRAS copies appear at relapse of anti-EGFR targeted therapies [1,4,9].…”

Section: Introductionmentioning

confidence: 99%

“…ecDNA occurs during episodes of chromosomal instability and contributes to cancer initiation and treatment resistance [5,6,7,8,9]. Double minute oncogene amplifications exist in 31.7% of all neuroblastoma and highly amplified extra-chromosomal KRAS copies appear at relapse of anti-EGFR targeted therapies [1,4,9]. Yet, the evolutionary fade Figure 1.…”

Section: Introductionmentioning

confidence: 99%

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Stochastic dynamics of extra-chromosomal DNA

Pichugin

Huang

Werner

2019

Preprint

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Nuclear extra-chromosomal DNA (ecDNA) is highly prevalent in human tumours. ecDNA amplifications can promote accessible chromatin, oncogen over-expression and imply a worse clinical prognosis.Yet, little is known about the evolutionary process of ecDNA in human cancers. Here, we develop the theoretical foundation of the ecDNA somatic evolutionary process combining mathematical, computational and experimental approaches. We show that random ecDNA segregation leads to unintuitive dynamics even if ecDNA is under very strong positive selection. Patterns of inter-and intra-tumour ecDNA and chromosomal heterogeneity differ markedly and standard approaches are not directly applicable to quantify ecDNA evolution. We show that evolutionary informed modelling leads to testable predictions on how to distinguish positively selected from neutral ecDNA dynamics. Our predictions describe the dynamics of circular amplicons in GBM39 cell line experiments, suggesting a 300% fitness increase due to circular extra-chromosomal EGFRvI I I amplifications. Our work lies the basis for further studies to quantitate ecDNA somatic evolutionary processes.

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DNA‐Based Materials Inspired by Natural Extracellular DNA

Qin

Wang

Zhang

et al. 2023

Adv Funct Materials

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The advent of biotechnology has expedited the understanding of the biochemistry of deoxyribonucleic acids (DNA). In the past, DNA are thought to be present only in cell nucleus as bearers of the genetic code. With the identification of extracellular DNA in circulating body fluids, DNA are now utilized, at least experimentally, for diagnosis and treatment of diseases. Extracellular DNA of host origin trigger immune responses, and are closely linked to autoimmune disease, cancer-related inflammation, bacteria adhesion and thrombosis. Recent advancements in DNA nanotechnology have led to the development of a series of DNA-based materials for treating diseases because of their structural programmability. Current discussions on biosafety and immunogenicity of artificial DNA materials are insufficient. This issue severely restricts the clinical translation of these novel biotechnologies. The present review attempts to bridge the gap between natural extracellular DNA and their derivatives, DNA-based materials. The pathological attributes of endogenous extracellular DNA motivate the design of targeting DNA materials. In addition, the fate of exogenous DNA in the host inspires the optimization of DNA materials in reducing immune rejection. These bioinspired strategies provide the blueprint for utilizing DNA materials in the management of diseases that are currently challenging to diagnose or treat.

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Circular ecDNA promotes accessible chromatin and high oncogene expression

Cited by 427 publications

References 35 publications

Enhancer hijacking determines intra- and extrachromosomal circularMYCNamplicon architecture in neuroblastoma

Enhancer hijacking determines intra- and extrachromosomal circularMYCNamplicon architecture in neuroblastoma

Stochastic dynamics of extra-chromosomal DNA

DNA‐Based Materials Inspired by Natural Extracellular DNA

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