在人类癌细胞中,染色体外DNA物种的协调继承
King L Hung1, Matthew G Jones1, Ivy Tsz-Lo Wong2,3
1Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA 94305, USA.
bioRxiv : the preprint server for biology
|July 28, 2023
概括
外染色体DNA (ecDNA) 物种在细胞分裂过程中合作并共同遗传. 这种协调的遗传稳定了瘤基因的合作,推动了癌症的进化,并提供了新的治疗点.
科学领域:
- 遗传学 是一个遗传学.
- 癌症生物学 癌症生物学
- 分子生物学分子生物学
背景情况:
- 染色体遗传理论控制了基因分离,但癌症中的染色体外DNA (ecDNA) 动态不太清楚.
- 外染色体DNA (ecDNA) 通过潜在的随机分离驱动瘤基因放大和内异质性.
- 癌细胞中多个共存的ecDNA物种的遗传模式在很大程度上是未知的.
研究的目的:
- 研究癌细胞内多种ecDNA物种的遗传机制.
- 了解ecDNA的共存和共分离如何促进癌细胞进化.
- 探索针对合作的ecDNA元素的治疗策略.
主要方法:
- 单细胞成像和分析人类癌细胞.
- 对ecDNA共同分离和共同选择的计算建模.
- 在含有增强元件的ecDNA上进行功能研究.
主要成果:
- 编码不同的癌基因的多个ecDNA物种同时发生,并在人类癌细胞中显示相关的副本数量.
- 在线粒分裂过程中,ecDNA物种被协调分离不对称,导致子细胞同时增加拷贝数量.
- 计算模型准确地预测了ecDNA共同分离和共同选择模式.
- 协调的ecDNA遗传使仅增强剂的ecDNAs能够共同放大,并使瘤基因合作的稳定性.
结论:
- 合作性ecDNA物种通过线粒体共分离协调地遗传,从而使瘤基因合作具有稳定性.
- 这种协调继承建立了新的基因调节回路,并促进了有利的表观遗传状态的传播.
- 了解ecDNA遗传为癌症演变提供了洞察力,并提出了共同针对合作的ecDNA瘤基因的策略.
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