Orthologous CRISPR–Cas9 enzymes for combinatorial genetic screens

Najm, Fadi J; Strand, Christine; Donovan, Katherine F; Hegde, Mudra; Sanson, Kendall R; Vaimberg, Emma W; Sullender, Meagan E; Hartenian, Ella; Kalani, Zohra; Fusi, Nicolo; Listgarten, Jennifer; Younger, Scott T; Bernstein, Bradley E; Root, David E; Doench, John G

doi:10.1038/nbt.4048

Cited by 283CRISPR and Genetic EngineeringRNA Interference and Gene DeliveryVirus-based gene therapy research

Orthologous CRISPR–Cas9 enzymes for combinatorial genetic screens

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Najm, Fadi J, Strand, Christine, Donovan, Katherine F, Hegde, Mudra, Sanson, Kendall R, Vaimberg, Emma W, Sullender, Meagan E, Hartenian, Ella +7 more·2018·Nature Biotechnology

DOI 10.1038/nbt.4048PMC PMC5800952

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Abstract

Combinatorial genetic screening using CRISPR-Cas9 is a useful approach to uncover redundant genes and to explore complex gene networks. However, current methods suffer from interference between the single-guide RNAs (sgRNAs) and from limited gene targeting activity. To increase the efficiency of combinatorial screening, we employ orthogonal Cas9 enzymes from Staphylococcus aureus and Streptococcus pyogenes. We used machine learning to establish S. aureus Cas9 sgRNA design rules and paired S. aureus Cas9 with S. pyogenes Cas9 to achieve dual targeting in a high fraction of cells. We also developed a lentiviral vector and cloning strategy to generate high-complexity pooled dual-knockout libraries to identify synthetic lethal and buffering gene pairs across multiple cell types, including MAPK pathway genes and apoptotic genes. Our orthologous approach also enabled a screen combining gene knockouts with transcriptional activation, which revealed genetic interactions with TP53. The "Big Papi" (paired aureus and pyogenes for interactions) approach described here will be widely applicable for the study of combinatorial phenotypes.

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Direct capture of sgRNA molecules lets ECCITE-seq avoid the barcode-swapping problems reported for Perturb-seq.
“ECCITE-seq is readily applicable to any sgRNA library with the Cas9 S. pyogenes scaffold sequence and, by allowing direct capture of sgRNA molecules, overcomes documented problems of barcode swapping events observed with Perturb-seq that have the potential to confound single cell perturbation screens17–20.”
From Multiplexed detection of proteins, transcriptomes, clonotypes and CRISPR perturbations in single cells (2019) · cites this paper as [19]

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Li, R., Klingbeil, O., Monducci, D., Young, M. J., Rodriguez, D. J., Bayyat, Z., Dempster, J. M., Kesar, D., Yang, X., Zamanighomi, M., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-30196-9 · Cited by 36 · see citing works
Abstract 2950: CRISPR/saCas9 and CRISPR/spCas9 systems for combinatorial genetic screens (CRISPR-KO, CRISPRa, CRISPRi)
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PrePAIRing Cas9s for screening success
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Generation of dual-gRNA library for combinatorial CRISPR screening of synthetic lethal gene pairs
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Big Papi uncovers genetic interactions
(2018) · Nature Methods · doi:10.1038/nmeth.4589

Authors: Najm, F. J., Strand, C., Donovan, K. F., Hegde, M., Sanson, K. R., Vaimberg, E. W., Sullender, M. E., Hartenian, E., Kalani, Z., Fusi, N., Listgarten, J., Younger, S. T., Bernstein, B. E., Root, D. E., & Doench, J. G.
Affiliations: Broad Institute (US)
Microsoft Research New England (United States) (US)
Corresponding author: Doench, John G
ORCID: Najm, Fadi J
Strand, Christine
Donovan, Katherine F
Hegde, Mudra
Vaimberg, Emma W
Sullender, Meagan E
Hartenian, Ella
Kalani, Zohra
Fusi, Nicolo
Listgarten, Jennifer
Younger, Scott T
Bernstein, Bradley E
Root, David E
Doench, John G
Venue: Nature Biotechnology
Publisher: Springer Science and Business Media LLC
Published: 2017-12-18
Volume: 36
Issue: 2
Pages: 179-189
ISSN: 0733-222X (ISSN-L)
1087-0156
1546-1696
DOI: 10.1038/nbt.4048
PMC: PMC5800952
OpenAlex: W2781417302
Cited by: 279
References: 54
Citations by year: 2026: 16 · 2025: 22 · 2024: 26 · 2023: 32 · 2022: 26 · 2021: 45 · 2020: 39 · 2019: 36 · 2018: 37
FWCI: 12.51
Type: journal article
Language: en
Open access: green
europepmc.org
Licence: www.springer.com/tdm (tdm)
Locations: Nature Biotechnology (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
Funders: National Cancer Institute (DP1CA216873)
National Institute of General Medical Sciences (T32GM007226)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
Keywords: CRISPR/Cas9, SaCas9, SpCas9, single guide RNA design, dual targeting, synthetic lethality, MAPK signaling, apoptosis, TP53, transcriptional activation, lentiviral vectors
MeSH terms: Machine Learning, RNA, Guide, CRISPR-Cas Systems, Epistasis, Genetic, Genetic Testing, Humans, Staphylococcus aureus, Streptococcus pyogenes, Signal Transduction, Tumor Suppressor Protein p53, Apoptosis, Gene Targeting, Mitogen-Activated Protein Kinase Kinases, Gene Knockout Techniques, CRISPR-Cas Systems

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