TY - JOUR TI - Genome-wide DNA hypomethylation and RNA:DNA hybrid accumulation in Aicardi–Goutières syndrome AU - Lim, Yoong Wearn AU - Sanz, Lionel A AU - Xu, Xiaoqin AU - Hartono, Stella R AU - Chédin, Frédéric A2 - Ren, Bing VL - 4 PY - 2015 DA - 2015/07/16 SP - e08007 C1 - eLife 2015;4:e08007 DO - 10.7554/eLife.08007 UR - https://doi.org/10.7554/eLife.08007 AB - 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. KW - Aicardi–Goutières syndrome KW - DNA methylation KW - RNA:DNA hybrid KW - RNase H2 JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -