Coupled Single-Cell CRISPR Screening and Epigenomic Profiling Reveals Causal Gene Regulatory Networks
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- Coupled Single-Cell CRISPR Screening and Epigenomic Profiling Reveals Causal Gene Regulatory Networks
- Rubin, Adam J.; Parker, Kevin R.; Satpathy, Ansuman T.; Qi, Yanyan; Wu, Beijing; Ong, Alvin J.; Mumbach, Maxwell R.; Ji, Andrew L.; Kim, Daniel S.; Cho, Seung Woo; Zarnegar, Brian J.; Greenleaf, William J.; Chang, Howard Y.; Khavari, Paul A.
- single-cell genomics; CRISPR; pooled screens; epigenomics; ATAC-seq; chromatin accessibility
- Issue Date
- CELL PRESS
- CELL, v.176, no.1-2, pp.361 - 376
- Here, we present Perturb-ATAC, a method that combines multiplexed CRISPR interference or knockout with genome-wide chromatin accessibility profiling in single cells based on the simultaneous detection of CRISPR guide RNAs and open chromatin sites by assay of transposase-accessible chromatin with sequencing (ATAC-seq). We applied Perturb-ATAC to transcription factors (TFs), chromatin-modifying factors, and noncoding RNAs (ncRNAs) in ∼4,300 single cells, encompassing more than 63 genotype-phenotype relationships. Perturb-ATAC in human B lymphocytes uncovered regulators of chromatin accessibility, TF occupancy, and nucleosome positioning and identified a hierarchy of TFs that govern B cell state, variation, and disease-associated cis-regulatory elements. Perturb-ATAC in primary human epidermal cells revealed three sequential modules of cis-elements that specify keratinocyte fate. Combinatorial deletion of all pairs of these TFs uncovered their epistatic relationships and highlighted genomic co-localization as a basis for synergistic interactions. Thus, Perturb-ATAC is a powerful strategy to dissect gene regulatory networks in development and disease.
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