Understanding Epigenetic Control to Develop Novel Cancer Drugs
To design effective cancer therapies, it is essential to decipher the molecular details and interplay between the key pathways that control proliferation, and identify the molecular defects that occur in cancer. The retinoblastoma protein pRb is a tumour suppressor that acts in a negative way on proliferation, and is mutated in tumour cells. Transcription factor E2F is a critical target through which pRb influences proliferation. Our work is focused on the mechanisms which control E2F activity, and how they become de-regulated in cancer. The epigenetic arginine methylation mark acts as a crucial cancer-relevant mechanism by targeting E2F activity, enabling cells to remain in the proliferative cycle. The goal of this project is to gain a mechanistic understanding of how arginine methylation influences E2F, focussing on its genome-wide effects on different levels of gene expression control. The student will use genome-wide technologies to probe the role of arginine methylation on gene expression and chromatin control, complemented by chemical biology approaches with small molecule inhibitors. Arginine methylation will be compared across a range of different tumours, with the ultimate aim of leveraging the information to identify biomarkers for tumours that respond favourably to PRMT5 inhibition.