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

Abstract
Data availability
Article and author information
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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

1. Ahmed I
2. Yang SH
3. Ogden S
4. Zhang W
5. Li Y
6. OCCAMS Consortium
7. Sharrocks AD
(2022) KAS-seq in OE19 cells
EBI ArrayExpress, E-MTAB-11357.

https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-11357
1. Ahmed I
2. Yang SH
3. Ogden S
4. Zhang W
5. Li Y
6. OCCAMS Consortium
7. Sharrocks AD
(2022) CUT&TAG of OE19 cell line
EBI ArrayExpress, E-MTAB-11356.

https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-11356
1. Ahmed I
2. Yang SH
3. Ogden S
4. Zhang W
5. Li Y
6. OCCAMS Consortium
7. Sharrocks AD
(2023) HiC data in OE19 cells
EBI ArrayExpress, E-MTAB-12664.

http://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-12664

The following previously published data sets were used

(2021) Sequencing data for oesophageal and related samples - Ogden et al release
European Genome Phenome Archive, EGAD00001007496.

https://ega-archive.org/datasets/EGAD00001007496
1. Britton
2. E
3. Rogerson
4. C
5. Mehta
6. S
7. Li
8. Y
9. Li
10. X
11. Fitzgerald
12. RC
13. Ang
14. YS
15. and Sharrocks
16. AD
(2017) ATAC-seq of oesophageal cell lines and tissue samples
EBI ArrayExpress, E-MTAB-5169.

https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-5169
1. Rogerson
2. C.
3. Britton
4. E.
5. Withey
6. S.
7. Hanley
8. N.
9. Ang
10. Y.S.
11. and Sharrocks
12. A.D
(2019) ATAC-seq of human Barrett's oesophagus tissue
EBI ArrayExpress, E-MTAB-6751.

https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-6751
1. Rogerson
2. C
3. Britton
4. E
5. Withey
6. S
7. Hanley
8. N
9. Ang
10. YS
11. and Sharrocks
12. AD
(2020) ATAC-seq of oesophageal adenocarcinoma patient samples
EBI ArrayExpress, E-MTAB-8447.

https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-8447
1. Corces MR
2. Granja JM
3. Shams S
4. Louie BH
5. Seoane JA
6. Zhou W
7. Silva TC
8. Groeneveld C
9. Wong CK
10. Cho SW
11. Satpathy AT
12. Mumbach MR
13. Hoadley KA
14. Robertson AG
15. Sheffield NC
16. Felau I
17. Castro MAA
18. Berman BP
19. Staudt LM
20. Zenklusen JC
21. Laird PW
22. Curtis C; Cancer Genome Atlas Analysis Network
23. Greenleaf WJ
24. and Chang
25. H.Y
(2018) TCGA-generated ATAC-seq of oesophageal adenocarcinoma patient samples
NIH GDC, ATAC-AWG.

https://gdc.cancer.gov/about-data/publications/ATACseq-AWG
1. Ogden
2. S
3. Carys
4. K
5. Bruce
6. J
7. The OCCAMS Consortium
8. and Sharrocks
9. AD
(2021) ChIP-seq of H3K27Ac in oesophageal adenocarcinoma OE19 cells
EBI ArrayExpress, E-MTAB-10319.

https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-10319
1. Ooi WF
2. Xing M
3. Xu C
4. Yao X
5. Ramlee MK
6. Lim MC
7. Cao F
8. Lim K
9. Babu D
10. Poon LF
11. Lin Suling J
12. Qamra A
13. Irwanto A
14. Qu Zhengzhong J
15. Nandi T
16. Lee-Lim AP
17. Chan YS
18. Tay ST
19. Lee MH
20. Davies JO
21. Wong WK
22. Soo KC
23. Chan WH
24. Ong HS
25. Chow P
26. Wong CY
27. Rha SY
28. Liu J
29. Hillmer AM
30. Hughes JR
31. Rozen S
32. Teh BT
33. Fullwood MJ
34. Li S
35. Tan P
(2016) Somatic Promoter Landscape of Primary Gastric Adenocarcinoma Delineated by Epigenomic Profiling
Gene Expression Omnibus, GSE75898.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE75898
1. Rogerson
2. C
3. Ogden
4. S
5. Britton
6. E
7. OCCAMS Consortium
8. Ang
9. YS
10. and Sharrocks
11. AD
(2020) ATAC-seq of oesophageal adenocarcinoma patient samples
EBI ArrayExpress, E-MTAB-8447.

https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-8447
1. Rogerson
2. C
3. Ogden
4. S
5. Britton
6. E
7. OCCAMS Consortium
8. Ang
9. YS
10. and Sharrocks
11. AD
(2020) RNA-seq of OE19 cells treated with siNT or siKLF5 for 72 hours
EBI ArrayExpress, E-MTAB-8568.

https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-8447
1. Rogerson
2. C
3. Ogden
4. S
5. Britton
6. E
7. OCCAMS Consortium
8. Ang
9. YS
10. and Sharrocks
11. AD
(2020) KLF5 ChIP-seq in CP-A and OE19 cells
EBI ArrayExpress, E-MTAB-8568.

https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-8568
1. Ogden
2. S
3. Ahmed
4. I
5. Yang
6. S-H
7. Fullwood
8. P
9. The OCCAMS Consortium
10. Francavilla
11. C
12. and Sharrocks
13. AD
(2023) OE19 dnFOS RNA-seq
EBI ArrayExpress, E-MTAB-10334.

https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-10334

Article and author information

Author details

Ibrahim Ahmed

Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-7424-6658
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.
Samuel Ogden

Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-0217-881X
Wei Zhang

Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Yaoyong Li

Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom

Competing interests
The authors declare that no competing interests exist.
The OCCAMS Consortium
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.

"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

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.