Investigating the role of RNA cap regulation in T cell activation
Primary Supervisor: Professor Vicky Cowling, School of Cancer Services
Second Supervisor: Dr Ed Roberts, School of Cancer Services
Third Supervisor: Dr Leo Carlin, School of Cancer Services
Rotation project:
T cells are one of our most effective defences against cancer. On encountering cancer cells, T cells proliferate rapidly and differentiate into potent effectors which target cancer cells for neutralisation using several strategies. When activated in response to tumour antigens, T cells undergo major changes in gene expression to synthesise the proteins required to produce rapidly proliferating effectors cells. We study how a potent structure in gene expression, the RNA cap, is regulated in response to T cell activation and the impact on gene regulation, cell proliferation and effector functions. The RNA cap is critical for gene expression; it is added to RNA pol II transcripts (mRNA, miRNA, lncRNA etc) to recruit factors involved in transcription, RNA processing and translation. The family of RNA capping enzymes are regulated when T cells are activated and this impacts on the rate and extent of RNA cap formation on different genes, directing gene expression, cell fate decisions and effector functions.
We are interested in the roles that the different capping enzymes play in T cells in the response to cancer. T cells respond effectively to many different types of cancer initially but over time become “exhausted” and effector functions fail. If we can understand the impact of the capping enzymes on gene expression and T cell function in cancer, we may be able to target these enzymes in therapeutic scenarios. The project will study how the RNA capping enzymes activity and gene specificity are regulated in response to cancers. We collaborate with Ed Roberts to investigate the impact of targeting the RNA capping enzymes in the latest cancer models. We investigate capping enzymes gene specificity and activity using advanced RNA/DNA sequencing technologies, protein biochemistry and mass spectrometry.
Upregulation of RNA cap methyltransferase RNMT drives ribosome biogenesis during T cell activation