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阶段分离驱动异常的染色质循环和癌症的发展
Jeong Hyun Ahn1,2, Eric S Davis3, Timothy A Daugird4
1Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
Nature
|June 24, 2021
概括
癌症蛋白中的内在无序区域 (IDR) 通过形成相隔凝结物来驱动癌症发生. 这些凝结物增强基因向性,改变3D染色体结构,促进白血病的发展.
科学领域:
- 分子生物学
- 癌症研究
- 表观遗传学
背景情况:
- 癌症的发展与影响内在无序区域 (IDR) 的蛋白质的遗传变化有关.
- 在白血病中发现的NUP98-HOXA9等核波林嵌合体含有这些IDR,但它们在瘤发生中的作用尚不清楚.
研究的目的:
- 研究NUP98-HOXA9内在无序区域 (IDR) 在白血病转化中的作用.
- 了解这些IDR如何影响转录因子行为和染色体组织.
主要方法:
- 研究了NUP98-HOXA9中IDRs在液态分离 (LLPS) 和白血病转化中的功能.
- 使用人工HOX模拟器与无关的IDR来评估LLPS驱动的效应.
- 使用深度测序的Hi-C来分析全基因组的染色体相互作用.
主要成果:
- 在NUP98-HOXA9中,IDR对于形成相分离凝聚物和诱导白血病至关重要.
- NUP98-HOXA9的LLPS增强其染色质占用率,并在白血病基因中产生超级增强剂样式.
- 阶段分离的NUP98-HOXA9诱导了原癌基因的CTCF独立的染色体循环.
结论:
- 癌症可以利用突变通过LLPS创建瘤转录因子凝聚物,增强基因向并改变3D染色体结构.
- 这种驱动瘤发生的相分离机制可能广泛适用于涉及LLPS分子的各种疾病.
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