Time: 13:45-14:45 on Mon.,Oct.9, 2023

Venue：E109,Biomedicine Hall

Speaker: Dr.Chong Li

Host: Dr.Song-Hai Shi

Title: Decoding Neurodevelopmental Disorders through Single-Cell CRISPR Brain Organoid Screening

Abstract：

The development of the human brain involves unique processes not observed in many other species, and these processes can contribute to neurodevelopmental disorders. 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 utilizes inducible CRISPR–Cas9-based genetic disruption and single-cell transcriptomics for pooled loss-of-function screening in mosaic organoids. Leveraging our system, we perturbed 36 high-risk autism spectrum disorder genes in parallel and identified their effects on cell fate determination. We found that dorsal intermediate progenitors, ventral progenitors, and upper-layer excitatory neurons are among the most vulnerable cell types. We constructed a developmental gene regulatory network of cerebral organoids using single-cell transcriptomes and chromatin modalities and identified autism spectrum disorder-associated and perturbation-enriched regulatory modules. Perturbing members of the BRG1/BRM-associated factor (BAF) chromatin remodeling complex leads to an 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 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.

Biography：

Chong Li received his Ph.D. degree in Human Genetics and Genomics from the University of Miami, Miller School of Medicine in 2018. During his Ph.D. research, he used Drosophila as a model system to investigate mechanisms contributing to rare genetic neurological disorders and synaptic degeneration. After obtaining his Ph.D., he relocated to Austria and has been working as a postdoctoral researcher in Dr. Jürgen Knoblich's lab at the Institute of Molecular Biotechnology of the Austrian Academy of Sciences. His research focuses on understanding the regulatory principles of human brain development and modeling brain disorders using stem cell-derived 3D brain organoids. He established the CRISPR-human organoids-single-cell RNA-seq (CHOOSE) system, a functional genomics approach to quantitatively study cell type-specific defects in neurodevelopmental disorders. He conducted pioneering research on disease-relevant screening of transcriptional and epigenetic regulators associated with autism. Through his work, he identified that certain neural progenitors, neurons, and gene regulatory networks are particularly susceptible to genetic perturbations associated with autism. In this lecture, Dr. Li will introduce how cutting-edge single-cell genomics and high-throughput CRISPR screening in organoids can facilitate gene function and disease studies.