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

Abstract

The immune system protects the body from attack by bacteria, viruses, and other microbes. A key feature of this system is the ability to discriminate between the body's own cells and potential foreign invaders. Occasionally, this process can go wrong and the immune system starts attacking its own tissues, which can lead to arthritis, diabetes, lupus, and other ‘autoimmune’ diseases. Aicardi–Goutières syndrome (AGS) is an autoimmune disease that leads to severe mental and physical symptoms. Recent research has revealed that the disease is caused by mutations in genes that make enzymes called nucleases. In healthy people, these enzymes destroy DNA molecules and other nucleic acids. In AGS patients, the failure of the nucleases to act is thought to lead to the accumulation of unwanted DNA and RNA molecules. These molecules, in turn, are thought to be mistakenly identified by the immune system as ‘foreign’ and to cause an autoimmune response. However, it is not clear how this works. Here, Lim et al. studied skin cells called fibroblasts from patients with Aicardi–Goutières syndrome. The experiments found that the patients' cells had excessive numbers of RNA molecules binding to sections of matching DNA. These unusual DNA–RNA ‘hybrids’ accumulated in regions of the genome that do not contain many genes, perhaps as a result of breaks in the DNA. It is possible that they may mimic nucleic acids from viruses and could trigger an autoimmune response. In healthy individuals, small ‘methyl’ groups are often attached to DNA in a process known as DNA methylation. This serves to maintain the stability of the genome and controls the activity of genes. Unexpectedly, Lim et al. found that the DNA in AGS patients had far fewer methyl groups, especially in areas where the DNA–RNA hybrids had accumulated. This may lead to genome destabilization, alterations in gene activity, and may mean that the DNA in these regions may be mistaken for foreign DNA by the immune system. Altogether, Lim et al.'s findings suggest that Aicardi–Goutières syndrome may be caused by immune responses triggered by the accumulation of RNA–DNA hybrids and lower levels of DNA methylation. These findings may aid the development of new therapies to treat Aicardi–Goutières syndrome, lupus, and other similar diseases.