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一个CHD8-TRRAP轴促进MYC和E2F在人类神经干细胞中的基因调节

Lize Meert¹, Mariana Pelicano de Almeida¹, Mike R Dekker¹

¹Department of Cell Biology, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, the Netherlands.

|March 19, 2025

概括

CHD8基因的突变与自闭症和大脑过度生长有关. 这项研究揭示了CHD8与TRRAP复合体相互作用,调节神经干细胞中的MYC和E2F基因,影响细胞生长.

科学领域:

遗传学和分子生物学
神经科学是一个神经科学.
发展生物学发展生物学

背景情况:

依赖ATP的染色体重塑剂CHD8的突变是单遗传自闭症的常见原因,并与大脑过度生长有关.
在与自闭症相关的细胞类型中,特别是神经干细胞中,CHD8的确切功能仍然不完全理解.

研究的目的:

研究CHD8在人类神经干细胞中的分子活动.
确定CHD8相互作用伙伴,并了解其在与自闭症谱系障碍相关的基因调节中的作用.

主要方法:

从人类神经干细胞中净化CHD8蛋白.
质谱测量以确定CHD8的相互作用伙伴.
全基因组局部化研究和ChIP-seq分析.
使用siRNA评估基因调节效应的枯竭研究.

主要成果:

已知MYC和E2F转录因子的共同激活剂TRRAP复合体被确定为CHD8的重要相互作用伙伴.
在人类神经干细胞中,CHD8和TRRAP在全基因组内进行同位化,并与MYC和E2F目标基因的促进物结合.
CHD8或TRRAP的枯竭导致MYC和E2F目标基因的下调,并导致细胞循环进入S阶段的受损.

结论:

在人类神经干细胞中,CHD8与TRRAP复合体相互作用.
这种相互作用促进MYC和E2F目标基因的调节,这些基因对细胞生长和增殖至关重要.
这些发现将CHD8功能障碍与与自闭症和大脑过度生长相关的基因调节途径的改变联系起来.

关键词:

分子遗传学分子遗传学分子生物学分子生物学干细胞研究的研究.

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