转录调节元件的大规模并行表征
Vikram Agarwal1,2, Fumitaka Inoue3,4,5, Max Schubach6
1Department of Genome Sciences, University of Washington, Seattle, WA, USA. vikram.agarwal@sanofi.com.
Nature
|January 15, 2025
概括
研究人员使用基于lentivirus的大规模并行报告测试 (lentiMPRAs) 绘制了数百万个cis-regulatory元素 (cCREs). 这项研究揭示了控制cCRE活动和细胞类型特异性的序列特征,进步了我们对基因调控的理解.
科学领域:
- 基因组学
- 表观遗传学
- 分子生物学
背景情况:
- 人类基因组中的数百万候选c-regulatory元素 (cRE) 表现出对健康和疾病至关重要的细胞类型特异性活动.
- 缺乏对控制cCRE活性和细胞类型特异性的功能性理解.
研究的目的:
- 在多种细胞类型中对大量注释的cCREs进行功能性表征.
- 确定确定cCRE活性和细胞类型特异性的序列特征.
- 开发cCRE功能和变异效应的预测模型.
主要方法:
- 基于lentivirus的大规模并行报告测试 (lentiMPRA) 用于测试超过68万个序列的调节活性.
- 在三个细胞类型 (HepG2,K562,WTC11) 中进行了实验,测试了两个方向的序列.
- 使用lentiMPRA数据开发了基于序列的模型来预测cCRE功能和调节动机效应.
主要成果:
- 在41. 7%的cCRE测试序列中显示出活性.
- 促进剂表现出链导向偏差,并作为非细胞类型特定的"开关",而增强剂表现出较弱的导向偏差,但具有更强的组织特征.
- 基于序列的模型在预测cCRE功能和变异效应方面取得了很高的准确性,识别了调节动机及其组合作用.
结论:
- 这项研究提供了三种细胞系中功能性CREs的广泛目录.
- 大规模的功能测量有效地解剖调节语法,揭示控制cCRE活动和细胞类型特异性的序列特征.
- 这些发现有助于更深入地了解健康和疾病中的基因调节.
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