Wellcome Trust PhD Programme for Clinicians at the University of Cambridge. (360G-Wellcome-106563_Z_14_Z)

CTCF is a DNA-binding protein that regulates enhancer-promoter interactions and defines transcriptional and chromatin domains. CTCF-binding elements and the location of its chromatin binding sites are much more highly conserved across species than other transcription factors, supporting an integral role of CTCF in genomic stability. Indeed, CTCF has been implicated as a tumour supressor gene: Ctcf haploinsufficient mice develop multiple spontaneous tumours, and CTCF mutations have been identified in human malignancies.My study will investigate how altering the genomic concentration of a major chromatin organising factor impacts genome organisation, stability, and unltimately cancer formation. To accomplish this we will analyse chemically induced tumours in a genetically engineered mouse model using functional genomics and proteomics.In aim 1 we will explore which tumour suppressors and oncogenes are near CTCF binding sites and are sensitive to CTCF depletion. In aim 2 we will explore which chromatin organisation machineries are directly dependant on proper CTCF expression by whole proteome analysis. In aim 3 we will use a chemical carcinogen N-nitrosodiethylamine to examine the effect of CTCF loss on hepatocarcenogenisis. Together my Aims will help reveal the mechanisms by which CTCF controls the genome organisation required for tissue homeostatsis and which molecular players facilitate carcinogenisis.