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Circular ecDNA promotes accessible chromatin and high oncogene expression

机译：环状ecDNA促进可利用的染色质和高癌基因表达

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摘要

Oncogenes are commonly amplified on particles of extrachromosomal DNA (ecDNA) in cancer(1,2), but our understanding of the structure of ecDNA and its effect on gene regulation is limited. Here, by integrating ultrastructural imaging, long-range optical mapping and computational analysis of whole-genome sequencing, we demonstrate the structure of circular ecDNA. Pan-cancer analyses reveal that oncogenes encoded on ecDNA are among the most highly expressed genes in the transcriptome of the tumours, linking increased copy number with high transcription levels. Quantitative assessment of the chromatin state reveals that although ecDNA is packaged into chromatin with intact domain structure, it lacks higher-order compaction that is typical of chromosomes and displays significantly enhanced chromatin accessibility. Furthermore, ecDNA is shown to have a significantly greater number of ultra-long-range interactions with active chromatin, which provides insight into how the structure of circular ecDNA affects oncogene function, and connects ecDNA biology with modern cancer genomics and epigenetics.

机译：癌基因通常在癌症的染色体外DNA（ecDNA）颗粒上扩增（1,2），但我们对ecDNA的结构及其对基因调控的影响的理解是有限的。在这里，通过整合超微结构成像，远程光学作图和全基因组测序的计算分析，我们证明了环状ecDNA的结构。泛癌分析显示，在ecDNA上编码的癌基因是肿瘤转录组中表达最高的基因之一，将增加的拷贝数与高转录水平联系起来。染色质状态的定量评估表明，尽管ecDNA被包装到具有完整域结构的染色质中，但它缺乏典型的染色体高阶压缩，并且显示出显着增强的染色质可及性。此外，显示ecDNA与活跃的染色质具有明显更多的超远程相互作用，这提供了对环状ecDNA结构如何影响癌基因功能的了解，并将ecDNA生物学与现代癌症基因组学和表观遗传学联系起来。

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《Nature》 |2019年第7784期|699-703|共5页
作者
Wu Sihan; Turner Kristen M.; Nam Nguyen; Raviram Ramya; Erb Marcella; Santini Jennifer; Luebeck Jens; Rajkumar Utkrisht; Diao Yarui; Li Bin; Zhang Wenjing; Jameson Nathan; Corces M. Ryan; Granja Jeffrey M.; Chen Xingqi; Coruh 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.;
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作者单位

Univ Calif San Diego Ludwig Inst Canc Res La Jolla CA 92093 USA;

Univ Calif San Diego Ludwig Inst Canc Res La Jolla CA 92093 USA|Boundless Bio Inc La Jolla CA USA;

Univ Calif San Diego Dept Comp Sci & Engn La Jolla CA 92093 USA|Boundless Bio Inc La Jolla CA USA;

Univ Calif San Diego Dept Neurosci UCSD Light Microscopy Core Facil La Jolla CA 92093 USA;

Univ Calif San Diego Bioinformat & Syst Biol Grad Program La Jolla CA 92093 USA;

Univ Calif San Diego Dept Comp Sci & Engn La Jolla CA 92093 USA|Duke Univ Sch Med Dept Cell Biol Regenerat Next Initiat Durham NC USA;

Univ Calif San Diego Ludwig Inst Canc Res La Jolla CA 92093 USA|Duke Univ Sch Med Dept Orthopaed Surg Regenerat Next Initiat Durham NC USA;

Stanford Univ Ctr Personal Dynam Regulomes Stanford CA 94305 USA;

Stanford Univ Ctr Personal Dynam Regulomes Stanford CA 94305 USA|Uppsala Univ Dept Immunol Genet & Pathol Uppsala Sweden;

Salk Inst Biol Studies Plant Mol & Cellular Biol Lab 10010 N Torrey Pines Rd La Jolla CA 92037 USA;

Cleveland Clin Fdn Lerner Res Inst Dept Quantitat Hlth Sci 9500 Euclid Ave Cleveland OH 44195 USA;

Jackson Lab Genom Med Farmington CT USA;

Stanford Univ Ctr Personal Dynam Regulomes Stanford CA 94305 USA|Stanford Univ Howard Hughes Med Inst Stanford CA 94305 USA;

Univ Calif San Diego Ludwig Inst Canc Res La Jolla CA 92093 USA|Univ Calif San Diego Ctr Epigen Dept Cellular & Mol Med La Jolla CA 92093 USA|Univ Calif San Diego Moores Canc Ctr Inst Genom Med La Jolla CA 92093 USA;

Univ Calif San Diego Dept Comp Sci & Engn La Jolla CA 92093 USA;

Univ Calif San Diego Ludwig Inst Canc Res La Jolla CA 92093 USA|Univ Calif San Diego Moores Canc Ctr La Jolla CA 92093 USA|Univ Calif San Diego Dept Pathol La Jolla CA 92093 USA;

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收录信息美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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2. Sequencing of methylase-accessible regions in integral circular extrachromosomal DNA reveals differences in chromatin structure [J] . Chen Weitian, Weng Zhe, Xie Zhe, Epigenetics & Chromatin . 2021,第1期

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3. DNA of a circular minichromosome linearized by restriction enzymes or other reagents is resistant to further cleavage: an influence of chromatin topology on the accessibility of DNA [J] . Kumala Slawomir, Hadj-Sahraoui Yasmina, Rzeszowska-Wolny Joanna, Nucleic Acids Research . 2012,第19期

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4. Regulation of gene expression in mast cells: micro-RNA expression and chromatin structural analysis of cytokine genes [C] . Silvia Monticelli, K. Mark Ansel, Dong U. Lee, Symposium on Mast Cells and Basophils: Development, Activation and Roles in Allergic/Autoimmune Disease . 2005

机译：肥大细胞中基因表达的调节：细胞因子基因的微RNA表达和染色质结构分析
5. Deciphering Epigenomic Regulatory Mechanisms of Lens Cell Differentiation through Spatiotemporal Chromatin Accessibility, Gene Expression and Proteomic Analysis [D] . Zhao, Yilin. 2019

机译：通过时空染色质染色质，基因表达和蛋白质组学分析来解密晶状体细胞分化的表观胶质调节机制
6. Genome-Wide Association between Transcription Factor Expression and Chromatin Accessibility Reveals Regulators of Chromatin Accessibility [O] . David Lamparter, Daniel Marbach, Rico Rueedi, 2017

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7. Faculty Opinions recommendation of Circular ecDNA promotes accessible chromatin and high oncogene expression. [O] . Yi Lu 2019

机译：循环EcDNA的教师意见推荐促进可获得的染色质和高癌基因表达。

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