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Tissue-specific activation of gene expression by the Synergistic Activation Mediator (SAM) CRISPRa system in mice

Author

Listed:
  • Charleen Hunt

    (Regeneron Pharmaceuticals, Inc.)

  • Suzanne A. Hartford

    (Regeneron Pharmaceuticals, Inc.)

  • Derek White

    (Regeneron Pharmaceuticals, Inc.)

  • Evangelos Pefanis

    (Regeneron Pharmaceuticals, Inc.)

  • Timothy Hanna

    (Regeneron Pharmaceuticals, Inc.)

  • Clarissa Herman

    (Regeneron Pharmaceuticals, Inc.)

  • Jarrell Wiley

    (Regeneron Pharmaceuticals, Inc.)

  • Heather Brown

    (Regeneron Pharmaceuticals, Inc.)

  • Qi Su

    (Regeneron Pharmaceuticals, Inc.)

  • Yurong Xin

    (Regeneron Pharmaceuticals, Inc.)

  • Dennis Voronin

    (Regeneron Pharmaceuticals, Inc.)

  • Hien Nguyen

    (Regeneron Pharmaceuticals, Inc.)

  • Judith Altarejos

    (Regeneron Pharmaceuticals, Inc.)

  • Keith Crosby

    (Regeneron Pharmaceuticals, Inc.)

  • Jeffery Haines

    (Regeneron Pharmaceuticals, Inc.)

  • Sarah Cancelarich

    (Regeneron Pharmaceuticals, Inc.)

  • Meghan Drummond

    (Regeneron Pharmaceuticals, Inc.)

  • Sven Moller-Tank

    (Regeneron Pharmaceuticals, Inc.)

  • Ryan Malpass

    (Regeneron Pharmaceuticals, Inc.)

  • Jacqueline Buckley

    (Regeneron Pharmaceuticals, Inc.)

  • Maria Pilar Molina-Portela

    (Regeneron Pharmaceuticals, Inc.)

  • Gustavo Droguett

    (Regeneron Pharmaceuticals, Inc.)

  • David Frendewey

    (Regeneron Pharmaceuticals, Inc.)

  • Eric Chiao

    (Regeneron Pharmaceuticals, Inc.)

  • Brian Zambrowicz

    (Regeneron Pharmaceuticals, Inc.)

  • Guochun Gong

    (Regeneron Pharmaceuticals, Inc.)

Abstract

CRISPR-based transcriptional activation is a powerful tool for functional gene interrogation; however, delivery difficulties have limited its applications in vivo. Here, we created a mouse model expressing all components of the CRISPR-Cas9 guide RNA-directed Synergistic Activation Mediator (SAM) from a single transcript that is capable of activating target genes in a tissue-specific manner. We optimized Lipid Nanoparticles and Adeno-Associated Virus guide RNA delivery approaches to achieve expression modulation of one or more genes in vivo. We utilized the SAM mouse model to generate a hypercholesteremia disease state that we could bidirectionally modulate with various guide RNAs. Additionally, we applied SAM to optimize gene expression in a humanized Transthyretin mouse model to recapitulate human expression levels. These results demonstrate that the SAM gene activation platform can facilitate in vivo research and drug discovery.

Suggested Citation

  • Charleen Hunt & Suzanne A. Hartford & Derek White & Evangelos Pefanis & Timothy Hanna & Clarissa Herman & Jarrell Wiley & Heather Brown & Qi Su & Yurong Xin & Dennis Voronin & Hien Nguyen & Judith Alt, 2021. "Tissue-specific activation of gene expression by the Synergistic Activation Mediator (SAM) CRISPRa system in mice," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22932-4
    DOI: 10.1038/s41467-021-22932-4
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    Cited by:

    1. Yexuan Deng & Sarah T. Diepstraten & Margaret A. Potts & Göknur Giner & Stephanie Trezise & Ashley P. Ng & Gerry Healey & Serena R. Kane & Amali Cooray & Kira Behrens & Amy Heidersbach & Andrew J. Kue, 2022. "Generation of a CRISPR activation mouse that enables modelling of aggressive lymphoma and interrogation of venetoclax resistance," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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