Oxygen-induced stress reveals context-specific gene regulatory effects in human brain organoids

In this manuscript, we used brain organoids to investigate how different cell types and environmental contexts influence gene regulation. Using a collection of genotyped human stem cell lines, we generated organoids modeling early cerebral cortex development and exposed them to different oxygen stress conditions. We then mapped expression quantitative trait loci (eQTLs) across cell types and conditions, revealing a vast number of gene regulatory effects that are latent under baseline conditions. These regulatory effects are likely consequential, as over 1,700 disease-associated genes are regulated by an oxygen-responsive eQTL effect. Moreover, our results can revise and refine the interpretation of human disease genetics data by linking variants to genes that are not apparent targets using a simple nearest-gene heuristic, and by pinpointing cell types and contexts in which regulatory associations are active. The framework we employed can be flexibly adapted to other disease-relevant treatment paradigms, allowing this novel use of organoid technology to be extended to studies of other gene-environment interactions.

Recommended citation: Benjamin D Umans and Yoav Gilad (2024). "Oxygen-induced stress reveals context-specific gene regulatory effects in human brain organoids" bioRxiv. 2024.09.03.611030.
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