发现具有CRISPR激活的刺激反应免疫增强剂
Dimitre R Simeonov1,2,3,4, Benjamin G Gowen4,5, Mandy Boontanrart4,5
1Biomedical Sciences Graduate Program, University of California, San Francisco, California 94143, USA.
Nature
|August 31, 2017
概括
科学家开发了一个新的CRISPR激活平台,以发现刺激反应增强剂,揭示非编码DNA中的遗传变异如何影响免疫功能障碍和自身免疫风险.
科学领域:
- 基因组学
- 免疫学
- 分子生物学
背景情况:
- 大多数常见的疾病遗传变异会影响增强剂,这些增强剂控制基因表达.
- 了解增强剂功能是解读非编码DNA在疾病中的作用的关键.
- 目前用于映射增强剂的方法受到细胞环境的限制.
研究的目的:
- 开发一个独立于刺激暴露的刺激反应增强剂识别平台.
- 研究增强剂在自身免疫风险位置 (CD69和IL2RA) 的作用.
主要方法:
- 使用式CRISPR激活 (CRISPRa) 在大型基因组区域中合成激活增强剂.
- 使用工程小鼠模型在体内研究增强剂功能.
- 对增强剂扰动的反应分析了染色体特征和基因表达的变化.
主要成果:
- 确定了一些具有刺激反应增强剂特征的CRISPRa反应元素.
- 发现一种具有自身免疫风险的IL2RA增强剂.
- 证明扰乱与疾病相关的Il2ra增强剂延迟了基因激活,而不是阻断了T细胞分化.
结论:
- 克里斯普拉平台有效地识别了功能性刺激反应增强剂.
- 增强剂中的非编码变体可以改变基因调节时间和免疫细胞功能.
- 这项研究提供了免疫功能障碍和自身免疫力的遗传基础.
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