1. Chromosomes and Gene Expression
  2. Genetics and Genomics
Download icon

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
Research Article
  • Cited 65
  • Views 4,818
  • Annotations
Cite this article as: eLife 2015;4:e08007 doi: 10.7554/eLife.08007

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.

Article and author information

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.

Reviewing Editor

  1. Bing Ren, University of California, San Diego School of Medicine, United States

Publication history

  1. Received: April 9, 2015
  2. Accepted: July 15, 2015
  3. Accepted Manuscript published: July 16, 2015 (version 1)
  4. Version of Record published: August 7, 2015 (version 2)

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.

Metrics

  • 4,818
    Page views
  • 1,024
    Downloads
  • 65
    Citations

Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Chromosomes and Gene Expression
    Steven Z Deluca et al.
    Research Article

    Polycomb silencing represses gene expression and provides a molecular memory of chromatin state that is essential for animal development. We show that Drosophila female germline stem cells (GSCs) provide a powerful system for studying Polycomb silencing. GSCs have a non-canonical distribution of PRC2 activity and lack silenced chromatin, like embryonic progenitors. As GSC daughters differentiate into nurse cells and oocytes, nurse cells silence genes in traditional Polycomb domains and in generally inactive chromatin like embryonic somatic cells. Developmentally controlled expression of two Polycomb repressive complex 2 (PRC2)-interacting proteins, Pcl and Scm, initiate silencing during differentiation. In GSCs, abundant Pcl inhibits PRC2-dependent silencing globally, while in nurse cells Pcl declines and newly-induced Scm concentrates PRC2 activity on traditional Polycomb domains. Our results suggest that PRC2-dependent silencing is developmentally regulated by accessory proteins that either increase the concentration of PRC2 at target sites or inhibit the rate that PRC2 samples chromatin.

    1. Chromosomes and Gene Expression
    2. Evolutionary Biology
    Carlos Martinez-Ruiz et al.
    Research Article

    Supergene regions maintain alleles of multiple genes in tight linkage through suppressed recombination. Despite their importance in determining complex phenotypes, our empirical understanding of early supergene evolution is limited. Here we focus on the young "social" supergene of fire ants, a powerful system for disentangling the effects of evolutionary antagonism and suppressed recombination. We hypothesize that gene degeneration and social antagonism shaped the evolution of the fire ant supergene, resulting in distinct patterns of gene expression. We test these ideas by identifying allelic differences between supergene variants, characterizing allelic expression across populations, castes and body parts, and contrasting allelic expression biases with differences in expression between social forms. We find strong signatures of gene degeneration and gene-specific dosage compensation. On this background, a small portion of the genes has the signature of adaptive responses to evolutionary antagonism between social forms.