斯坦福大学Howard Y. Chang研究组取得一项新突破。他们揭示了遗传因素促进癌细胞染色体外DNA的保留。2025年11月19日，国际知名学术期刊《自然》发表了这一成果。

在这里，该团队确定了一个家族的人类基因组元件，称为保留元件，系住插曲到有丝分裂染色体，以增加ecDNA传递到子细胞。使用保留序列，研究人员开发的一种基因组规模测定，研究人员揭示了人类保留元素的需求，这些保留元素赋予异基因片段世代持久性。保留元件包括一组选择的富含CpG的基因启动子，并加性地起作用。活细胞成像和染色体构象捕获表明，保留元件在有丝分裂时被转录因子和染色质蛋白标记的区域与有丝分裂染色体发生物理相互作用。这种活性在分子间概括了启动子-增强子的相互作用。

在人类癌症中，多个保留元件与癌基因在单个ecDNA上共同扩增，并形成其大小和结构。富含CpG的保留元素局部低甲基化。靶向胞嘧啶甲基化消除了保留活性并导致ecDNA丢失，这表明甲基化敏感的相互作用调节了外泌体DNA保留。这些结果突出了有丝分裂ecDNA保留的DNA元件和调控逻辑。保留元件的扩增促进了致癌ecDNA在几代癌细胞中的维持，并揭示了人类基因组固有的片段不朽原理。

据了解，染色体外DNA （ecDNA）是一种在癌症中普遍存在且具有破坏性的癌基因扩增形式。环状巨酶大小的ecDNA缺乏着丝粒，在细胞分裂期间随机分离，并持续许多代。已经超过40年了自从ecDNA首次被观察到搭便车到有丝分裂染色体进入子细胞核以来，这一过程的机制仍然不清楚。

附：英文原文

Title: Genetic elements promote retention of extrachromosomal DNA in cancer cells

Author: Sankar, Venkat, Hung, King L., Gnanasekar, Aditi, Wong, Ivy Tsz-Lo, Shi, Quanming, Kraft, Katerina, Jones, Matthew G., He, Britney Jiayu, Yan, Xiaowei, Belk, Julia A., Liu, Kevin J., Agarwal, Sangya, Wang, Sean K., Henssen, Anton G., Mischel, Paul S., Chang, Howard Y.

Issue&Volume: 2025-11-19

Abstract: Extrachromosomal DNA (ecDNA) is a prevalent and devastating form of oncogene amplification in cancer1,2. Circular megabase-sized ecDNAs lack centromeres, stochastically segregate during cell division3,4,5,6 and persist over many generations. It has been more than 40years since ecDNAs were first observed to hitchhike on mitotic chromosomes into daughter cell nuclei, but the mechanism underlying this process remains unclear3,7. Here we identify a family of human genomic elements, termed retention elements, that tether episomes to mitotic chromosomes to increase ecDNA transmission to daughter cells. Using Retain-seq, a genome-scale assay that we developed, we reveal thousands of human retention elements that confer generational persistence to heterologous episomes. Retention elements comprise a select set of CpG-rich gene promoters and act additively. Live-cell imaging and chromosome conformation capture show that retention elements physically interact with mitotic chromosomes at regions that are mitotically bookmarked by transcription factors and chromatin proteins. This activity intermolecularly recapitulates promoter–enhancer interactions. Multiple retention elements are co-amplified with oncogenes on individual ecDNAs in human cancers and shape their sizes and structures. CpG-rich retention elements are focally hypomethylated. Targeted cytosine methylation abrogates retention activity and leads to ecDNA loss, which suggests that methylation-sensitive interactions modulate episomal DNA retention. These results highlight the DNA elements and regulatory logic of mitotic ecDNA retention. Amplifications of retention elements promote the maintenance of oncogenic ecDNA across generations of cancer cells, and reveal the principles of episome immortality intrinsic to the human genome.

DOI: 10.1038/s41586-025-09764-8

Source: https://www.nature.com/articles/s41586-025-09764-8