Identification of a primitive intestinal transcription factor network shared between esophageal adenocarcinoma and its precancerous precursor state
- Connor Rogerson1,
- Edward Britton1,
- Sarah Withey2,
- Neil Hanley2,3,
- Yeng S. Ang2,4 and
- Andrew D. Sharrocks1
- 1School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, United Kingdom;
- 2School of Medical Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Sciences Centre, University of Manchester, Manchester M13 9PT, United Kingdom;
- 3Endocrinology Department, Central Manchester University Hospitals NHS Foundation Trust, Manchester M13 9WU, United Kingdom;
- 4GI Science Centre, Salford Royal NHS FT, University of Manchester, Salford M6 8HD, United Kingdom
Abstract
Esophageal adenocarcinoma (EAC) is one of the most frequent causes of cancer death, and yet compared to other common cancers, we know relatively little about the molecular composition of this tumor type. To further our understanding of this cancer, we have used open chromatin profiling to decipher the transcriptional regulatory networks that are operational in EAC. We have uncovered a transcription factor network that is usually found in primitive intestinal cells during embryonic development, centered on HNF4A and GATA6. These transcription factors work together to control the EAC transcriptome. We show that this network is activated in Barrett's esophagus, the putative precursor state to EAC, thereby providing novel molecular evidence in support of stepwise malignant transition. Furthermore, we show that HNF4A alone is sufficient to drive chromatin opening and activation of a Barrett's-like chromatin signature when expressed in normal human epithelial cells. Collectively, these data provide a new way to categorize EAC at a genome scale and implicate HNF4A activation as a potential pivotal event in its malignant transition from healthy cells.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.243345.118.
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Freely available online through the Genome Research Open Access option.
- Received August 29, 2018.
- Accepted April 3, 2019.
This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
