神经元MAPT表达通过与cis调节元件的长距离相互作用进行介导
Brianne B Rogers1, Ashlyn G Anderson2, Shelby N Lauzon2
1HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA; University of Alabama at Birmingham, Birmingham, AL 35294, USA.
American journal of human genetics
|January 17, 2024
概括
研究人员确定了控制MAPT基因表达的调节元件,这对于理解病症至关重要. 这些元素的遗传变异可能通过减少MAPT表达来保护神经退行性疾病.
科学领域:
- 神经科学是一个神经科学.
- 遗传学 遗传学 是一个
- 分子生物学分子生物学
背景情况:
- 病是一种神经退行性疾病,其特征是异常的蛋白聚合物,由MAPT基因编码.
- 在神经分化过程中,MAPT基因表达增加,这表明细胞类型特定的调节控制.
- 了解MAPT调节对于神经退行病原和疾病风险评估至关重要.
研究的目的:
- 确定控制在分化神经元中MAPT表达的cis调节元件 (cCREs).
- 在MAPT上功能验证已识别的cCREs的监管作用.
- 研究cCREs内遗传变异与神经退行性疾病风险的关联.
主要方法:
- 染色体构成测定 (Hi-C,Capture-C) 的方法
- 单核多组学 (RNA-seq, ATAC-seq) 是一种单核多组学.
- 大量ATAC-seq,ChIP-seq (H3K27ac,CTCF) 的使用情况
- 路西法酶测定和CRISPR干扰 (CRISPRi) 用于功能验证.
- 对神经退行症队列中遗传变异的分析.
主要成果:
- 确定了调节MAPT表达的近端和远端cCREs.
- 证实了几个cCREs的调节功能,包括超出H1/H2哈普洛型逆转的区域.
- 在痴呆症患者中发现了cCREs罕见,有害变异的枯竭,这表明它起着保护作用.
结论:
- 发现了控制MAPT表达的新型cis-regulatory元素.
- 证明了破坏MAPT增强剂活性的变体可能对神经退行性疾病有保护作用.
- 强调详细的cCRE知识对于理解基因调节和疾病风险的重要性.
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