Format

Send to

Choose Destination
Cell. 2017 Dec 14;171(7):1495-1507.e15. doi: 10.1016/j.cell.2017.10.025. Epub 2017 Dec 7.

In Vivo Target Gene Activation via CRISPR/Cas9-Mediated Trans-epigenetic Modulation.

Author information

1
Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
2
Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Universidad Catolica, San Antonio de Murcia, Campus de los Jeronimos, 135, 30107 Guadalupe, Spain.
3
Department of Pediatrics and Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
4
Universidad Catolica, San Antonio de Murcia, Campus de los Jeronimos, 135, 30107 Guadalupe, Spain.
5
Fundacion Pedro Guillen, Clinica CEMTRO, Avenida Ventisquero de la Condesa, 42, 28035 Madrid, Spain.
6
Hospital Clinic of Barcelona, Carrer Villarroel, 170, 08036 Barcelona, Spain.
7
Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92037, USA.
8
Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Electronic address: belmonte@salk.edu.

Abstract

Current genome-editing systems generally rely on inducing DNA double-strand breaks (DSBs). This may limit their utility in clinical therapies, as unwanted mutations caused by DSBs can have deleterious effects. CRISPR/Cas9 system has recently been repurposed to enable target gene activation, allowing regulation of endogenous gene expression without creating DSBs. However, in vivo implementation of this gain-of-function system has proven difficult. Here, we report a robust system for in vivo activation of endogenous target genes through trans-epigenetic remodeling. The system relies on recruitment of Cas9 and transcriptional activation complexes to target loci by modified single guide RNAs. As proof-of-concept, we used this technology to treat mouse models of diabetes, muscular dystrophy, and acute kidney disease. Results demonstrate that CRISPR/Cas9-mediated target gene activation can be achieved in vivo, leading to measurable phenotypes and amelioration of disease symptoms. This establishes new avenues for developing targeted epigenetic therapies against human diseases. VIDEO ABSTRACT.

KEYWORDS:

CRISPR/Cas9; chromatin remodeling; disease model; epigenetic modification; epigenetic therapy; gene editing; muscular dystrophy; regenerative medicine; stem cells; transdifferentiation

PMID:
29224783
PMCID:
PMC5732045
DOI:
10.1016/j.cell.2017.10.025
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center