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CRISPR/Cas9-mediated in vivo Epigenetic Remodeling: A New Means to Treat Disease?



Review of “In Vivo Target Gene Activation via CRISPR/Cas9-Mediated Trans-epigenetic Modulation” from Cell by Stuart P. Atkinson

While the DNA altering function of CRISPR/Cas9 systems may have hogged the recent limelight, a new study from the laboratory of Juan Carlos Izpisua Belmonte (Salk Institute for Biological Studies, La Jolla, CA, USA) now extols the potential for another CRISPR/Cas9 mode in treating disease: transcriptionally-activating gene expression in vivo via targeted epigenetic remodeling [1].

This inventive new system devised by Liao et al. employed mice overexpressing Cas9 and the expression of an optimized plasmid containing coding sequences for engineered gene-specific “dead” sgRNAs (dgRNAs) and a MS2:P65:HSF1 (MPH) transcriptional activation complex. Importantly, the engineered dgRNAs can recruit both Cas9 and the MPH complex to facilitate epigenetic remodeling at the regulatory sequences of a specific gene without causing DNA double-strand breaks (DSBs) [2]. 

The authors successfully demonstrated that their system functioned in vivo by promoting epigenetic remodeling of the mouse follistatin gene, which led to increased gene expression and the expected increase in muscle mass [3]. This success then prompted assessments of this novel system as means to treat disease, with applications including:

  • Amelioration of symptoms in a mouse model of human acute kidney injury, via the rescue of lost Klotho expression or induction of Interleukin-10 expression
  • Promotion of transdifferentiation of liver cells into insulin-producing cells in mouse model of type I diabetes, via the induction of Pdx1 expression 
  • Compensation for genetic defects by ameliorating disease phenotype in Dystrophin-deficient mouse model of muscular dystrophy, via targeting the expression of Klotho and Utrophin

As a step toward the use of CRISPR/Cas9-mediated transcriptional activation in humans, the study finally successfully applied a Cas9 expression plasmid alongside dgRNA/MPH expression to target the Utrophin gene and ameliorate muscular dystrophy symptoms in mdx mice that do not overexpress Cas9.

Is targeting the epigenome in vivo via CRISPR/Cas9 the next big thing in treating human disease? The authors note that the adeno-associated virus delivery of the plasmids employed in this study may lead to unwanted host immune system responses, while other aspects still require further optimization to ensure safety and efficacy. 

Stay tuned to the Stem Cells Portal to discover more regarding this fascinating new advance!


  1. Liao H-K, Hatanaka F, Araoka T, et al., In vivo Target Gene Activation via CRISPR/Cas9-Mediated Trans-epigenetic Modulation. Cell;171:1495-1507.e15.
  2. Dahlman JE, Abudayyeh OO, Joung J, et al., Orthogonal gene knockout and activation with a catalytically active Cas9 nuclease. Nat Biotechnol 2015;33:1159-61.
  3. Haidet AM, Rizo L, Handy C, et al., Long-term enhancement of skeletal muscle mass and strength by single gene administration of myostatin inhibitors. Proc Natl Acad Sci U S A 2008;105:4318-22.