Human miRNA miR-675 inhibits DUX4 expression and may be exploited as a potential treatment for Facioscapulohumeral muscular dystrophy

Nat Commun. 2021 Dec 8;12(1):7128. doi: 10.1038/s41467-021-27430-1.


Facioscapulohumeral muscular dystrophy (FSHD) is a potentially devastating myopathy caused by de-repression of the DUX4 gene in skeletal muscles. Effective therapies will likely involve DUX4 inhibition. RNA interference (RNAi) is one powerful approach to inhibit DUX4, and we previously described a RNAi gene therapy to achieve DUX4 silencing in FSHD cells and mice using engineered microRNAs. Here we report a strategy to direct RNAi against DUX4 using the natural microRNA miR-675, which is derived from the lncRNA H19. Human miR-675 inhibits DUX4 expression and associated outcomes in FSHD cell models. In addition, miR-675 delivery using gene therapy protects muscles from DUX4-associated death in mice. Finally, we show that three known miR-675-upregulating small molecules inhibit DUX4 and DUX4-activated FSHD biomarkers in FSHD patient-derived myotubes. To our knowledge, this is the first study demonstrating the use of small molecules to suppress a dominant disease gene using an RNAi mechanism.

Publication types

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

MeSH terms

  • Adult
  • Aged
  • Animals
  • Cell Death / drug effects
  • Disease Models, Animal
  • Drug Delivery Systems
  • Female
  • Gene Expression Regulation / drug effects*
  • Genetic Therapy
  • HEK293 Cells
  • Homeodomain Proteins / drug effects*
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism*
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • MicroRNAs / pharmacology*
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology
  • Muscular Diseases
  • Muscular Dystrophy, Facioscapulohumeral / drug therapy*
  • Muscular Dystrophy, Facioscapulohumeral / pathology
  • Open Reading Frames / drug effects
  • RNA Interference


  • Dux4 protein, mouse
  • Homeodomain Proteins
  • MIRN675 microRNA, human
  • MIRN675 microRNA, mouse
  • MicroRNAs