Combining CRISPRi with scRNA-seq enables high-throughput perturbation of disease-associated genes coupled to transcriptional readout. We recently implemented this approach as a rapid and powerful method to study the loss of function of many ASD risk genes simultaneously in human neurons. In ongoing work, we are performing a large-scale perturbation of multiple ASD genes in iPSC-derived neural progenitors cells and neurons. This project will improve our knowledge of ASD gene mechanisms, pinpoint commonly disrupted pathways, and nominate therapeutic drug candidates.

Understanding where transcription factors (TFs) and other gene expression regulators bind in the genome and how they orchestrate gene expression is a central goal in genomics. We have recently developed a novel, rapid, and affordable method called barcoded self-reporting transposon calling cards to simultaneously identify the genomic binding sites of TFs and the functional consequences of binding on gene expression. A significant proportion of causative genes in ASD are transcriptional regulators. We are using barcoded calling cards to map the binding sites of these factors in human neural cells relevant to ASD pathogenesis.

Nerve cells extend long, branched projections called axons and dendrites (collectively termed neurites) and communicate using synapses at these projections. Synaptic proteins and other genes involved in neuronal communication are commonly disrupted in individuals with ASD and other neurodevelopmental disorders. We are developing a novel method called POINT-MAP to perform Pooled Optical Imaging, Neurite Tracing, and Morphometry Across Perturbations. This technology will enable high-throughput evaluation of the contributions of NDD risk genes on neuronal and synaptic morphology.