Epigenetic Control of Keratinocyte Innate Immunity

The innate immune system is crucial for protecting the skin from pathogens like bacteria and viruses. Keratinocytes, beyond their structural role in the epidermis, act as immune sensors by detecting danger signals, such as viral or bacterial nucleic acids, and triggering an immediate immune response. While this mechanism is essential for pathogen defense, strict regulation is necessary to prevent excessive reactions to the bodys own nucleic acids. Epigenetic modifications, such as DNA methylation, are important for maintaining genome stability and preventing the activation of transposable elements (transposons). Our recent research in mice with genetically reduced DNA methylation in keratinocytes revealed the reactivation of transposons and decreased genomic stability. Both phenomena result in nucleic acids accumulating in the cytoplasm, activating the innate immune system, and causing severe, life-threatening skin inflammation. These findings suggest that DNA methylation is a critical safeguard against unwanted immune activation in the epidermis. Based on this mouse study, our project aims to determine whether similar mechanisms play a role in human skin. We will investigate whether reduced DNA methylation in human keratinocytes leads to cytosolic DNA accumulation, transposon reactivation, and an autoimmune response. Using innovative 2D and 3D human cell culture models, we will recreate the complex interactions between keratinocytes and immune cells to analyze how epigenetic changes affect skin integrity. Additionally, by studying clinical samples from patients with inflammatory skin diseases and skin tumors, we aim to link DNA methylation patterns with disease progression and immune activation. The study will provide deeper insights into the molecular relationship between epigenetic modifications and immune regulation in human skin. In addition, it may provide valuable insights into how epigenetic drugs work in tumor therapy.