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

  1. Yoong Wearn Lim
  2. Lionel A Sanz
  3. Xiaoqin Xu
  4. Stella R Hartono
  5. Frédéric Chédin  Is a corresponding author
  1. University of California, Davis, United States

Abstract

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.

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Author details

  1. Yoong Wearn Lim

    Department of Molecular and Cellular Biology, University of California, Davis, Davis, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Lionel A Sanz

    Department of Molecular and Cellular Biology, University of California, Davis, Davis, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Xiaoqin Xu

    Department of Molecular and Cellular Biology, University of California, Davis, Davis, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Stella R Hartono

    Department of Molecular and Cellular Biology, University of California, Davis, Davis, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Frédéric Chédin

    Department of Molecular and Cellular Biology, University of California, Davis, Davis, United States
    For correspondence
    flchedin@ucdavis.edu
    Competing interests
    The authors declare that no competing interests exist.

Copyright

© 2015, Lim et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Yoong Wearn Lim
  2. Lionel A Sanz
  3. Xiaoqin Xu
  4. Stella R Hartono
  5. Frédéric Chédin
(2015)
Genome-wide DNA hypomethylation and RNA:DNA hybrid accumulation in Aicardi-Goutières syndrome
eLife 4:e08007.
https://doi.org/10.7554/eLife.08007

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https://doi.org/10.7554/eLife.08007