(Vienna, 05 October 2021) The innate human immune system is capable of recognizing and fighting pathogens such as viruses, bacteria or parasites. In addition to other conserved structure, it can detect pathogens based on their RNA and DNA. Since these nucleic acids are also present in human cells the immune system must be able to differentiate endogenous substances from exogenous ones in order to avoid autoinflammation or autoimmune diseases. This mechanism is also known as self/non-self discrimination. In a study now published in the renowned EMBO Journal, the research group of Christian Seiser (Center for Anatomy and Cell Biology at MedUni Vienna) could show that the epigenetic key enzyme DNA methyltransferase 1 is an important factor in preventing autoinflammation.
"Methylation of DNA is the most important epigenetic mechanism in our cells. It not only controls cell-specific gene expression but prevents the activation of endogenous viruses, the so-called transposons, which can change their position within the genome and may induce cellular defence mechanisms," explains Seiser. "We have now shown in our study that autoinflammation and pathological changes occur in the skin when the key epigenetic enzyme DNA methyltransferase 1 is absent."
In addition to the activation of transposons, reduced DNA methylation results in genomic instability, leading to the formation of cytoplasmic DNA (Micronuclei, DNA blebs). "When micronuclei are formed, cGAS, one of the main regulators of the innate immune system, erroneously recognizes the DNA as foreign or "non-self" and activates the immune system."
The results of this study are particularly relevant for further investigations to understand the molecular mechanisms of autoinflammatory diseases but may also provide an explanation for the positive effects of epigenetic drugs on the efficacy of immunotherapy against cancer.
Service: The EMBO Journal
"DNA hypomethylation leads to cGAS-induced autoinflammation in the epidermis."
Mirjam A. Beck, Heinz Fischer, Lisa M. Grabner, Tamara Groffics, Mircea Winter, Simone Tangermann, Tina Meischel, Barbara Zaussinger-Haas, Patrick Wagner, Carina Fischer, Christina Folie, Julia Arand, Christian Schöfer, Bernard Ramsahoye, Sabine Lagger, Georg Machat, Gregor Eisenwort, Stephanie Schneider, Alexandra Podhornik, Michael Kothmayer, Ursula Reichart, Martin Glösmann, Ido Tamir, Michael Mildner, Raheleh Sheibani-Tezerji, Lukas Kenner, Peter Petzelbauer, Gerda Egger, Maria Sibilia, Andrea Ablasser, Christian Seiser. DOI 10.15252/embj.2021108234.