Single-cell brain organoid screening identifies developmental defects in autism

Chong Li (), Jonas Simon Fleck, Catarina Martins-Costa, Thomas R. Burkard, Jan Themann, Marlene Stuempflen, Angela Maria Peer, Ábel Vertesy, Jamie B. Littleboy, Christopher Esk, Ulrich Elling, Gregor Kasprian, Nina S. Corsini, Barbara Treutlein () and Juergen A. Knoblich ()
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Chong Li: Institute of Molecular Biotechnology of the Austrian Academy of Science (IMBA)
Jonas Simon Fleck: ETH Zürich
Catarina Martins-Costa: Institute of Molecular Biotechnology of the Austrian Academy of Science (IMBA)
Thomas R. Burkard: Institute of Molecular Biotechnology of the Austrian Academy of Science (IMBA)
Jan Themann: Institute of Molecular Biotechnology of the Austrian Academy of Science (IMBA)
Marlene Stuempflen: Medical University of Vienna
Angela Maria Peer: Institute of Molecular Biotechnology of the Austrian Academy of Science (IMBA)
Ábel Vertesy: Institute of Molecular Biotechnology of the Austrian Academy of Science (IMBA)
Jamie B. Littleboy: Institute of Molecular Biotechnology of the Austrian Academy of Science (IMBA)
Christopher Esk: Institute of Molecular Biotechnology of the Austrian Academy of Science (IMBA)
Ulrich Elling: Institute of Molecular Biotechnology of the Austrian Academy of Science (IMBA)
Gregor Kasprian: Medical University of Vienna
Nina S. Corsini: Institute of Molecular Biotechnology of the Austrian Academy of Science (IMBA)
Barbara Treutlein: ETH Zürich
Juergen A. Knoblich: Institute of Molecular Biotechnology of the Austrian Academy of Science (IMBA)

Nature, 2023, vol. 621, issue 7978, 373-380

Abstract: Abstract The development of the human brain involves unique processes (not observed in many other species) that can contribute to neurodevelopmental disorders1–4. Cerebral organoids enable the study of neurodevelopmental disorders in a human context. We have developed the CRISPR–human organoids–single-cell RNA sequencing (CHOOSE) system, which uses verified pairs of guide RNAs, inducible CRISPR–Cas9-based genetic disruption and single-cell transcriptomics for pooled loss-of-function screening in mosaic organoids. Here we show that perturbation of 36 high-risk autism spectrum disorder genes related to transcriptional regulation uncovers their effects on cell fate determination. We find that dorsal intermediate progenitors, ventral progenitors and upper-layer excitatory neurons are among the most vulnerable cell types. We construct a developmental gene regulatory network of cerebral organoids from single-cell transcriptomes and chromatin modalities and identify autism spectrum disorder-associated and perturbation-enriched regulatory modules. Perturbing members of the BRG1/BRM-associated factor (BAF) chromatin remodelling complex leads to enrichment of ventral telencephalon progenitors. Specifically, mutating the BAF subunit ARID1B affects the fate transition of progenitors to oligodendrocyte and interneuron precursor cells, a phenotype that we confirmed in patient-specific induced pluripotent stem cell-derived organoids. Our study paves the way for high-throughput phenotypic characterization of disease susceptibility genes in organoid models with cell state, molecular pathway and gene regulatory network readouts.

Date: 2023
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DOI: 10.1038/s41586-023-06473-y

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