Epigenetic control of the innate immune system

The innate immune system targets pathogens such as bacteria and viruses and limits their ability to spread in our body. One of the features of pathogens that is recognized by the innate immune system is their genetic material: the DNA and, for some viruses, the RNA. DNA methylation is an important epigenetic mechanism with a crucial function for silencing of mobile elements (transposons) and for the maintenance of the integrity of our genome. We have recently discovered that mice with a genetically induced reduction of DNA methylation in the outermost layer of the skin, the epidermis, show massive inflammation. This leads to dramatic changes in the architecture of the skin of these animals. In this process, the innate immune system attacks the body`s own cells in a process called autoinflammation. We have experimental evidence that impaired DNA methylation in the epidermis results in genome destabilization and DNA delocalization from the nucleus to the cytosol. In the cytosol the DNA is wrongly recognized as sign of infection by pathogens. Furthermore, DNA hypomethylation results in the activation of mobile elements in the epidermis and production of transposon RNA, which is taken as indication for viral infection (viral mimicry). Both phenomena result in life- threatening inflammation of the skin. These data indicate that DNA methylation has an important function in preventing the activation of the innate immune system by nucleic acid recognizing mechanisms. In this project we will investigate in detail the mechanisms that erroneously recognize under these conditions self DNA and self RNA as pathogen derived nucleic acids. To this end, we will use a combination of genetic, immunological and cell biological methods. Our study will contribute to our understanding of the impact of epigenetic mechanisms on autoinflammatory diseases. Given that combinations of epigenetic and immunotherapeutic agents are currently discussed as novel approaches in tumor therapy our study will also provide new insights for cancer research.

DNA methylation is an Important mechanism in the epigenetic control of the innate immune system The innate human immune system is able to recognize and neutralize pathogens such as viruses, bacteria or parasites and rendering them harmless. It recognizes infectious agents by their RNA and DNA, among other things. However, these nucleic acids are also present in human cells. The immune system must therefore be able to distinguish endogenous substances from exogenous ones, in order to avoid autoinflammation or autoimmune diseases. This is also called self/non-self discrimination. DNA methylation is an important epigenetic mechanism in our cells. It controls cell type-specific gene expression. In addition, this mechanism prevents the activation of cellular viruses, the so-called transposons, which can change their position in the genome. In this project it was shown that autoinflammation and pathological changes occur in the skin when DNA methylation is strongly reduced by inactivation of the key epigenetic enzyme DNA methyltransferase 1. However, such reduced DNA methylation not only causes the activation of transposons, but also a certain genomic instability, which leads to the emergence of DNA outside the nucleus as micronuclei. When micronuclei form, cGAS, one of the main regulators of the innate immune system, mistakenly recognizes the DNA as foreign or "non-self" and activates the immune system. The results of this study are not only relevant for further investigations into the cause of autoinflammatory diseases but may also provide an explanation for the positive effects of epigenetic drugs on the efficacy of immunotherapy against cancer.