< Back to previous page

Project

Role of RNA modification in immune cell function

The regulation of cell development, homeostasis, differentiation and function requires the well-orchestrated interplay of molecular events at the level of DNA, RNA and protein. Further, maturation and functional specialisation, such as observed for many immune cell types, require extensive transcriptional rewiring and proteomic changes. Increasing evidence points at dynamic RNA modification as a key regulator in a number of processes, ranging from gene regulation, stemness, cell development and metabolism to stress responses. The most abundant RNA modification is the isomerisation of the nucleoside uridine to pseudouridine (Ψ) – called pseudouridylation. Interestingly, uridines can be specifically modified in a conditional manner, such as during cellular stress, suggesting that Ψ can steer cellular adaptation, however, understanding the roles of this RNA modification in immune cells is currently lacking, possibly because it is complicated by the presence of 13 non-redundant writers (pseudouridine synthases, PUS) displaying differential tropism for RNA types. The immune system is a complex network of various functionally distinct cell types with the ability to detect pathogens and to launch an effective immune response. Innate immune cells with limited receptors to detect foreign molecules and adaptive immune cells with millions of highly specific receptors fulfil specific functions in the defense of the host. The immune system fulfils all requirements for the necessity of fast-acting, dynamic regulatory mechanisms. Developing from hematopoietic stem cells via committed progenitors, immune cells are functionally very diverse and, importantly, plastic. Further, immune challenges require fast functional differentiation and cell migration controlled at a molecular level by DNA modifications, RNA modifications (as shown for RNA methylation), transcriptional rewiring and extensive proteomic changes. In line with these considerations we hypothesize that the regulatory potential of pseudouridylation in immune cells is particularly unleashed in situations of functional (re-)orientation i.e. during immune challenges. This PhD research aims at dissecting the roles of the 13 PUS in immune cells with particular focus on T cells in heath and disease, as well as, understanding the cumulative deficiency of pseudouridylation in immune cell development, homeostasis and function. State-of-the-art NGS and crispr/Cas9 techniques will be applied in steady state in vivo in mice as well as in murine disease models. Further, we aim to dissect the roles of PUS in human functional T cell differentiation as well.

Date:1 Oct 2021 →  Today
Keywords:RNA-modification, Pseudouridylation
Disciplines:Adaptive immunology
Project type:PhD project