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

eLife

Frédéric Chédin¹  Lionel A Sanz¹  Yoong Wearn Lim¹  Xiaoqin Xu¹  Stella R Hartono¹ 

[1] Department of Molecular and Cellular Biology, University of California, Davis, Davis, United States;

关键词: Aicardi–Goutières syndrome;    DNA methylation;    RNA:DNA hybrid;    RNase H2;   

DOI  :  10.7554/eLife.08007

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown