Combinatorial single-cell CRISPR screens by direct guide RNA capture and targeted sequencing

Single-cell CRISPR screens enable the exploration of mammalian gene function and genetic regulatory networks. However, use of this technology has been limited by reliance on indirect indexing of single-guide RNAs (sgRNAs). Here we present direct-capture Perturb-seq, a versatile screening approach in...

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Published inNature biotechnology Vol. 38; no. 8; pp. 954 - 961
Main Authors Replogle, Joseph M., Norman, Thomas M., Xu, Albert, Hussmann, Jeffrey A., Chen, Jin, Cogan, J. Zachery, Meer, Elliott J., Terry, Jessica M., Riordan, Daniel P., Srinivas, Niranjan, Fiddes, Ian T., Arthur, Joseph G., Alvarado, Luigi J., Pfeiffer, Katherine A., Mikkelsen, Tarjei S., Weissman, Jonathan S., Adamson, Britt
Format Journal Article
LanguageEnglish
Published New York Nature Publishing Group US 01.08.2020
Nature Publishing Group
Subjects
631/208/191/1472
631/208/191/2018
631/337/2019
631/553/2490/1472
Agriculture
Bioinformatics
Biomedical and Life Sciences
Biomedical Engineering/Biotechnology
Biomedicine
Biotechnology
Cholesterol
Combinatorial analysis
CRISPR
CRISPR-Cas Systems
Deoxyribonucleic acid
DNA
DNA repair
Epistasis
Expression vectors
Gene Expression Regulation
Gene sequencing
Gene Targeting
HEK293 Cells
High-Throughput Nucleotide Sequencing
Humans
Hybridization
Letter
Libraries
Life Sciences
Methods
Nucleic Acid Amplification Techniques - methods
Perturbation
Ribonucleic acid
RNA
RNA sequencing
RNA, Guide, CRISPR-Cas Systems - genetics
Single-Cell Analysis
Transcriptome
United States
Online AccessGet full text
ISSN1087-0156
1546-1696
1546-1696
DOI10.1038/s41587-020-0470-y

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Abstract Single-cell CRISPR screens enable the exploration of mammalian gene function and genetic regulatory networks. However, use of this technology has been limited by reliance on indirect indexing of single-guide RNAs (sgRNAs). Here we present direct-capture Perturb-seq, a versatile screening approach in which expressed sgRNAs are sequenced alongside single-cell transcriptomes. Direct-capture Perturb-seq enables detection of multiple distinct sgRNA sequences from individual cells and thus allows pooled single-cell CRISPR screens to be easily paired with combinatorial perturbation libraries that contain dual-guide expression vectors. We demonstrate the utility of this approach for high-throughput investigations of genetic interactions and, leveraging this ability, dissect epistatic interactions between cholesterol biogenesis and DNA repair. Using direct capture Perturb-seq, we also show that targeting individual genes with multiple sgRNAs per cell improves efficacy of CRISPR interference and activation, facilitating the use of compact, highly active CRISPR libraries for single-cell screens. Last, we show that hybridization-based target enrichment permits sensitive, specific sequencing of informative transcripts from single-cell RNA-seq experiments. Single-cell CRISPR screens are readily multiplexed and scaled with an improved version of Perturb-seq.
AbstractList Single-cell CRISPR screens enable the exploration of mammalian gene function and genetic regulatory networks. However, use of this technology has been limited by reliance on indirect indexing of single-guide RNAs (sgRNAs). Here we present direct-capture Perturb-seq, a versatile screening approach in which expressed sgRNAs are sequenced alongside single-cell transcriptomes. Direct-capture Perturb-seq enables detection of multiple distinct sgRNA sequences from individual cells and thus allows pooled single-cell CRISPR screens to be easily paired with combinatorial perturbation libraries that contain dual-guide expression vectors. We demonstrate the utility of this approach for high-throughput investigations of genetic interactions and, leveraging this ability, dissect epistatic interactions between cholesterol biogenesis and DNA repair. Using direct capture Perturb-seq, we also show that targeting individual genes with multiple sgRNAs per cell improves efficacy of CRISPR interference and activation, facilitating the use of compact, highly active CRISPR libraries for single-cell screens. Last, we show that hybridization-based target enrichment permits sensitive, specific sequencing of informative transcripts from single-cell RNA-seq experiments.Single-cell CRISPR screens are readily multiplexed and scaled with an improved version of Perturb-seq.
