斯坦福大学医学院Howard Y. Chang小组取得一项新突破。他们研制了染色体外DNA转座因子激活增强子。相关论文于2025年10月21日发表于国际顶尖学术期刊《自然—细胞生物学》杂志上。

在这里，课题组绘制了结直肠癌细胞中MYC扩增的ecDNA的三维结构图，并鉴定了68个ecDNA相互作用元件——富含转座元件的基因组位点，这些元件经常被整合到ecDNA上。研究人员将重点放在与MYC共同扩增的L1M4a1#LINE/L1片段上，该片段仅在ecDNA扩增的情况下起作用。通过CRISPR- CATCH、CRISPR干扰和报告基因检测，该课题组研究人员证实了它在ecDNA上的存在、增强子的活性和对癌细胞适应性的重要性。这些发现表明，重复元件可以作为ecDNA上的功能序列而不是非活性序列被重新激活和增选，从而潜在地驱动癌基因表达和肿瘤进化。他们的研究揭示了ecDNA利用重复元素塑造癌症表型的机制，这对诊断和治疗具有重要意义。

据介绍，在侵袭性癌症中，染色体外DNA （ecDNA）驱动癌基因扩增和瘤内异质性。虽然转座因子再激活在癌症中很常见，但其在ecDNA中的作用仍未被探索。

附：英文原文

Title: Enhancer activation from transposable elements in extrachromosomal DNA

Author: Kraft, Katerina, Murphy, Sedona E., Jones, Matthew G., Shi, Quanming, Bhargava-Shah, Aarohi, Luong, Christy, Hung, King L., He, Britney J., Li, Rui, Park, Seung Kuk, Montgomery, Michael T., Weiser, Natasha E., Wang, Yanbo, Luebeck, Jens, Bafna, Vineet, Boeke, Jef D., Mischel, Paul S., Boettiger, Alistair N., Chang, Howard Y.

Issue&Volume: 2025-10-21

Abstract: Extrachromosomal DNA (ecDNA) drives oncogene amplification and intratumoural heterogeneity in aggressive cancers. While transposable element reactivation is common in cancer, its role on ecDNA remains unexplored. Here we map the 3D architecture of MYC-amplified ecDNA in colorectal cancer cells and identify 68 ecDNA-interacting elements—genomic loci enriched for transposable elements that are frequently integrated onto ecDNA. We focus on an L1M4a1#LINE/L1 fragment co-amplified with MYC, which functions only in the ecDNA-amplified context. Using CRISPR-CATCH, CRISPR interference and reporter assays, we confirm its presence on ecDNA, enhancer activity and essentiality for cancer cell fitness. These findings reveal that repetitive elements can be reactivated and co-opted as functional rather than inactive sequences on ecDNA, potentially driving oncogene expression and tumour evolution. Our study uncovers a mechanism by which ecDNA harnesses repetitive elements to shape cancer phenotypes, with implications for diagnosis and therapy.

DOI: 10.1038/s41556-025-01788-6

Source: https://www.nature.com/articles/s41556-025-01788-6