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Understanding the regulatory chromatin landscape of oesophageal adenocarcinoma
[Thesis]. Manchester, UK: The University of Manchester; 2020.
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Abstract
Oesophageal adenocarcinoma (OAC) is one of the most frequent causes of cancer deaths and yet compared to other common cancers, we know relatively little about the molecular composition of this tumour type. Developmentally, OAC progresses from its precancerous precursor, Barrett's oesophagus (BO). To further our understanding of this cancer we have used open chromatin profiling (ATAC-seq) of normal oesophagus, Barrett's oesophagus and OAC human tissue, and integrated ChIP-seq and RNA-seq of cell-lines to decipher the transcriptional regulatory networks that are operational during OAC development. First by analysing the open chromatin profiles of normal and OAC tissue, we have uncovered an active transcription factor network, which is usually found in primitive intestinal cells during embryonic development, centred on HNF4A and GATA6. By exploring BO ATAC-seq data, we show that this transcription factor network is activated in BO. We also show that HNF4A alone is sufficient to drive chromatin opening and activate a BO-like chromatin signature in normal human oesophageal cells. Second, by focussing on RNA-seq of BO and OAC tissue, we have also identified activation of a cell cycle gene signature during progression from BO to OAC. By integrating ATAC-seq of BO and OAC, we have implicated KLF5 in activating this cell cycle signature. KLF5 binds to cell cycle associated genes specifically in OAC, and patients with high expression of KLF5 target genes have a worse prognosis that those that do not. This thesis has provided a molecular timeline of activation and function of transcription factors, and their target genes, involved in the development of BO and OAC and provided new targets for biomarkers and therapeutics.
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Keyword(s)
ATAC-seq; Barrett's oesophagus; GATA6; HNF4A; KLF5; Oesophageal adenocarcinoma