转录因子结合和瓦尔酸甲基因性的个体遗传风险
Alison Anderson1,2, Piero Perucca1,2,3,4,5, Elena Vianca1,6
1Department of Neuroscience, School of Translational Medicine, Monash University, Melbourne, Victoria, Australia.
Neurology
|January 14, 2026
概括
母亲DNA中的遗传变异可以改变转录因子的结合方式,从而影响怀孕期间氨酸 (VPA) 暴露产生的出生缺陷风险. 这项研究确定EP300是VPA产性中的关键基因,为个性化风险评估铺平了道路.
科学领域:
- 遗传学 是一个遗传学.
- 药理学 药理学是指药理学的学科.
- 发展生物学 发展生物学
背景情况:
- 怀孕期间使用酸 (VPA) 与出生缺陷有关,但个体风险各不相同,这表明存在遗传因素.
- 了解母亲对VPA的基因影响对于怀孕前咨询和开发风险预测生物标志物至关重要.
研究的目的:
- 调查影响转录因子 (TF) 结合亲缘关系的母体基因组变异在VPA相关产性中的作用.
- 为了确定潜在的药物基因组生物标志物来预测VPA诱导的出生缺陷风险.
主要方法:
- 从发作怀孕登记册和基因组学联盟中对母亲外体变异的分析.
- 应用基于网络的方法,将变异与与出生缺陷相关的基因联系起来,并识别变异敏感的TFs.
- 利用基因负担测试和多模式证据在hESC模型中识别关键的TF及其相互作用,包括EP300.
主要成果:
- 与其他抗发作药物 (ASM) 相比,在暴露于VPA的怀孕中,在32种出生缺陷类型 (OR 1.73) 中,变异负担更高.
- 确定了359个变种敏感的TF,形成了一个连接网络,EP300与这些TF的41%相互作用.
- 在胚胎干细胞模型中,VPA暴露被证明会改变EP300-TF相互作用.
结论:
- 与EP300相关的基因调节的VPA诱导的干扰是一种潜在的致病机制,是各种出生缺陷的基础.
- 这种机制对遗传变异敏感,支持制药基因组风险生物标志物的开发.
- 这些发现对更安全的药物开发和个性化医疗对生育年龄的妇女有影响.
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