In vivo target gene activation via CRISPR/Cas9-mediated trans-epigenetic modulation
Open accessAbstract
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.
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Liao et al. reported that endogenous gene was activated via trans-epigenetic remodelling using CRISPR-cas9, and phenotypic changes were observed in acute kidney injury, type 1 diabetes and Duchenne muscular dystrophy rodent models.
“Liao and colleagues reported that the endogenous gene was activated via trans-epigenetic remodelling by using a CRISPR-cas9 system, and phenotypic changes were observed in acute kidney injury, type 1 diabetes and Duchenne muscular dystrophy rodent models (307).”
From Epigenetic Modifications in Stress Response Genes Associated With Childhood Trauma (2019) · cites this paper as [307]
CRISPR-Cas9 system can trans-epigenetic remodel the endogenous gene.
“Furthermore, CRISPR-cas9 system can trans-epigenetic remodel the endogenous gene.429”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [429]
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- Authors
- Liao, H.-K., Hatanaka, F., Araoka, T., Reddy, P., Wu, M.-Z., Sui, Y., Yamauchi, T., Sakurai, M., O’Keefe, D. D., Núñez-Delicado, E., Guillen, P., Campistol, J. M., Wu, C.-J., Lu, L.-F., Esteban, C. R., & Izpisua Belmonte, J. C.
- Affiliations
- Salk Institute for Biological Studies (US)
- University of California San Diego (US)
- Hospital Clínic de Barcelona (ES)
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2017-12
- Volume
- 171
- Issue
- 7
- Pages
- 1495-1507.e15
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5732045
- OpenAlex
- W2772697618
- Cited by
- 451
- References
- 59
- Citations by year
- 2026: 29 · 2025: 38 · 2024: 45 · 2023: 36 · 2022: 55 · 2021: 40 · 2020: 56 · 2019: 78 · 2018: 70 · 2017: 3
- FWCI
- 23.11
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Leona M. and Harry B. Helmsley Charitable Trust
- Moxie Foundation
- Muscular Dystrophy Association
- Uehara Memorial Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- CRISPR/Cas9, epigenetic therapy, transcriptional activation, in vivo gene regulation, diabetes mellitus, muscular dystrophy, acute kidney disease
- MeSH terms
- Klotho Proteins, Animals, Base Sequence, Disease Models, Animal, Membrane Proteins, Mice, Inbred C57BL, Genetic Therapy, Transcriptional Activation, Dystrophin, Interleukin-10, Gene Targeting, Muscular Dystrophy, Duchenne, Epigenesis, Genetic, Utrophin, Mice, CRISPR-Cas Systems
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