Tissue-specific activation of gene expression by the Synergistic Activation Mediator (SAM) CRISPRa system in mice
| Autor: | Jeffery Haines, Derek White, Maria del Pilar Molina-Portela, Brian Zambrowicz, Gustavo Droguett, Jarrell Wiley, Clarissa Herman, Timothy Hanna, Judith Altarejos, Hien Nguyen, Sven Moller-Tank, Qi Su, Heather Brown, Sarah Cancelarich, Dennis Voronin, Jacqueline Buckley, Evangelos Pefanis, Eric Chiao, Suzanne Hartford, David Frendewey, Meghan Drummond, Ryan Malpass, Keith Crosby, Charleen Hunt, Yurong Xin, Guochun Gong |
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| Rok vydání: | 2021 |
| Předmět: |
Transcriptional Activation
0301 basic medicine CRISPR-Cas systems Science Hypercholesterolemia Gene Expression General Physics and Astronomy Mice Transgenic Article General Biochemistry Genetics and Molecular Biology Cell Line Mice 03 medical and health sciences 0302 clinical medicine Mediator In vivo Gene expression Animals Humans Prealbumin CRISPR Guide RNA Gene Dyslipidaemias Regulation of gene expression Multidisciplinary Molecular engineering Chemistry Drug discovery food and beverages General Chemistry Cell biology Mice Inbred C57BL HEK293 Cells 030104 developmental biology Gene Expression Regulation Liposomes Nanoparticles Genetic Engineering 030217 neurology & neurosurgery RNA Guide Kinetoplastida |
| Zdroj: | Nature Communications Nature Communications, Vol 12, Iss 1, Pp 1-14 (2021) |
| ISSN: | 2041-1723 |
| Popis: | 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. CRISPR-Cas9 is a gene editing tool that can be used to modulate gene expression. Here, the authors report the generation of a mouse model that express all components of the CRISPR-Cas9 guide directed Synergistic Activation Mediator (SAM), demonstrate that gene activation can be achieved with various delivery methods and include generation of a disease model of hypercholesterolemia |
| Databáze: | OpenAIRE |
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