基于压力和炎症的动态调节人类神经元中的精神病风险位置
Kayla G Retallick-Townsley1,2,3, Seoyeon Lee4,5, Sam Cartwright1,3
1Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
bioRxiv : the preprint server for biology
|July 19, 2024
概括
产前压力和炎症可以加剧脑部疾病的遗传风险. 这项研究使用了人类神经元的大规模记者试验来识别影响基因调节的基因型x环境相互作用.
科学领域:
- 神经科学是一个神经科学.
- 遗传学 是一个遗传学.
- 发展生物学 发展生物学
背景情况:
- 产前环境显著影响神经发育,增加对精神疾病的易感性.
- 了解胎儿暴露如何与遗传倾向相互作用,对于复杂的大脑疾病至关重要.
研究的目的:
- 研究人类神经元中的基因型x环境 (GxE) 相互作用.
- 列出胎儿压力 (皮激素) 和炎症 (IL-6,干扰素α) 如何影响GWAS位点的基因调节.
主要方法:
- 采用了一个大规模的,上下文依赖的大规模并行报告员测试 (MPRA).
- 人类诱导的多能干细胞 (hiPSC) 衍生的谷氨酸性神经元被用来测试240个GWAS位点的约3,500个候选调节元件 (CREs).
- 实证评估了皮,IL-6和干扰素α对转录活性的影响.
主要成果:
- 11%的CREs在基线时活跃;基因特异性活性在6% (IL-6) 到23% (皮) 之间.
- 环境线索改变了转录因子的结合,影响了为大脑,代谢和免疫疾病而丰富的基因标.
- 特定风险变体在产前压力或炎症暴露后表现出更高的敏感性.
结论:
- 基因调节是动态的,在神经发育过程中受到环境因素的影响.
- GxE相互作用揭示了脑变性和可变透性在脑疾病中的机制.
- 已识别的风险变体和机制为心理健康干预提供了潜在的治疗目标.
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