Hypoxic remodeling of the epigenetic landscape in the context of innate immune memory

• Applicant: Rebekka Bauer, Ph.D.
• Subject Area: Immunology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 547467817

While immune memory was originally associated exclusively with the adaptive immune system, it is now widely accepted that innate immune cells also develop a non-specific immunological memory. The underlying metabolic and epigenetic reprogramming of innate immune cells upon an initial inflammatory or metabolic stimulus causes long-lasting increased (trained immunity) or decreased (immune tolerance) responsiveness to a secondary challenge. Of note, oxygen deprivation causes extensive metabolic remodeling and profound changes in the epigenetic landscape. Surprisingly though, the impact of hypoxia on trained immunity/immune tolerance is not investigated in detail. Therefore, the aim of the project is to study if hypoxic training can initiate or influence the induction of innate immune memory. For this purpose, an in vitro setup will be established, in which human primary monocytes are trained under hypoxia, reoxygenated and differentiated, before they are challenged with a secondary pro-inflammatory stimulus. Next-generation sequencing approaches will be used to characterize global changes in chromatin accessibility (ATAC-Seq) and transcriptome (RNA-Seq) of hypoxic trained cells, and consequently to determine a hypoxic memory signature. Since metabolic and epigenetic remodeling as well as hypoxia-inducible factor (HIF) activation are hallmarks of both innate immune memory and adaptation of cells to oxygen deprivation, pharmacological inhibitors will be used to investigate the contribution of different metabolic pathways, (oxygen-dependent) epigenetic modifiers, and HIF to the hypoxic innate immune memory phenotype. Dependent on the supposed involved metabolic pathways/epigenetic modifiers, hypoxic trained cells will be further characterized regarding their metabolic state (e.g., glycolytic activity or changes in the lipidome) and changes in specific chromatin modifications (histone marks or DNA methylation). Altogether, the aim of the project is to investigate the ability of oxygen deprivation to initiate or influence the induction of innate immune memory, and to identify responsible metabolic pathways and epigenetic enzymes. In the long term, the project will pave the way to translational research investigating the influence of hypoxemia for the development of innate immune memory in people exposed to high altitude or in patients with severe cases of respiratory diseases.

• DFG Programme: WBP Fellowship
• International Connection: Netherlands
• Host: Professor Dr. Mihai G. Netea