CRISPR-mediated activation of a promoter or enhancer rescues obesity caused by haploinsufficiency

Science. 2019 Jan 18;363(6424):eaau0629. doi: 10.1126/science.aau0629. Epub 2018 Dec 13.


A wide range of human diseases result from haploinsufficiency, where the function of one of the two gene copies is lost. Here, we targeted the remaining functional copy of a haploinsufficient gene using CRISPR-mediated activation (CRISPRa) in Sim1 and Mc4r heterozygous mouse models to rescue their obesity phenotype. Transgenic-based CRISPRa targeting of the Sim1 promoter or its distant hypothalamic enhancer up-regulated its expression from the endogenous functional allele in a tissue-specific manner, rescuing the obesity phenotype in Sim1 heterozygous mice. To evaluate the therapeutic potential of CRISPRa, we injected CRISPRa-recombinant adeno-associated virus into the hypothalamus, which led to reversal of the obesity phenotype in Sim1 and Mc4r haploinsufficient mice. Our results suggest that endogenous gene up-regulation could be a potential strategy to treat altered gene dosage diseases.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Cell Line
  • Clustered Regularly Interspaced Short Palindromic Repeats*
  • Dependovirus
  • Disease Models, Animal
  • Enhancer Elements, Genetic*
  • Female
  • Gene Expression Regulation
  • Gene Transfer Techniques
  • Haploinsufficiency*
  • Heterozygote
  • Hypothalamus
  • Loss of Function Mutation
  • Male
  • Mice
  • Mice, Transgenic
  • Obesity / genetics*
  • Obesity / therapy
  • Phenotype
  • Promoter Regions, Genetic*
  • Receptor, Melanocortin, Type 4 / genetics
  • Repressor Proteins / genetics
  • Up-Regulation
  • Weight Gain


  • Basic Helix-Loop-Helix Transcription Factors
  • MC4R protein, mouse
  • Receptor, Melanocortin, Type 4
  • Repressor Proteins
  • Sim1 protein, mouse