Umans Benjamin D, Gilad Yoav
The University of Chicago.
The University of Chicago
Genome Res. 2025 Jun 2. doi: 10.1101/gr.280219.124.
The interaction between genetic variants and environmental stressors is key to understanding the mechanisms underlying neurological diseases. In this study, we used human brain organoids to explore how varying oxygen levels expose context-dependent gene regulatory effects. By subjecting a genetically diverse panel of 21 brain organoids to hypoxic and hyperoxic conditions, we identified hundreds of gene regulatory changes that are undetectable under baseline conditions, with 148 trait-associated genes showing regulatory effects only in response to oxygen stress. To capture more nuanced transcriptional patterns, we employed topic modeling, which revealed context-specific gene regulation linked to dynamic cellular processes and environmental responses, offering a deeper understanding of how gene regulation is modulated in the brain. These findings underscore the importance of genotype-environment interactions in genetic studies of neurological disorders and provide new insights into the hidden regulatory mechanisms influenced by environmental factors in the brain.
基因变异与环境应激源之间的相互作用是理解神经疾病潜在机制的关键。在本研究中，我们使用人脑类器官来探究不同氧水平如何揭示依赖于背景的基因调控效应。通过将21个基因多样化的脑类器官置于低氧和高氧条件下，我们识别出了数百种在基线条件下无法检测到的基因调控变化，其中148个与性状相关的基因仅在对氧应激作出反应时显示出调控效应。为了捕捉更细微的转录模式，我们采用了主题建模，该方法揭示了与动态细胞过程和环境反应相关的特定背景基因调控，从而更深入地理解大脑中基因调控是如何被调节的。这些发现强调了基因型 - 环境相互作用在神经疾病遗传研究中的重要性，并为大脑中受环境因素影响的隐藏调控机制提供了新的见解。
