Dysregulation of the epigenetic modifier Polycomb Repressive Complex 2 (PRC2) is a common event in cancer. The PRC2 subunit EZH2 trimethylates histone-H3 lysine-27 (H3K27me3), which represses gene expression.
Diffuse intrinsic pontine glioma (DIPG) is a highly-aggressive paediatric brain tumour with no effective treatment. 80% of cases harbour the H3K27M mutation, which inhibits EZH2 activity and causes a global depletion of H3K27me3. However, H3K27M increases PRC2 occupancy at some genes, including the tumour suppressor CDNK2A (p16INK4A). EZH2 inhibitors block DIPG growth, suggesting a potential avenue for therapy. However, these drugs reactivate genes across the genome, causing transcriptional instability and affecting healthy cells.
We have shown that G-quadruplex (G4) RNA inhibits PRC2 activity by preventing its interaction with chromatin (Beltran et al., (2019). Nat Struct Mol Biol). Utilising this mechanism, we have recently developed a method that tethers G4-RNA to chromatin to directly reverse polycomb-mediated silencing of specific tumour suppressor genes.
The aim of the project is to determine whether G4-RNA reactivates CDNK2A and other polycomb-target genes in DIPG. The student will also apply the method to primary tumour models to identify gene silencing events that drive tumourigenesis. The successful candidate will benefit from inter-disciplinary training in chromatin and RNA biology, genomics and bioinformatics, neural stem cell culture and tumour xenografts.
More detailed information about the research project is available on request from Richard Jenner at [email protected]