在活小鼠中对人类增强剂变异活性进行快速和定量功能性询问
Ethan W Hollingsworth1,2, Taryn A Liu1, Joshua A Alcantara1
1Department of Developmental and Cell Biology, University of California, Irvine, CA, USA.
Nature communications
|January 6, 2025
概括
研究人员开发了双-enSERT,这是一种用于快速评估活小鼠增强剂变体功能的新型报告系统. 这项技术通过分析基因表达和识别与疾病相关的变异来帮助理解先天性疾病.
科学领域:
- 遗传学 是一个遗传学.
- 发展生物学 发展生物学
- 分子生物学分子生物学
背景情况:
- 与先天性疾病相关的非编码变异的功能分析是困难的,因为体内模型有限.
- 了解增强剂的功能对于破译对发育性疾病的遗传贡献至关重要.
研究的目的:
- 引入双-enSERT,一种基于Cas9的双色光报告系统,用于快速,定量地在体内比较增强剂活性.
- 为了评估与四肢多肢症,自闭症谱系障碍和面形相关的增强器变体的功能影响.
- 确定参与增强器错误调节的候选途径,并验证与神经发育障碍相关的变异.
主要方法:
- 在活小鼠中开发和应用双EnSERT报告员系统.
- 增强剂等位基因活动的定量比较.
- 与单细胞转录组学集成,以分析基因表达模式.
- 测试了15种与神经发育障碍相关的非编码变异.
主要成果:
- 双-enSERT 能够快速 (不到两周) 在体内评估增强剂变体的功能.
- 已知疾病相关变异的功能增益和丧失效应被测量.
- 单细胞转录组学揭示了正常和宫外增强剂活性细胞的基因表达变化.
- 测试了15种新的非编码变体,其中一些被确定是改变OTX2和MIR9-2大脑增强剂活性,涉及到自闭症.
结论:
- 双-enSERT为非编码变体的功能基因组学提供了一个强大而高效的平台.
- 该系统有助于从变种识别到体内功能分析的快速过渡.
- 这项技术通过阐明增强剂变体的作用,推动了对先天性和神经发育障碍的研究.
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