Inferring and perturbing cell fate regulomes in human brain organoids

Jonas Simon Fleck, Sophie Martina Johanna Jansen, Damian Wollny, Fides Zenk, Makiko Seimiya, Akanksha Jain, Ryoko Okamoto, Malgorzata Santel, Zhisong He (), J. Gray Camp () and Barbara Treutlein ()
Additional contact information
Jonas Simon Fleck: ETH Zürich
Sophie Martina Johanna Jansen: ETH Zürich
Damian Wollny: Max Planck Institute for Evolutionary Anthropology
Fides Zenk: ETH Zürich
Makiko Seimiya: ETH Zürich
Akanksha Jain: ETH Zürich
Ryoko Okamoto: ETH Zürich
Malgorzata Santel: ETH Zürich
Zhisong He: ETH Zürich
J. Gray Camp: Institute of Molecular and Clinical Ophthalmology Basel
Barbara Treutlein: ETH Zürich

Nature, 2023, vol. 621, issue 7978, 365-372

Abstract: Abstract Self-organizing neural organoids grown from pluripotent stem cells1–3 combined with single-cell genomic technologies provide opportunities to examine gene regulatory networks underlying human brain development. Here we acquire single-cell transcriptome and accessible chromatin data over a dense time course in human organoids covering neuroepithelial formation, patterning, brain regionalization and neurogenesis, and identify temporally dynamic and brain-region-specific regulatory regions. We developed Pando—a flexible framework that incorporates multi-omic data and predictions of transcription-factor-binding sites to infer a global gene regulatory network describing organoid development. We use pooled genetic perturbation with single-cell transcriptome readout to assess transcription factor requirement for cell fate and state regulation in organoids. We find that certain factors regulate the abundance of cell fates, whereas other factors affect neuronal cell states after differentiation. We show that the transcription factor GLI3 is required for cortical fate establishment in humans, recapitulating previous research performed in mammalian model systems. We measure transcriptome and chromatin accessibility in normal or GLI3-perturbed cells and identify two distinct GLI3 regulomes that are central to telencephalic fate decisions: one regulating dorsoventral patterning with HES4/5 as direct GLI3 targets, and one controlling ganglionic eminence diversification later in development. Together, we provide a framework for how human model systems and single-cell technologies can be leveraged to reconstruct human developmental biology.

Date: 2023
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DOI: 10.1038/s41586-022-05279-8

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