Epigenetic Changes Associated with Interferon γ Induced Transposable Element Expression in Microglia

Sammanfattning

Introduction: Neuroinflammation is a key feature of neurodegenerative diseases, such as PD. Emerging evidence suggests that endogenous retroviruses (ERVs), epigenetically silenced relics of ancient viral infections, may become reactivated under inflammatory conditions and contribute to the inflammatory process and disease progression. Background: Previous work from the Jakobsson group has shown a correlation between an interferon (IFN) response signature and ERV expression in microglia from PD post-mortem tissue. In vitro, IFN-γ stimulation has been shown to induce ERV activation in microglia. Understanding the pathways involved in this process, particularly the epigenetic mechanisms regulating ERV activation, may provide insights into potential therapeutic targets for PD. Aim(s): The aim of this study was to describe ERV dysregulation in human induced pluripotent stem cell (hiPSC)-derived microglia under PD-associated inflammatory conditions, with a focus on the epigenetic changes at ERV loci induced by IFN stimulation. Methods: A hiPSC-derived microglia model was used to model PD-associated inflammation using IFN-γ stimulation. The reproducibility and identity of this cell model were validated through flow cytometry, immunocytochemistry (ICC), reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) and bulk ribonucleic acid (RNA) sequencing. The inflammatory response and associated ERV dysregulation were studied using bulk RNA sequencing and epigenetic mapping through cleavage under targets and release using nuclease technique (CUT&RUN). Results: A reproducible hiPSC-derived microglia model was successfully established across independent differentiation batches. IFN-γ stimulation induced a PD-associated inflammatory state with expected marker changes. Thirty significantly upregulated ERVs were identified, consistent with patterns previously observed in vitro. Locus-specific CUT&RUN analysis revealed changes in a permissive histone mark nearby ERV loci, suggesting upstream regulatory mechanisms either close at the ERV locus or in association with nearby genetic elements. Conclusion: These findings describe mechanisms underlying the association between IFN signaling and ERV derepression in microglia, laying a foundation for understanding the epigenetic mechanisms linking neuroinflammation and ERV dysregulation in PD.