Repurposing of KLF5 activates a cell cycle signature during the progression from a precursor state to Oesophageal Adenocarcinoma
Oesophageal adenocarcinoma (OAC) is one of the most common causes of cancer deaths. Barrett's oesophagus (BO) is the only known precancerous precursor to OAC, but our understanding about the molecular events leading to OAC development is limited. Here, we have integrated gene expression and chromatin accessibility profiles of human biopsies and identified a strong cell cycle gene expression signature in OAC compared to BO. Through analysing associated chromatin accessibility changes, we have implicated the transcription factor KLF5 in the transition from BO to OAC. Importantly, we show that KLF5 expression is unchanged during this transition, but instead, KLF5 is redistributed across chromatin to directly regulate cell cycle genes specifically in OAC cells. This new KLF5 target gene programme has potential prognostic significance as high levels correlate with poorer patient survival. Thus, the repurposing of KLF5 for novel regulatory activity in OAC provides new insights into the mechanisms behind disease progression.
All sequencing data are deposited in ArrayExpress. Additional OAC ATAC-seq data are available at E-MTAB-8447 and additional BO and OAC RNA-seq data are available at E-MTAB-8584. siKLF5 RNA-seq data are available at E-MTAB-8446. KLF5 ChIP-seq data are available at E-MTAB-8568. siERBB2 ATAC-seq and RNA-seq data are available at E-MTAB-8576 and E-MTAB-8579 respectively.
The chromatin accessibility landscape of primary human cancersGDC Data Portal, TCGA-ESCA.
Article and author information
Cancer Research UK (Clinical PhD and PhD funding)
- Connor Rogerson
- Edward Britton
- Yeng Ang
- Andrew D Sharrocks
Wellcome (Programme grant and studentship103857/Z/14/Z)
- Samuel Ogden
- Andrew D Sharrocks
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Human subjects: Ethical approval was via the ethics committee of Salford Royal NHS Foundation Trust (04/Q1410/57). Patient consent was obtained in written form and signed by the patient and doctor.
- Irwin Davidson, Institut de Génétique et de Biologie Moléculaire et Cellulaire, France
- Received: March 24, 2020
- Accepted: September 3, 2020
- Accepted Manuscript published: September 3, 2020 (version 1)
- Version of Record published: October 8, 2020 (version 2)
© 2020, Rogerson et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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