多尺度足迹揭示了 cis 调节元件的组织
Yan Hu1,2, Max A Horlbeck1,2,3, Ruochi Zhang1,2,4
1Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Nature
|January 22, 2025
概括
我们开发了一种新的计算方法,即PRINT, 这种工具揭示了CREs在细胞发育和衰老过程中如何变化,为基因调控和疾病提供了洞察力.
科学领域:
- 基因组学
- 计算生物学
- 表观遗传学
背景情况:
- 基因调节元件 (CREs) 对基因表达至关重要,但它们的动态蛋白质组织尚不清楚.
- 现有的方法限制了CREs的效应蛋白组织的全基因组分析,阻碍了细胞命运和疾病的功能研究.
研究的目的:
- 开发一种用于测量基因组中CRE的效应蛋白组织的计算方法.
- 推断转录因子和核细胞结合,并解释CREs的调节逻辑.
- 在血液形成和衰老过程中研究CRE动态.
主要方法:
- 开发了PRINT,一种从染色质可访问性数据中识别DNA-蛋白相互作用足迹的计算方法.
- 使用深度学习创建了seq2PRINT框架,用于精确推断蛋白质结合.
- 应用seq2PRINT对来自人类骨髓和小鼠造血干细胞的单细胞色素可访问性数据.
主要成果:
- 观察到的CREs的顺序建立和扩大集中在人类造血过程中的先驱因素上.
- 在小鼠造血干细胞中发现与年龄相关的CRE结构变化,包括减少的核细胞足迹.
- 在老鼠造血干细胞中发现了 de novo Ets 复合基因的增加.
结论:
- 建立了一种方法,从染色质可访问性数据中获取DNA结合蛋白的动态.
- 揭示了差异化和衰老过程中的调节元素的架构.
- 为了解细胞命运和疾病中的调节元件功能提供了一个框架.
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