PhD project: (Non-)canonical TYK2 – a monarch in signalling into chromatin?

...investigates the impact of enzymatically active and inactive TYK2 on DNA methylation and chromatin remodelling.

In the canonical linear JAK-STAT pathway, receptor-associated JAKs signal through STAT proteins into the nucleus. The recent development of inhibitors of JAK activity to treat malignancies and autoinflammatory/autoimmune diseases has led to a renewed interest in kinase-independent and/or non-receptor-associated functions of JAKs. Both mouse and human TYK2 have been shown to exert functions independent of their enzymatic activity, although with the exception of cytokine receptor scaffolding, these are ill-defined. We will characterize the molecular networks targeted by kinase-inactive TYK2 that regulate epigenetic (DNA methylation, chromatin landscape) and transcriptional changes under homeostatic and diseased conditions. We will build on the findings that kinase-inactive TYK2 drives NK-cell maturation and function and redirects CD8+ T-cell antitumour immunity and on evidence that at least some of these TYK2 functions are independent of STATs.