Tissue-specific Activation of Gene Expression by the Synergistic Activation Mediator (SAM) CRISPRa System in Mice

Overview

Journal Nat Commun

Specialty Biology

Date 2021 May 14

PMID 33986266

Citations 7

Authors

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 Altarejos

Keith Crosby

Jeffery Haines

Sarah Cancelarich

Meghan Drummond

Sven Moller-Tank

Ryan Malpass

Jacqueline Buckley

Maria Del Pilar Molina-Portela

Gustavo Droguett

David Frendewey

Eric Chiao

Brian Zambrowicz

Guochun Gong

Affiliations

Soon will be listed here.

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.

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