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

Animals CRISPR-Cas Systems / genetics Cell Line Gene Expression / genetics Gene Expression Regulation / genetics Genetic Engineering / methods HEK293 Cells Humans Hypercholesterolemia / genetics Liposomes / pharmacology Mice Mice, Inbred C57BL Mice, Transgenic Nanoparticles Prealbumin / genetics RNA, Guide, Kinetoplastida / genetics Transcriptional Activation / genetics

Journal

Nature communications

ISSN: 2041-1723

Titre abrégé: Nat Commun

Pays: England

ID NLM: 101528555

Informations de publication

Date de publication:
13 05 2021

Historique:

received: 17 01 2020

accepted: 06 04 2021

entrez: 14 5 2021

pubmed: 15 5 2021

medline: 1 6 2021

Statut: epublish

Résumé

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.

Identifiants

DOI: 10.1038/s41467-021-22932-4 PMID: 33986266 PMC: PMC8119962

pubmed: 33986266

doi: 10.1038/s41467-021-22932-4

pii: 10.1038/s41467-021-22932-4

pmc: PMC8119962

doi:

Substances chimiques

Lipid Nanoparticles 0

Liposomes 0

Prealbumin 0

RNA, Guide 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Pagination

2770

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