人类iPSC神经元中的基因特异性开放色素阐明了功能性疾病变异
Siwei Zhang1, Hanwen Zhang1, Yifan Zhou2,3
1Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, IL 60201, USA.
Science (New York, N.Y.)
|August 1, 2020
概括
研究人员在人类神经元中发现了基因特异性开放色素 (ASoC),揭示了基因变异如何影响大脑发育和神经精神疾病风险. 这种方法有助于确定精神分裂症等疾病的功能性风险基因.
科学领域:
- 神经遗传学
- 表观遗传学
- 发展神经科学
背景情况:
- 大多数神经精神疾病的遗传风险因素都存在于非编码DNA中,因此它们的功能影响尚不清楚.
- 调节性DNA元素,如增强剂,通常存在于开放的染色体区域.
- 神经发育期间的染色质可访问性变化可能受到疾病风险变异的影响.
研究的目的:
- 调查神经精神疾病风险变异是否会影响人类神经发育过程中的染色质可访问性.
- 使用基因特异性开放色素 (ASoC) 在iPSC衍生的神经元中识别非编码风险变异的功能机制.
主要方法:
- 利用人类诱导的多能干细胞 (iPSC) 衍生的神经元来建模早期的大脑发育.
- 在这些神经元模型中发现了成千上万的基因变异,显示出基因特异性开放色素 (ASoC).
- 分析了ASoCs,转录因子结合,基因增强剂和染色质接触之间的关系.
主要成果:
- 发现了成千上万个神经元的ASoC,
- 发现ASoC受转录因子结合的影响,并富含脑基因增强剂和表达定量特征位点 (eQTL).
- 证明ASoCs通过染色体接触连接远端基因,并为神经精神疾病风险变异增强,包括功能性精神分裂症风险变异.
结论:
- 基因特异性开放色素 (ASoC) 是非编码神经精神疾病风险变体的关键功能机制.
- 这种方法提供了一个强大的框架来识别与大脑疾病有关的因果变异和基因.
- 了解神经发育中的ASoC对于解读神经精神疾病的遗传结构至关重要.
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