Epigenetic changes driving progression in colorectal cancer

The role of epigenetics in colorectal cancer (CRC) progression remain undetermined. The genome is a complex 3D structure, whereby the wrapping of DNA around an underlying chromatin 'scaffold' determines gene expression and ultimately cancer cell phenotypes. Frequent alterations to the chromatin scaffold are unobserved in CRCs, but the causes and consequences and the timing of these alterations remain undertermined. In this project we map chromatin changes through progression in colorectal cancer and unexplore the drivers and consequences for CRC biology.

1. Map chromatin architecture in normal colon, adenomas (pre-cancers) and in colorectal cancers. Concomitantly map DNA methylation and gene expression same samples. Genetically sequence chromatin modifier genes and somatic copy number alterations.
2. Use the statistical framework of expression quantitative trait loci (eQTL) to determine the likely consequences of chromatin rearrangements. Use regression to determine the interrelationship between chromatin changes and copy number alterations, and to detect a potentially causative role between DNA methylation and chromatin modifier gene somatic mutations, and chromatin state.
3. Use mathematical modelling of data from (1) and (2) to evaluate the hypothesis that chromatin architecture changes enable cellular plasticity that drives tumour evolution.

The project will comprehensively measure changes in chromatin architecture that occur during progression to cancer in the colon, focusing on the explored changes in chromatin architecture that occur in adenomas. To understand the causes and consequences of these chromatin changes, the interrelationship between chromatin changes, DNA sequence variation and epigenetic modification, and gene expression will be explored. Finally, we will use mathematical modelling (stochastic branching processes) parameterized using the laboratory data to explore the likely roles of chromatin changes during the evolution of malignancy in the colon.

The PhD project is highly interdisciplinary, involving epi(genomics) work in the wet lab, and bioinformatics and mathematical modelling of these data in the dry-lab.