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Inducible, tunable and multiplex human gene regulation using CRISPR-Cpf1-based transcription factors

Yu Gyoung Tak, Benjamin P. Kleinstiver, James K. Nuñez, Jonathan Y. Hsu, Jingyi Gong, Jonathan S. Weissman, J. Keith Joung
doi: https://doi.org/10.1101/150656
Yu Gyoung Tak
1Molecular Pathology Unit, Center for Cancer Research, and Center for Computational and Integrative Biology, Massachusetts General Hospital, Charlestown, MA 02129 USA
2Department of Pathology, Harvard Medical School, Boston, MA 02115 USA
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Benjamin P. Kleinstiver
1Molecular Pathology Unit, Center for Cancer Research, and Center for Computational and Integrative Biology, Massachusetts General Hospital, Charlestown, MA 02129 USA
2Department of Pathology, Harvard Medical School, Boston, MA 02115 USA
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James K. Nuñez
3Department of Cellular & Molecular Pharmacology University of California, San Francisco, San Francisco, CA 94158 USA and Howard Hughes Medical Institute
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Jonathan Y. Hsu
1Molecular Pathology Unit, Center for Cancer Research, and Center for Computational and Integrative Biology, Massachusetts General Hospital, Charlestown, MA 02129 USA
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Jingyi Gong
1Molecular Pathology Unit, Center for Cancer Research, and Center for Computational and Integrative Biology, Massachusetts General Hospital, Charlestown, MA 02129 USA
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Jonathan S. Weissman
3Department of Cellular & Molecular Pharmacology University of California, San Francisco, San Francisco, CA 94158 USA and Howard Hughes Medical Institute
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J. Keith Joung
1Molecular Pathology Unit, Center for Cancer Research, and Center for Computational and Integrative Biology, Massachusetts General Hospital, Charlestown, MA 02129 USA
2Department of Pathology, Harvard Medical School, Boston, MA 02115 USA
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ABSTRACT

Targeted and inducible regulation of mammalian gene expression is a broadly important research capability that may also enable development of novel therapeutics for treating human diseases. Here we demonstrate that a catalytically inactive RNA-guided CRISPR-Cpf1 nuclease fused to transcriptional activation domains can up-regulate endogenous human gene expression. We engineered drug-inducible Cpf1-based activators and show how this system can be used to tune the regulation of endogenous gene transcription in human cells. Leveraging the simpler multiplex capability of the Cpf1 platform, we show that we can induce both synergistic and combinatorial gene expression in human cells. Our work should enable the creation of other Cpf1-based gene regulatory fusion proteins and the development of multiplex gene perturbation library screens for understanding complex cellular phenotypes.

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Posted June 15, 2017.
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Inducible, tunable and multiplex human gene regulation using CRISPR-Cpf1-based transcription factors
Yu Gyoung Tak, Benjamin P. Kleinstiver, James K. Nuñez, Jonathan Y. Hsu, Jingyi Gong, Jonathan S. Weissman, J. Keith Joung
bioRxiv 150656; doi: https://doi.org/10.1101/150656
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Inducible, tunable and multiplex human gene regulation using CRISPR-Cpf1-based transcription factors
Yu Gyoung Tak, Benjamin P. Kleinstiver, James K. Nuñez, Jonathan Y. Hsu, Jingyi Gong, Jonathan S. Weissman, J. Keith Joung
bioRxiv 150656; doi: https://doi.org/10.1101/150656

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