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部分拯救了基因表达和增强剂活性从AKAP11的异构结合性淘汰,同时诱导新的差异性变化

Nargess Farhangdoost^1,2, Alessia Pietrantonio^2,3, Yumin Liu^2,3

¹Department of Human Genetics, McGill University, Montreal, QC, Canada.

Scientific reports

|October 30, 2025

概括

治疗部分地使神经元中的基因表达变化正常化,这些神经元具有双极性障碍 (BD) 和精神分裂症 (SCZ) 的特定遗传风险. 这表明可能有助于患有影响这些疾病的AKAP11基因变异患者.

科学领域:

神经科学是一个神经科学.
遗传学是一个遗传学.
药理学药理学是指药理学的学科.

背景情况:

双极性障碍 (BD) 和精神分裂症 (SCZ) 是复杂的精神疾病.
(Li) 是BD的有效情绪稳定剂,但其机制尚不清楚.
AKAP11是BD和SCZ的共同风险基因.

研究的目的:

研究对人类iPSC衍生神经元的转录组和表观基因组的影响,这些神经元具有异合体AKAP11-Knockout (Het-AKAP11-KO).
为了确定是否可以使与AKAP11功能丧失相关的转录和表观基因组变化正常化.

主要方法:

使用全基因组方法来分析转录组和表观基因组.
使用人类诱导多能干细胞 (iPSC) 衍生的Het-AKAP11-KO神经元培养.
评估了慢性治疗的影响.

主要成果:

处理上调调节了以前由Het-AKAP11-KO下调节的通路.
部分挽救了转录基因的变化,使它们更接近野生类型 (WT) 的水平.
观察到诱导的基因素H3K27ac的调节和增强的GSK3β酸化.

结论:

显示出与AKAP11变异相关的BD和SCZ细胞模型中的转录基因变异的正常化潜力.
机制包括表观遗传修饰 (H3K27ac) 和GSK3β/WNT信号的调制.
这些发现支持对于BD和SCZ的特定患者亚组的治疗作用.

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