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Comparative Single-Cell Profiling of CRISPR Knockout and Interference Defines Modality-Specific Strengths in Functional Genomics

Gupta, N.; Sayer, A.; Prater, M.; Mastrokalou, C.; Saeed, K.; Company, C.; Hart, C.; Miragaia, R.; Trehan, A.; Functional Genomics Centre, ; McDermott, U.; Strauss, M. E.; Ross-Thriepland, D.; Walter, D.; Kalinka, A.

2026-08-27 genomics
10.64898/2026.08.26.747303 bioRxiv
Show abstract

Pooled CRISPR screens coupled with single-cell RNA sequencing enable high-throughput functional interrogation of gene regulatory networks, yet systematic comparisons of CRISPR knockout (CRISPRko) and CRISPR interference (CRISPRi) remain limited. We established a single-cell CRISPRko workflow and benchmarked it against CRISPRi using 87 sgRNAs targeting 29 unfolded protein response genes. CRISPRko generated transcriptional phenotypes are highly concordant with CRISPRi, and induced comparable pathway-level responses. While CRISPRi allows direct assessment of target gene repression, CRISPRko provides an effective complementary approach for complete loss-of-function studies, expanding the toolkit for single-cell functional genomics.

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