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Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
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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.

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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.

关键词:
阿尔茨海默氏症是阿尔茨海默氏症的疾病马普特 (MAPT) 是一个增强剂是一种增强剂.基因调节 基因调节 基因调节神经元神经元的神经元

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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.