Genome-wide DNA hypomethylation and RNA:DNA hybrid accumulation in Aicardi-Goutières syndrome

Elife. 2015 Jul 16;4:e08007. doi: 10.7554/eLife.08007.


Aicardi-Goutières syndrome (AGS) is a severe childhood inflammatory disorder that shows clinical and genetic overlap with systemic lupus erythematosus (SLE). AGS is thought to arise from the accumulation of incompletely metabolized endogenous nucleic acid species owing to mutations in nucleic acid-degrading enzymes TREX1 (AGS1), RNase H2 (AGS2, 3 and 4), and SAMHD1 (AGS5). However, the identity and source of such immunogenic nucleic acid species remain undefined. Using genome-wide approaches, we show that fibroblasts from AGS patients with AGS1-5 mutations are burdened by excessive loads of RNA:DNA hybrids. Using MethylC-seq, we show that AGS fibroblasts display pronounced and global loss of DNA methylation and demonstrate that AGS-specific RNA:DNA hybrids often occur within DNA hypomethylated regions. Altogether, our data suggest that RNA:DNA hybrids may represent a common immunogenic form of nucleic acids in AGS and provide the first evidence of epigenetic perturbations in AGS, furthering the links between AGS and SLE.

Keywords: Aicardi–Goutières syndrome; DNA methylation; RNA:DNA hybrids; RNase H2; chromosomes; evolutionary biology; genes; genomics; human.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Autoimmune Diseases of the Nervous System / pathology*
  • Cells, Cultured
  • DNA / genetics
  • DNA / immunology
  • DNA / metabolism*
  • DNA Methylation*
  • Epigenesis, Genetic
  • Fibroblasts / pathology
  • Humans
  • Immunologic Factors / metabolism
  • Nervous System Malformations / pathology*
  • RNA / genetics
  • RNA / immunology
  • RNA / metabolism*


  • Immunologic Factors
  • RNA
  • DNA

Supplementary concepts

  • Aicardi-Goutieres syndrome