Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA, USA.
Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
Nature. 2024 Nov;635(8037):201-209. doi: 10.1038/s41586-024-07861-8. Epub 2024 Nov 6.
The chromosomal theory of inheritance dictates that genes on the same chromosome segregate together while genes on different chromosomes assort independently. Extrachromosomal DNAs (ecDNAs) are common in cancer and drive oncogene amplification, dysregulated gene expression and intratumoural heterogeneity through random segregation during cell division. Distinct ecDNA sequences, termed ecDNA species, can co-exist to facilitate intermolecular cooperation in cancer cells. How multiple ecDNA species within a tumour cell are assorted and maintained across somatic cell generations is unclear. Here we show that cooperative ecDNA species are coordinately inherited through mitotic co-segregation. Imaging and single-cell analyses show that multiple ecDNAs encoding distinct oncogenes co-occur and are correlated in copy number in human cancer cells. ecDNA species are coordinately segregated asymmetrically during mitosis, resulting in daughter cells with simultaneous copy-number gains in multiple ecDNA species before any selection. Intermolecular proximity and active transcription at the start of mitosis facilitate the coordinated segregation of ecDNA species, and transcription inhibition reduces co-segregation. Computational modelling reveals the quantitative principles of ecDNA co-segregation and co-selection, predicting their observed distributions in cancer cells. Coordinated inheritance of ecDNAs enables co-amplification of specialized ecDNAs containing only enhancer elements and guides therapeutic strategies to jointly deplete cooperating ecDNA oncogenes. Coordinated inheritance of ecDNAs confers stability to oncogene cooperation and novel gene regulatory circuits, allowing winning combinations of epigenetic states to be transmitted across cell generations.
染色体遗传理论表明，同一染色体上的基因一起分离，而不同染色体上的基因则独立分配。染色体外 DNA（ecDNA）在癌症中很常见，通过细胞分裂过程中的随机分离，驱动癌基因扩增、基因表达失调和肿瘤内异质性。不同的 ecDNA 序列，称为 ecDNA 物种，可以共存，从而促进癌细胞之间的分子间合作。在体细胞世代中，肿瘤细胞内的多个 ecDNA 物种如何被分配和维持尚不清楚。在这里，我们表明，合作性的 ecDNA 物种通过有丝分裂共分离而协调遗传。成像和单细胞分析表明，多个编码不同癌基因的 ecDNA 共同出现，并且在人类癌细胞中的拷贝数相关。ecDNA 物种在有丝分裂过程中不对称地协调分离，导致子细胞在多个 ecDNA 物种同时发生拷贝数增加之前进行选择。分子间的接近和有丝分裂开始时的活跃转录促进了 ecDNA 物种的协调分离，而转录抑制则减少了共分离。计算模型揭示了 ecDNA 共分离和共选择的定量原则，预测了它们在癌细胞中的观察分布。ecDNA 的协调遗传使仅含有增强子元件的特殊 ecDNA 能够共同扩增，并指导联合消耗协同 ecDNA 致癌基因的治疗策略。ecDNA 的协调遗传赋予了致癌基因合作和新的基因调控回路的稳定性，使表观遗传状态的获胜组合能够在细胞世代中传递。
