eRNA profiling uncovers the enhancer landscape of oesophageal adenocarcinoma and reveals new deregulated pathways

Abstract

Cancer is driven by both genetic and epigenetic changes that impact on gene expression profiles and the resulting tumourigenic phenotype. Enhancers are transcriptional regulatory elements that are key to our understanding of how this rewiring of gene expression is achieved in cancer cells. Here we have harnessed the power of RNA-seq data from hundreds of patients with oesophageal adenocarcinoma (OAC) or its precursor state Barrett's oesophagus (BO) coupled with open chromatin maps to identify potential enhancer RNAs (eRNAs) and their associated enhancer regions in this cancer. We identify ~1000 OAC-specific enhancers and use this data to uncover new cellular pathways that are operational in OAC. Among these are enhancers for JUP, MYBL2 and CCNE1, and we show that their activity is required for cancer cell viability. We also demonstrate the clinical utility of our dataset for identifying disease stage and patient prognosis. Our data therefore identify an important set of regulatory elements that enhance our molecular understanding of OAC and point to potential new therapeutic directions.

Data availability

All data have been deposited at ArrayExpress; OE19 KAS-seq and CUT&TAG data (E-MTAB-11357 and E-MTAB-11356, respectively) and OE19 HiC data (E-MTAB-12664).

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

Article and author information

Author details

  1. Ibrahim Ahmed

    Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7424-6658
  2. Shen-Hsi Yang

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

    Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0217-881X
  4. Wei Zhang

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

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

  7. 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

Medical Research Council (MR/V010263/1)

  • Samuel Ogden

Wellcome Trust (102171/B/13/Z)

  • Ibrahim Ahmed

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2023, Ahmed 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.

Metrics

  • 2,232
    views
  • 273
    downloads
  • 9
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Ibrahim Ahmed
  2. Shen-Hsi Yang
  3. Samuel Ogden
  4. Wei Zhang
  5. Yaoyong Li
  6. The OCCAMS Consortium
  7. Andrew D Sharrocks
(2023)
eRNA profiling uncovers the enhancer landscape of oesophageal adenocarcinoma and reveals new deregulated pathways
eLife 12:e80840.
https://doi.org/10.7554/eLife.80840

Share this article

https://doi.org/10.7554/eLife.80840

Further reading

    1. Cancer Biology
    Qianqian Ju, Wenjing Sheng ... Cheng Sun
    Research Article

    TAK1 is a serine/threonine protein kinase that is a key regulator in a wide variety of cellular processes. However, the functions and mechanisms involved in cancer metastasis are still not well understood. Here, we found that TAK1 knockdown promoted esophageal squamous cancer carcinoma (ESCC) migration and invasion, whereas TAK1 overexpression resulted in the opposite outcome. These in vitro findings were recapitulated in vivo in a xenograft metastatic mouse model. Mechanistically, co-immunoprecipitation and mass spectrometry demonstrated that TAK1 interacted with phospholipase C epsilon 1 (PLCE1) and phosphorylated PLCE1 at serine 1060 (S1060). Functional studies revealed that phosphorylation at S1060 in PLCE1 resulted in decreased enzyme activity, leading to the repression of phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis. As a result, the degradation products of PIP2 including diacylglycerol (DAG) and inositol IP3 were reduced, which thereby suppressed signal transduction in the axis of PKC/GSK-3β/β-Catenin. Consequently, expression of cancer metastasis-related genes was impeded by TAK1. Overall, our data indicate that TAK1 plays a negative role in ESCC metastasis, which depends on the TAK1-induced phosphorylation of PLCE1 at S1060.

    1. Cancer Biology
    2. Cell Biology
    Rui Hua, Jean X Jiang
    Insight

    Cell crowding causes high-grade breast cancer cells to become more invasive by activating a molecular switch that causes the cells to shrink and spread.