Project Details
Projekt
Transposable Elements in Macrophage Immunometabolism in Granuloma annulare
Applicant
Dr. Henning Klapproth
Subject Area
Dermatology
Term
since 2026
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 579799337
Almost half of the human genetic material consists of so-called transposable elements (TEs) – genetic sequences that have integrated within the genome due to host-microbiota interactions during evolution. Although most of them no longer change position, they have not become silent bystanders: growing evidence suggests that they can influence if and how certain genes become active and that they can even become gene products themselves, a process called exonization. This may play a crucial role in inflammatory responses of our immune cells. As a barrier organ, the skin harbors various immune cell types including macrophages that orchestrate the immune response to external triggers, such as pathogens. However, macrophages can also be activated by non-infectious conditions through inciting messenger molecules, such as interferon gamma (IFN-γ). Upon stimulation with this cytokine, macrophages undergo changes in their cellular metabolism to facilitate pro-inflammatory cytokine expression, and, interestingly, increase TE exonization. Preliminary data suggests that this immuno-metabolic axis is crucial for TE exonization, potentially shaping immune effector gene diversity. This project therefore sets out to investigate the metabolic regulation of TE exonization in human IFN-γ-activated macrophages and to translate these findings into macrophage-rich (granulomatous) skin inflammation. The project is structured into three aims over twelve months. To test whether IFN-γ induces TE exonization in human monocyte-derived macrophages, TE exonization events will be systematically characterized using long-read RNA sequencing (RNA-seq). Next, the role of mitochondrial respiration as a critical regulator of this process will be explored by parallelly performing transcriptome and ATAC sequencing to link chromatin accessibility at TE loci with isoform diversity upon metabolic perturbation. Finally, these findings will be applied to the clinical context of granuloma annulare (GA). GA serves as a unique model disease due to its macrophage-rich inflammatory lesions and clear links to IFN-γ and mitochondrial respiratory activity. Using patient-derived long-read RNA-seq and re-analysis of single-cell RNA-seq datasets, the project will identify disease-specific TE exonization events and correlate them with macrophage metabolic signatures. In summary, by investigating how TEs are regulated through metabolic processes in macrophages, and by linking these findings to the well-defined clinical model of granuloma annulare, this project aims to provide new insights into the immuno-metabolic mechanisms driving TE exonization in chronic granulomatous inflammation. This research holds promise to identify novel diagnostic and therapeutic targets that could improve understanding and treatment of granulomatous skin conditions and potentially other macrophage-driven inflammatory diseases, ultimately contributing to better patient outcomes and advancing the field of immunology.
DFG Programme
WBP Fellowship
International Connection
France
