A Genome-wide CRISPR Screen in Primary Immune Cells to Dissect Regulatory Networks
Open accessAbstract
Finding the components of cellular circuits and determining their functions systematically remains a major challenge in mammalian cells. Here, we introduced genome-wide pooled CRISPR-Cas9 libraries into dendritic cells (DCs) to identify genes that control the induction of tumor necrosis factor (Tnf) by bacterial lipopolysaccharide (LPS), a key process in the host response to pathogens, mediated by the Tlr4 pathway. We found many of the known regulators of Tlr4 signaling, as well as dozens of previously unknown candidates that we validated. By measuring protein markers and mRNA profiles in DCs that are deficient in known or candidate genes, we classified the genes into three functional modules with distinct effects on the canonical responses to LPS and highlighted functions for the PAF complex and oligosaccharyltransferase (OST) complex. Our findings uncover new facets of innate immune circuits in primary cells and provide a genetic approach for dissection of mammalian cell circuits.
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Historically pooled screens rely on enriching populations for a phenotype followed by NGS to measure perturbation abundance.
“Historically, pooled screens have relied on enriching populations of cells for a phenotype of interest, followed by next-generation sequencing (NGS) to measure changes in perturbation abundance.”
From Optical Pooled Screens in Human Cells (2019) · cites this paper as Parnas et al., 2015
Pooling gene perturbations increases scalability but cannot be combined with imaging of complex or dynamic cellular phenotypes.
“Pooling gene perturbations greatly improves scalability, but is not compatible with imaging of complex and dynamic cellular phenotypes.”
From Optical Pooled Screens in Human Cells (2019) · cites this paper as Parnas et al., 2015
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Self-citationSingle-cell epigenomic variability reveals functional cancer heterogeneity
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Scalable genetic screening for regulatory circuits using compressed Perturb-seq
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Self-citationSynthetic Lethal Vulnerabilities in <i>KRAS</i>-Mutant Cancers
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Guide Swap enables genome-scale pooled CRISPR-Cas9 screening in human primary cells
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Multiplexed, image-based pooled screens in primary cells and tissues with PerturbView
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Self-citationPooled genetic perturbation screens with image-based phenotypes
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- Authors
- Parnas, O., Jovanovic, M., Eisenhaure, T. M., Herbst, R. H., Dixit, A., Ye, C. J., Przybylski, D., Platt, R. J., Tirosh, I., Sanjana, N. E., Shalem, O., Satija, R., Raychowdhury, R., Mertins, P., Carr, S. A., Zhang, F., Hacohen, N., & Regev, A.
- Affiliations
- Broad Institute (US)
- University of California, San Francisco (US)
- New York Genome Center (US)
- Corresponding author
- Hacohen, Nir
- Regev, Aviv
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2015-07
- Volume
- 162
- Issue
- 3
- Pages
- 675-686
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4522370
- OpenAlex
- W2106296224
- Cited by
- 440
- References
- 71
- Citations by year
- 2026: 14 · 2025: 25 · 2024: 35 · 2023: 31 · 2022: 37 · 2021: 42 · 2020: 44 · 2019: 46 · 2018: 46 · 2017: 61 · 2016: 45 · 2015: 12 · 2013: 1
- FWCI
- 26.96
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- PMC
- Funders
- National Science Foundation (1122374, NCC 9-58)
- Howard Hughes Medical Institute
- National Aeronautics and Space Administration (1122374, NASA NCC 9‐58, NCC958)
- Damon Runyon Cancer Research Foundation
- National Space Biomedical Research Institute (NASA NCC 9‐58, NCC 9‐58)
- Broad Institute
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- National Institutes of Health (NCC9-58, K99-HG008171)
- FAS Center for Systems Biology, Harvard University
- Klarman Cell Observatory, Broad Institute
- Simons Center for the Social Brain, Massachusetts Institute of Technology
- National Institute of Mental Health (DP1MH100706, 5DP1-MH100706, R01MH110049)
- National Human Genome Research Institute (K99HG008171, P50HG006193, HG006193)
- National Institute of Diabetes and Digestive and Kidney Diseases (5R01-DK097768, R01DK097768, P30DK043351)
- National Center for Chronic Disease Prevention and Health Promotion (5DP1-MH100706)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- CRISPR/Cas9 genome-wide screen, dendritic cells, TLR4 signaling, lipopolysaccharide, innate immunity, PAF complex, oligosaccharyltransferase, host-pathogen response, gene regulatory networks, primary immune cells
- MeSH terms
- Animals, Bone Marrow Cells, Cell Differentiation, Cell Survival, Dendritic Cells, Genetic Techniques, Hexosyltransferases, Immunity, Innate, Membrane Proteins, Mice, Transgenic, Tumor Necrosis Factor-alpha, Toll-Like Receptor 4, Mice, Gene Regulatory Networks, Gene Knockout Techniques, CRISPR-Cas Systems
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