脑细胞类型特定的增强剂-促进剂相互作用图和疾病-风险关联
Alexi Nott1, Inge R Holtman1,2, Nicole G Coufal3,4
1Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Science (New York, N.Y.)
|November 16, 2019
概括
与阿尔茨海默氏症 (AD) 相关的遗传变异在微质调节区域中发现,而不仅仅是神经元. 这表明微质在阿尔茨海默氏症的发病过程中起着关键作用,并确定新的基因标.
科学领域:
- 神经遗传学
- 基因组学
- 细胞生物学
背景情况:
- 非编码的遗传变异对表型多样性有重大影响,但其功能性解释,特别是在大脑疾病中,仍然是一个挑战.
- 了解基因变异在细胞类型特异性调节元素中的作用对于破译疾病机制至关重要.
研究的目的:
- 在主要的人类脑细胞类型中识别和描述非编码调节区域.
- 研究基因变异与精神疾病和阿尔茨海默病 (AD) 的细胞类型特定关联.
- 阐明AD相关的非编码变体对特定脑细胞类型的基因表达的功能影响.
主要方法:
- 在主要的人类脑细胞类型中定义非编码的调节元素 (增强剂,促进剂).
- 基因变异与精神疾病和零星AD的关联分析.
- 构建互动组图以将细胞类型特定的增强剂与向基因联系起来.
- 使用基因编辑 (CRISPR) 进行功能验证,以评估增强剂活性和基因表达 (例如BIN1).
主要成果:
- 精神疾病变体主要与神经元增强剂和促进剂有关.
- 阿尔茨海默氏症 (AD) 变体主要局部化为微质特异性增强剂.
- 互动组映射显示了与AD风险变异相关的扩大微质基因网络.
- 删除一种携带AD风险的微质增强剂可显著降低微质中的BIN1表达,但不能降低神经元或星球细胞的表达.
结论:
- 与AD相关的非编码变体主要通过微质中的调节元素起作用.
- 这些发现表明微质及其调节网络与阿尔茨海默氏症的发病有关.
- 这项研究扩大了受AD非编码变异影响的基因列表,并确定了微质细胞为它们的关键细胞类型.
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