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Ligand-binding domains of nuclear receptors facilitate tight control of split CRISPR activity

Author

Listed:
  • Duy P. Nguyen

    (University of California, San Francisco)

  • Yuichiro Miyaoka

    (Gladstone Institute of Cardiovascular Disease
    Present address: Regenerative Medicine Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan)

  • Luke A. Gilbert

    (University of California, San Francisco)

  • Steven J. Mayerl

    (Gladstone Institute of Cardiovascular Disease)

  • Brian H. Lee

    (University of California, San Francisco
    Present address: Visolis Inc., 1904 Haste Street, Berkeley, California 94704, USA)

  • Jonathan S. Weissman

    (University of California, San Francisco
    Howard Hughes Medical Institute, University of California)

  • Bruce R. Conklin

    (Gladstone Institute of Cardiovascular Disease
    University of California, San Francisco
    University of California, San Francisco)

  • James A. Wells

    (University of California, San Francisco
    University of California, San Francisco)

Abstract

Cas9-based RNA-guided nuclease (RGN) has emerged to be a versatile method for genome editing due to the ease of construction of RGN reagents to target specific genomic sequences. The ability to control the activity of Cas9 with a high temporal resolution will facilitate tight regulation of genome editing processes for studying the dynamics of transcriptional regulation or epigenetic modifications in complex biological systems. Here we show that fusing ligand-binding domains of nuclear receptors to split Cas9 protein fragments can provide chemical control over split Cas9 activity. The method has allowed us to control Cas9 activity in a tunable manner with no significant background, which has been challenging for other inducible Cas9 constructs. We anticipate that our design will provide opportunities through the use of different ligand-binding domains to enable multiplexed genome regulation of endogenous genes in distinct loci through simultaneous chemical regulation of orthogonal Cas9 variants.

Suggested Citation

  • Duy P. Nguyen & Yuichiro Miyaoka & Luke A. Gilbert & Steven J. Mayerl & Brian H. Lee & Jonathan S. Weissman & Bruce R. Conklin & James A. Wells, 2016. "Ligand-binding domains of nuclear receptors facilitate tight control of split CRISPR activity," Nature Communications, Nature, vol. 7(1), pages 1-10, November.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12009
    DOI: 10.1038/ncomms12009
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