(MRC DTP) The role of the non-coding genome in oesophageal cancer formation.

Cancer is a multi-step process characterised by the transition through different cell states as it develops and progresses. Each stage is locked in place through the establishment of a unique regulatory chromatin environment, and disease progression occurs through oncogene-driven alterations to this landscape. Oesophageal adenocarcinoma (OAC) is a cancer of unmet need due its poor survival rates, and we know very little about the fundamental nature of its regulatory chromatin environment, how it is established and how it is then maintained. Oncogenic transcription factors play an important role in tumourigenesis and these proteins act to change the chromatin environment and control gene expression through binding to promoter and enhancer elements. Several potential oncogenic transcription factors have been identified in OAC (Stachler et al., 20015; Wiseman et al., 2015). In the context of cancer, a subclass of enhancer elements known as “super enhancers” appears to be particularly important and attractive targets for therapeutic intervention (Loven et al., 2013). This class of enhancer represents a cluster of active regulatory non-coding genomic regions that are associated with a single locus.

In this project we will investigate how these super enhancers are created, maintained and function in oesophageal cancer cells. In this context, we will also study the role of non-coding RNAs (LincRNAs and eRNAs) and how they contribute to enhancer function. The project will provide training in a wide range of molecular, cell biology and biochemical skills. In addition, genome-wide approach such as RNA-seq, ChIP-seq and ATAC-seq will be used in conjunction with bioinformatics analysis. Importantly, the project will also have clinical focus with work on patient-derived biopsies and experiments designed to test the therapeutic potential of targeting super enhancers in OAC.

http://sharrocks.lab.ls.manchester.ac.uk/