小柯机器人

环状的染色体外DNA（ecDNA）促进可及染色质和癌基因高表达，这一成果由美国加州大学圣地亚哥分校Paul S. Mischel、Vineet Bafna、任兵（Bing Ren）和斯坦福大学Howard Y. Chang等研究人员合作完成。相关论文2019年11月20日在线发表于《自然》。

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，研究人员证明了环状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，但是它缺乏典型的染色体高阶压缩，并且显示出显著增强的染色质可及性。此外，研究显示出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见解，并将ecDNA生物学与目前癌症基因组学和表观遗传学联系起来。

据了解，癌基因通常在癌症的染色体外DNA（ecDNA）颗粒上扩增，但是我们对ecDNA的结构及其对基因调控的影响的理解是有限的。

附：英文原文

Title: Circular ecDNA promotes accessible chromatin and high oncogene expression

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

Issue&Volume: 2019-11-20

Abstract: Oncogenes are commonly amplified on particles of extrachromosomal DNA (ecDNA) in cancer1,2, 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. Imaging and sequencing approaches are combined to show that extrachromosomal DNA (ecDNA) in cancer is circular and has unique chromatin structure that amplifies oncogene output.

DOI: 10.1038/s41586-019-1763-5

Source:https://www.nature.com/articles/s41586-019-1763-5

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