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CRISPR-based functional genomics in human dendritic cells

View ORCID ProfileMarco Jost, Amy N. Jacobson, Jeffrey A. Hussmann, Giana Cirolia, View ORCID ProfileMichael A. Fischbach, View ORCID ProfileJonathan S. Weissman
doi: https://doi.org/10.1101/2020.12.22.423985
Marco Jost
1Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, California, USA
2Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, California, USA
3California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, California, USA
4Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, California, USA
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  • ORCID record for Marco Jost
Amy N. Jacobson
5Department of Bioengineering, Stanford University, Stanford, California, USA
6ChEM-H, Stanford University, Stanford, California, USA
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Jeffrey A. Hussmann
1Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, California, USA
2Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, California, USA
3California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, California, USA
4Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, California, USA
8Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA
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Giana Cirolia
7Chan Zuckerberg Biohub, San Francisco, California, USA
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Michael A. Fischbach
5Department of Bioengineering, Stanford University, Stanford, California, USA
6ChEM-H, Stanford University, Stanford, California, USA
7Chan Zuckerberg Biohub, San Francisco, California, USA
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  • For correspondence: weissman@wi.mit.edu fischbach@fischbachgroup.org
Jonathan S. Weissman
1Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, California, USA
2Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, California, USA
3California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, California, USA
8Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA
9Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
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  • ORCID record for Jonathan S. Weissman
  • For correspondence: weissman@wi.mit.edu fischbach@fischbachgroup.org
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Abstract

Dendritic cells (DCs) regulate processes ranging from antitumor and antiviral immunity to host-microbe communication at mucosal surfaces. It remains difficult, however, to genetically manipulate human DCs, limiting our ability to probe how DCs elicit specific immune responses. Here, we develop a CRISPR/Cas9 genome editing method for human monocyte-derived DCs (moDCs) that mediates knockouts with a median efficiency of >93% across >300 genes. Using this method, we perform genetic screens in moDCs, identifying mechanisms by which DCs tune responses to lipopolysaccharides from the human microbiome. In addition, we reveal donor-specific responses to lipopolysaccharides, underscoring the importance of assessing immune phenotypes in donor-derived cells, and identify genes that control this specificity, highlighting the potential of our method to pinpoint determinants of inter-individual variation in immune responses. Our work sets the stage for a systematic dissection of the immune signaling at the host-microbiome interface and for targeted engineering of DCs for neoantigen vaccination.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted December 22, 2020.
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CRISPR-based functional genomics in human dendritic cells
Marco Jost, Amy N. Jacobson, Jeffrey A. Hussmann, Giana Cirolia, Michael A. Fischbach, Jonathan S. Weissman
bioRxiv 2020.12.22.423985; doi: https://doi.org/10.1101/2020.12.22.423985
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CRISPR-based functional genomics in human dendritic cells
Marco Jost, Amy N. Jacobson, Jeffrey A. Hussmann, Giana Cirolia, Michael A. Fischbach, Jonathan S. Weissman
bioRxiv 2020.12.22.423985; doi: https://doi.org/10.1101/2020.12.22.423985

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