染色体依赖的动机语法定义了差异化轨迹.
Sevi Durdu1, Murat Iskar1, Luke Isbel2
1Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
Molecular cell
|August 8, 2025
概括
具有相似的DNA结合位点的两个转录因子 (TF) 驱动不同的细胞命运. 它们的特异性取决于染色质的可访问性,基因变异和相互作用伙伴,揭示了细胞分化中的关键机制.
科学领域:
- 分子生物学分子生物学
- 发展生物学 发展生物学
- 基因组学就是基因组学.
背景情况:
- 转录因子 (TFs) 结合DNA基因调节细胞身份.
- 管治TF特异性的精确机制仍然不完全理解.
- 神经原蛋白-2 (NGN2) 和MyoD1 TFs结合了类似的E-box动机,但分别诱导了不同的神经元和肌肉细胞命运.
研究的目的:
- 研究NGN2和MyoD1.1驱动的独特细胞命运选择的因素.
- 阐明染色体可访问性和DNA模式语法在TF特异性中的作用.
- 开发和应用机器学习方法来分析TF绑定动态.
主要方法:
- 在小鼠胚胎干细胞分化过程中监测TF结合动态.
- 使用可解释的机器学习模型,整合DNA可访问性数据.
- 通过细胞和体外分析验证具有约束力的预测.
主要成果:
- 一个染色体依赖的动机语法决定了共享和因子特定的TF结合.
- 共同的结合点位于开放的染色质中,受局部核细胞位的影响.
- 关闭染色体中的因子特定结合涉及先驱因子活性,动图变异,间距和相互作用伙伴.
结论:
- TF特异性来自于可访问的染色质中的机会性结合和特定于环境的染色质开放的组合.
- 染色质状态,DNA动图特征和蛋白质相互作用的相互作用决定了细胞分化轨迹.
- 开发的方法提供了一个框架,用于理解各种生物模型的TF特异性.
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