在单个哺乳动物的染色体纤维上,普遍和编程的核细胞体扭曲模式
Marty G Yang1, Hannah J Richter1,2, Simai Wang1,2
1Gladstone Institute of Data Science and Biotechnology, Gladstone Institutes, San Francisco, CA 94158.
bioRxiv : the preprint server for biology
|February 3, 2025
概括
我们开发了一种新的方法来绘制核细胞结构图,并发现大多数哺乳动物的核细胞被扭曲,揭示了由转录因子调节的DNA可访问性中的可塑性,这对基因调节很重要.
科学领域:
- 表观遗传学和基因组学
- 分子生物学分子生物学
- 染色素的结构和动力学
背景情况:
- 了解核细胞结构和蛋白质-DNA相互作用对于基因调节至关重要.
- 现有的方法往往缺乏分辨率,以单分子分辨率映射出不同的核细胞结构.
- 在不同的细胞环境中,染色质和核细胞体可塑性的动态性仍然不完全理解.
研究的目的:
- 开发和应用基因组规模的方法来绘制单分子核细胞共占和蛋白质-DNA相互作用的地图.
- 根据DNA可访问性模式对不同核细胞结构进行分类.
- 调查转录因子和表观基因组域在核细胞扭曲中的作用.
主要方法:
- 使用长时间读取的高分辨率腺因甲基转移酶足迹.
- 开发了反复定义的不可访问性长度 (IDLI) 来分类核体结构 (染色体,八核体,未包裹的核体,亚核体物种).
- 应用IDLI对小鼠胚胎干细胞 (mESC) 和小鼠初级肝细胞.
主要成果:
- 在个别哺乳动物的染色体纤维中发现了广泛的核体变异 (> 85%),表明了显著的核体内DNA可访问性.
- 观察到在调节元件的核细胞组扭曲的表观基因组域特异性模式.
- 证明转录因子结合直接编程结合部位的核体扭曲,并确定了FOXA2在肝细胞中的作用.
结论:
- 核体在单分子水平上表现出极端的,但受调节的,DNA可访问性的可塑性.
- IDLI方法为研究转录因子结合,核细胞体重塑和细胞类型特异性基因调节提供了一个新的框架.
- 这些发现突出了DNA序列,蛋白质结合和染色质结构在调节基因表达中的动态相互作用.
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