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eccDNAs are apoptotic products with high innate immunostimulatory activity

机译：ECCDNA是具有高先天免疫刺激活动的凋亡产品

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摘要

Extrachromosomal circular DNA elements (eccDNAs) have been described in the literature for several decades, and are known for their broad existence across different species(1,2). However, their biogenesis and functions are largely unknown. By developing a new circular DNA enrichment method, here we purified and sequenced full-length eccDNAs with Nanopore sequencing. We found that eccDNAs map across the entire genome in a close to random manner, suggesting a biogenesis mechanism of random ligation of genomic DNA fragments. Consistent with this idea, we found that apoptosis inducers can increase eccDNA generation, which is dependent on apoptotic DNA fragmentation followed by ligation by DNA ligase 3. Importantly, we demonstrated that eccDNAs can function as potent innate immunostimulants in a manner that is independent of eccDNA sequence but dependent on eccDNA circularity and the cytosolic DNA sensor Sting. Collectively, our study not only revealed the origin, biogenesis and immunostimulant function of eccDNAs but also uncovered their sensing pathway and potential clinical implications in immune response.By developing a new eccDNA purification and profiling method, the study revealed close-to-random genomic origination, mechanism of biogenesis and function of eccDNAs.
机译：在文献中已经在文献中已经描述了几十年，以其跨越不同物种（1,2）的广泛存在而描述了全孢囊肿圆形DNA元素（ECCDNA）。然而，它们的生物发生和功能在很大程度上是未知的。通过开发一种新的循环DNA富集方法，在这里，我们纯化并用纳米孔测序纯化和测序全长ECCDNA。我们发现ECCDNA以接近随机方式划过整个基因组，表明基因组DNA片段随机连接的生物发生机制。与此思想一致，我们发现凋亡诱导剂可以增加ECCDNA生成，其依赖于凋亡DNA碎片，然后通过DNA连接酶3进行连接。重要的是，我们证明ECCDNA可以以与ECCDNA无关的方式起到有效的先天免疫刺激剂序列，但依赖于EccDNA圆环和细胞溶质DNA传感器刺。集体，我们的研究不仅揭示了ECCDNA的起源，生物发生和免疫刺激功能，还揭示了他们的传感途径和免疫反应中的潜在临床意义。通过开发新的ECCDNA纯化和分析方法，该研究显示了近似随机的基因组起源，生物发生机制及菌委的功能。

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  • 来源
    《Nature》 |2021年第7884期|308-314|共7页
  • 作者

    Wang Yuangao; Wang Meng; Djekidel Mohamed Nadhir; Chen Huan; Liu Di; Alt Frederick W.; Zhang Yi;

  • 作者单位

    Howard Hughes Med Inst Boston MA 02115 USA|Boston Childrens Hosp Program Cellular & Mol Med Boston MA 02115 USA;

    Howard Hughes Med Inst Boston MA 02115 USA|Boston Childrens Hosp Program Cellular & Mol Med Boston MA 02115 USA;

    Howard Hughes Med Inst Boston MA 02115 USA|Boston Childrens Hosp Program Cellular & Mol Med Boston MA 02115 USA;

    Howard Hughes Med Inst Boston MA 02115 USA|Boston Childrens Hosp Program Cellular & Mol Med Boston MA 02115 USA;

    Harvard Univ Wyss Inst Biol Inspired Engn Boston MA 02115 USA|Harvard Med Sch Dept Syst Biol Boston MA 02115 USA;

    Howard Hughes Med Inst Boston MA 02115 USA|Boston Childrens Hosp Program Cellular & Mol Med Boston MA 02115 USA|Harvard Univ Dept Genet Boston MA 02163 USA;

    Howard Hughes Med Inst Boston MA 02115 USA|Boston Childrens Hosp Program Cellular & Mol Med Boston MA 02115 USA|Harvard Univ Dept Genet Boston MA 02163 USA|Harvard Stem Cell Inst WAB 149G Boston MA 02115 USA;

  • 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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