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.
Highlights
Aicardi–Goutieres syndrome (AGS) is a severe inflammatory encephalopathy characterized by neurological dysfunction, psychomotor retardation, seizures, unexplained fevers, joint stiffness, basal ganglia calcification, and chilblain skin lesions (Rice et al, 2007b)
In AGS2 and AGS4, where the effect was most marked, the DNA hypomethylation led to the formation of AGS-specific PMDs in addition to those normally observed in fibroblasts (Lister et al, 2009)
AGS-specific PMDs, but not common PMDs, were enriched over regions marked by H3K27me3, a mark of facultative heterochromatin associated with developmental silencing (Figure 5)
Summary
Aicardi–Goutieres syndrome (AGS) is a severe inflammatory encephalopathy characterized by neurological dysfunction, psychomotor retardation, seizures, unexplained fevers, joint stiffness, basal ganglia calcification, and chilblain skin lesions (Rice et al, 2007b). AGS has captured the attention of the scientific community due to its clinical, molecular, and genetic overlap with another, common, systemic autoimmune disorder, systemic lupus erythematosus (SLE) (Rice et al, 2007a, 2007b; Ravenscroft et al, 2011) (Gunther et al, 2015). Both diseases are characterized, and to a large extent driven, by excessive expression of interferon alpha, a potent anti-viral cytokine associated with heightened innate immune response and inflammation (Crow, 2011). Given the role of AGS enzymes in DNA and RNA metabolism, the innate immune response in AGS is thought to be triggered by the accumulation of incompletely metabolized endogenous nucleic acid elements
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