Single-cell CRISPR screens enable the exploration of mammalian gene function and genetic regulatory networks. However, use of this technology has been limited by reliance on indirect indexing of single-guide RNAs (sgRNAs). Here we present direct-capture Perturb-seq, a versatile screening approach in which expressed sgRNAs are sequenced alongside single-cell transcriptomes. Direct-capture Perturb-seq enables detection of multiple distinct sgRNA sequences from individual cells and thus allows pooled single-cell CRISPR screens to be easily paired with combinatorial perturbation libraries that contain dual-guide expression vectors. We demonstrate the utility of this approach for high-throughput investigations of genetic interactions and, leveraging this ability, dissect epistatic interactions between cholesterol biogenesis and DNA repair. Using direct capture Perturb-seq, we also show that targeting individual genes with multiple sgRNAs per cell improves efficacy of CRISPR interference and activation, facilitating the use of compact, highly active CRISPR libraries for single-cell screens. Last, we show that hybridization-based target enrichment permits sensitive, specific sequencing of informative transcripts from single-cell RNA-seq experiments. Single-cell CRISPR screens are readily multiplexed and scaled with an improved version of Perturb-seq.
Single-cell CRISPR screens enable the exploration of mammalian gene function and genetic regulatory networks. However, use of this technology has been limited by reliance on indirect indexing of single-guide RNAs (sgRNAs). Here we present direct-capture Perturb-seq, a versatile screening approach in which expressed sgRNAs are sequenced alongside single-cell transcriptomes. Direct-capture Perturb-seq enables detection of multiple distinct sgRNA sequences from individual cells and thus allows pooled single-cell CRISPR screens to be easily paired with combinatorial perturbation libraries that contain dual-guide expression vectors. We demonstrate the utility of this approach for high-throughput investigations of genetic interactions and, leveraging this ability, dissect epistatic interactions between cholesterol biogenesis and DNA repair. Using direct capture Perturb-seq, we also show that targeting individual genes with multiple sgRNAs per cell improves efficacy of CRISPR interference and activation, facilitating the use of compact, highly active CRISPR libraries for single-cell screens. Last, we show that hybridization-based target enrichment permits sensitive, specific sequencing of informative transcripts from single-cell RNA-seq experiments.
Single-cell CRISPR screens enable the exploration of mammalian gene function and genetic regulatory networks. However, use of this technology has been limited by reliance on indirect indexing of single-guide RNAs (sgRNAs). Here we present direct-capture Perturb-seq, a versatile screening approach in which expressed sgRNAs are sequenced alongside single-cell transcriptomes. Direct-capture Perturb-seq enables detection of multiple distinct sgRNA sequences from individual cells and thus allows pooled single-cell CRISPR screens to be easily paired with combinatorial perturbation libraries that contain dual-guide expression vectors. We demonstrate the utility of this approach for high-throughput investigations of genetic interactions and, leveraging this ability, dissect epistatic interactions between cholesterol biogenesis and DNA repair. Using direct capture Perturb-seq, we also show that targeting individual genes with multiple sgRNAs per cell improves the efficacy of CRISPR interference and activation, facilitating the use of compact, highly active CRISPR libraries for single-cell screens. Last, we show that hybridization-based target enrichment permits sensitive, specific sequencing of informative transcripts from single-cell RNA-seq experiments.
Single-cell CRISPR screens enable the exploration of mammalian gene function and genetic regulatory networks. However, use of this technology has been limited by reliance on indirect indexing of single-guide RNAs (sgRNAs). Here we present direct-capture Perturb-seq, a versatile screening approach in which expressed sgRNAs are sequenced alongside single-cell transcriptomes. Direct-capture Perturb-seq enables detection of multiple distinct sgRNA sequences from individual cells and thus allows pooled single-cell CRISPR screens to be easily paired with combinatorial perturbation libraries that contain dual-guide expression vectors. We demonstrate the utility of this approach for high-throughput investigations of genetic interactions and, leveraging this ability, dissect epistatic interactions between cholesterol biogenesis and DNA repair. Using direct capture Perturb-seq, we also show that targeting individual genes with multiple sgRNAs per cell improves efficacy of CRISPR interference and activation, facilitating the use of compact, highly active CRISPR libraries for single-cell screens. Last, we show that hybridization-based target enrichment permits sensitive, specific sequencing of informative transcripts from single-cell RNA-seq experiments.Single-cell CRISPR screens enable the exploration of mammalian gene function and genetic regulatory networks. However, use of this technology has been limited by reliance on indirect indexing of single-guide RNAs (sgRNAs). Here we present direct-capture Perturb-seq, a versatile screening approach in which expressed sgRNAs are sequenced alongside single-cell transcriptomes. Direct-capture Perturb-seq enables detection of multiple distinct sgRNA sequences from individual cells and thus allows pooled single-cell CRISPR screens to be easily paired with combinatorial perturbation libraries that contain dual-guide expression vectors. We demonstrate the utility of this approach for high-throughput investigations of genetic interactions and, leveraging this ability, dissect epistatic interactions between cholesterol biogenesis and DNA repair. Using direct capture Perturb-seq, we also show that targeting individual genes with multiple sgRNAs per cell improves efficacy of CRISPR interference and activation, facilitating the use of compact, highly active CRISPR libraries for single-cell screens. Last, we show that hybridization-based target enrichment permits sensitive, specific sequencing of informative transcripts from single-cell RNA-seq experiments.
