动态网络引导的CRISPRi屏幕识别了在细胞状态转换期间的CTCF循环受约束的非线性增强剂基因调控活性
Renhe Luo1,2, Jielin Yan1,2, Jin Woo Oh3
1Developmental Biology Program, Sloan Kettering Institute, New York City, NY, USA.
Nature genetics
|July 24, 2023
概括
发现基因增强剂是困难的,因为表达效应较弱. 这项研究使用细胞状态转换和CRISPRi查来更有效地发现增强剂,改善复杂疾病研究.
科学领域:
- 基因组学就是基因组学.
- 系统生物学 系统生物学
- 发展生物学 发展生物学
背景情况:
- 由于基因表达效应较弱,增强剂的发现具有挑战性,特别是在复杂疾病中.
- 基因调控网络建模表明,细胞转换期间的非线性动态可以增强增强剂发现灵敏度.
研究的目的:
- 在细胞状态转换期间利用非线性基因调节,以改善增强剂的发现.
- 在人类胚胎干细胞分化过程中识别核心内皮转录因子的增强剂.
主要方法:
- 在人类胚胎干细胞最终内皮分化的中期过渡期间利用CRISPR干扰 (CRISPRi) 查.
- 开发了一个CTCF循环受约束的交互活动模型,集成3D基因组数据.
- 将模型性能与基于Hi-C的增强剂-促进剂接触频率模型进行比较.
主要成果:
- 发现了对内皮转录因子的综合增强剂.
- 观察到增强剂具有强烈的中转效应,但过渡后效应较弱,与非线性时间响应预测保持一致.
- 基于CTCF循环的受约束模型比基于Hi-C的模型更好地预测功能增强剂.
结论:
- 在细胞状态转换期间非线性增强剂基因调节是敏感增强剂发现的强大策略.
- 开发的模型和选方法为识别功能增强剂提供了可通用的方法.
- 这项工作促进了对正常和病变细胞转换中的基因调节的理解.
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