The advent of population-based genome sequencing has made it possible to identify tumour suppressors and oncogenes systematically. A surprising outcome of such studies is that numerous factors acting at the level of chromatin act as tumour suppressors. This includes subunits of ATP-dependent chromatin remodelling complexes. These complexes act to regulate access to chromatin at many locations. They are often multi-subunit complexes and different subunits of related complexes act as tumour suppressors in different tissues (1). Acute depletion using proteolysis targeting chimera’s (PROTAC’S) or degron systems provides a means to study the pathway by which these factors act as tumour suppressors (2), (3). In this project we characterise the pathways via which loss of function to subunits of chromatin remodelling complexes drives cancer. The aim will be to identify points at which it is possible to intervene in the activation of oncogenic pathways following loss of these subunits.
The project will provide training in the culture and genetic manipulation of stem cells including differentiation to relevant organoid models and the use of genome editing. We use functional genomics approaches such as ATAC-seq and ChIP-seq, (single cell) transcriptomics and proteomics to characterise the changes occurring following acute loss of these subunits. Analysis of the data generated will provide experience in the use of high-performance computing and bioinformatics tools.