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Repurposing of KLF5 activates a cell cycle signature during the progression from a precursor state to Oesophageal Adenocarcinoma

  1. Connor Rogerson
  2. Samuel Ogden
  3. Edward Britton
  4. the OCCAMS consortium
  5. Yeng Ang  Is a corresponding author
  6. Andrew D Sharrocks  Is a corresponding author
  1. University of Cambridge, United Kingdom
  2. University of Manchester, United Kingdom
Research Article
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Cite this article as: eLife 2020;9:e57189 doi: 10.7554/eLife.57189

Abstract

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.

Data availability

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 following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Connor Rogerson

    Hutchison/MRC Research Centre, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1425-9668

  2. Samuel Ogden

    Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  3. Edward Britton

    Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  4. the OCCAMS consortium

  5. Yeng Ang

    School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
    For correspondence
    Yeng.Ang@srft.nhs.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0496-6710

  6. Andrew D Sharrocks

    Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
    For correspondence
    andrew.d.sharrocks@manchester.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7395-9552

Funding

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.

Ethics

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.

Reviewing Editor

  1. Irwin Davidson, Institut de Génétique et de Biologie Moléculaire et Cellulaire, France

Publication history

  1. Received: March 24, 2020
  2. Accepted: September 3, 2020
  3. Accepted Manuscript published: September 3, 2020 (version 1)
  4. Version of Record published: October 8, 2020 (version 2)

Copyright

© 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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