Pooled CRISPR screens with joint single-nucleus chromatin accessibility and transcriptome profiling

A high-throughput CRISPR screening platform with joint single nucleus chromatin accessibility, transcriptome, and guide RNA capture (MultiPerturb-seq) using combinatorial indexing combined with droplet microfluidics to scale throughput and integrate all three modalities. We apply MultiPerturb-seq to identify key genes whose loss can trigger differentiation in a rare pediatric cancer, atypical teratoid/rhabdoid tumor (AT/RT), driven by loss of the SWI/SNF chromatin remodeling subunit SMARCB1.