Epigenetic signalling in cancer
31 March 2024
The advent of population scale tumour genomics has revealed that the genes encoding proteins that normally act to regulate chromatin structure are amongst the most frequently mutated genes in a range of cancers. These include subunits of ATP-dependent chromatin remodelling complexes (1). By combining chemical and biology approaches Its possible to examine the acute response to loss of specific subunits (1)(2). In this proposal we will make use of organoid models of human kidney to establish a preclinical model for clear cell renal cancer. The major drivers for this disease Include the E3 ligase VHL and the PBRM1 subunit of the P/BAF chromatin remodelling complex (3). We will the establish PRTOAC or degron systems for acute depletion of both VHL and PBRM1. We will then characterise the pathways mis-regulated upon inactivation of these genes. This will include mapping genome wide changes to chromatin accessibility, monitoring transcription by RNAseq and single cell RNAseq. Ultimately, understanding these pathways will Inform the selection of new therapeutic approaches.
(1) Cell Rep 2021 Nov 2;37(5):109943. doi: 10.1016/j.celrep.2021.109943.
(2) Nat Chem Biol 2019 Jul;15(7):672-680. doi: 10.1038/s41589-019-0294-6. Epub 2019 Jun 10.
(3) Nature 2011 Jan 27;469(7331):539-42. doi: 10.1038/nature09639. Epub 2011 Jan 19.
How to apply
This project is open to self-funded and externally sponsored applicants, standard entry dates are January and September but we will consider applications year round. If you are interested in applying, please contact the supervisor directly in the first instance to discuss further, principal supervisors will ask you about your qualifications and your research experience to determine your suitability for the project. You will also be asked to indicate how you intend to fund your PhD (PhD fee information can be found here).
For general enquiries, contact SLS-PhDAdmin@dundee.ac.uk