Audience Academic
Author Replogle, Joseph M.
Fiddes, Ian T.
Arthur, Joseph G.
Chen, Jin
Norman, Thomas M.
Xu, Albert
Pfeiffer, Katherine A.
Meer, Elliott J.
Srinivas, Niranjan
Alvarado, Luigi J.
Cogan, J. Zachery
Hussmann, Jeffrey A.
Weissman, Jonathan S.
Terry, Jessica M.
Riordan, Daniel P.
Mikkelsen, Tarjei S.
Adamson, Britt
AuthorAffiliation 8 Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA
3 Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA
4 Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA
7 10x Genomics Inc., Pleasanton, California, 94566, USA
9 Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
1 Medical Scientist Training Program, University of California, San Francisco, San Francisco, CA 94158, USA
2 Tetrad Graduate Program, University of California, San Francisco, San Francisco, CA 94158, USA
6 Present address: Program for Computational and Systems Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
5 California Institute for Quantitative Biomedical Research, University of California, San Francisco, San Francisco, CA 94158, USA
AuthorAffiliation_xml – name: 3 Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA
– name: 8 Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA
– name: 6 Present address: Program for Computational and Systems Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
– name: 7 10x Genomics Inc., Pleasanton, California, 94566, USA
– name: 5 California Institute for Quantitative Biomedical Research, University of California, San Francisco, San Francisco, CA 94158, USA
– name: 9 Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
– name: 1 Medical Scientist Training Program, University of California, San Francisco, San Francisco, CA 94158, USA
– name: 2 Tetrad Graduate Program, University of California, San Francisco, San Francisco, CA 94158, USA
– name: 4 Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA
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  givenname: Joseph M.
  orcidid: 0000-0003-1832-919X
  surname: Replogle
  fullname: Replogle, Joseph M.
  organization: Medical Scientist Training Program, University of California, San Francisco, Tetrad Graduate Program, University of California, San Francisco, Department of Cellular and Molecular Pharmacology, University of California, San Francisco, Howard Hughes Medical Institute, University of California, San Francisco, California Institute for Quantitative Biomedical Research, University of California, San Francisco
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  givenname: Jin
  surname: Chen
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  givenname: J. Zachery
  surname: Cogan
  fullname: Cogan, J. Zachery
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  organization: 10x Genomics Inc
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  email: badamson@princeton.edu
  organization: Lewis-Sigler Institute for Integrative Genomics, Princeton University, Department of Molecular Biology, Princeton University
BackLink https://www.ncbi.nlm.nih.gov/pubmed/32231336$$D View this record in MEDLINE/PubMed
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J.M.R., T.M.N., J.S.W., and B.A. conceived, designed, and interpreted the experiments and wrote the manuscript. J.M.R. and B.A. designed, built, and validated modified guide constant regions, expression vectors, dual-guide constructs, and libraries. J.M.R. and B.A. performed Perturb-seq experiments with contributions from A.X., J.C., and J.Z.C. J.M.R. analyzed Perturb-seq data with support from T.M.N., J.A.H., and B.A. T.M.N. and J.M.R. designed the target enrichment strategy in discussion with I.T.F., J.G.A., L.J.A., and K.A.P. J.M.R. performed the target enrichment experiments and analysis. D.P.R. designed the library of candidate capture sequences. 10x Genomics with E.J.M, J.M.T, D.P.R., N.S., and T.S.M built the Chromium Single Cell 3’ Reagent Kits v3 with Feature Barcoding technology.
Author Contributions
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Snippet Single-cell CRISPR screens enable the exploration of mammalian gene function and genetic regulatory networks. However, use of this technology has been limited...
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StartPage 954
SubjectTerms 631/208/191/1472
631/208/191/2018
631/337/2019
631/553/2490/1472
Agriculture
Bioinformatics
Biomedical and Life Sciences
Biomedical Engineering/Biotechnology
Biomedicine
Biotechnology
Cholesterol
Combinatorial analysis
CRISPR
CRISPR-Cas Systems
Deoxyribonucleic acid
DNA
DNA repair
Epistasis
Expression vectors
Gene Expression Regulation
Gene sequencing
Gene Targeting
HEK293 Cells
High-Throughput Nucleotide Sequencing
Humans
Hybridization
Letter
Libraries
Life Sciences
Methods
Nucleic Acid Amplification Techniques - methods
Perturbation
Ribonucleic acid
RNA
RNA sequencing
RNA, Guide, CRISPR-Cas Systems - genetics
Single-Cell Analysis
Transcriptome
Title Combinatorial single-cell CRISPR screens by direct guide RNA capture and targeted sequencing
URI https://link.springer.com/article/10.1038/s41587-020-0470-y
https://www.ncbi.nlm.nih.gov/pubmed/32231336
https://www.proquest.com/docview/2430516525
https://www.proquest.com/docview/2476739807
https://www.proquest.com/docview/2385279432
https://pubmed.ncbi.nlm.nih.gov/PMC7416462
Volume 38
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