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

Publicado en: Cell


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.


  • A CRISPR/Cas9 system transcriptionally activates endogenous target genes in vivo
  • Recruiting the transcriptional machinery induces transepigenetic remodeling
  • Inducing target gene expression leads to physiological phenotypes in postnatal mammals
  • The system ameliorates symptoms associated with several mouse models of human diseases



  • Hsin-Kai Liao, Fumiyuki Hatanaka,
  • Toshikazu Araoka, …, Li-Fan Lu
  • Concepcion Rodriguez Esteban
  • Juan Carlos Izpisua Belmonte



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