Epigenomic profiling of primary gastric adenocarcinoma reveals super-enhancer heterogeneity

Wen Fong Ooi, Manjie Xing, Chang Xu, Xiaosai Yao, Muhammad Khairul Ramlee, Mei Chee Lim, Fan Cao, Kevin Lim, Deepak Babu, Lai-Fong Poon, Joyce Lin Suling, Aditi Qamra, Astrid Irwanto, James Qu Zhengzhong, Tannistha Nandi, Ai Ping Lee-Lim, Yang Sun Chan, Su Ting Tay, Ming Hui Lee, James O. J. Davies, Wai Keong Wong, Khee Chee Soo, Weng Hoong Chan, Hock Soo Ong, Pierce Chow, Chow Yin Wong, Sun Young Rha, Jianjun Liu, Axel M. Hillmer, Jim R. Hughes, Steve Rozen, Bin Tean Teh, Melissa Jane Fullwood, Shang Li and Patrick Tan ()
Additional contact information
Wen Fong Ooi: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore
Manjie Xing: Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School
Chang Xu: Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School
Xiaosai Yao: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore
Muhammad Khairul Ramlee: Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School
Mei Chee Lim: Cancer Science Institute of Singapore, National University of Singapore
Fan Cao: Cancer Science Institute of Singapore, National University of Singapore
Kevin Lim: Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School
Deepak Babu: Cancer Science Institute of Singapore, National University of Singapore
Lai-Fong Poon: Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School
Joyce Lin Suling: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore
Aditi Qamra: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore
Astrid Irwanto: Genome Institute of Singapore
James Qu Zhengzhong: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore
Tannistha Nandi: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore
Ai Ping Lee-Lim: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore
Yang Sun Chan: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore
Su Ting Tay: Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School
Ming Hui Lee: Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School
James O. J. Davies: Medical Research Council (MRC) Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford University
Wai Keong Wong: Singapore General Hospital
Khee Chee Soo: National Cancer Centre Singapore
Weng Hoong Chan: Singapore General Hospital
Hock Soo Ong: Singapore General Hospital
Pierce Chow: National Cancer Centre Singapore
Chow Yin Wong: Singapore General Hospital
Sun Young Rha: Yonsei University College of Medicine
Jianjun Liu: Genome Institute of Singapore
Axel M. Hillmer: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore
Jim R. Hughes: Medical Research Council (MRC) Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford University
Steve Rozen: Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School
Bin Tean Teh: Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School
Melissa Jane Fullwood: Cancer Science Institute of Singapore, National University of Singapore
Shang Li: Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School
Patrick Tan: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore

Nature Communications, 2016, vol. 7, issue 1, 1-17

Abstract: Abstract Regulatory enhancer elements in solid tumours remain poorly characterized. Here we apply micro-scale chromatin profiling to survey the distal enhancer landscape of primary gastric adenocarcinoma (GC), a leading cause of global cancer mortality. Integrating 110 epigenomic profiles from primary GCs, normal gastric tissues and cell lines, we highlight 36,973 predicted enhancers and 3,759 predicted super-enhancers respectively. Cell-line-defined super-enhancers can be subclassified by their somatic alteration status into somatic gain, loss and unaltered categories, each displaying distinct epigenetic, transcriptional and pathway enrichments. Somatic gain super-enhancers are associated with complex chromatin interaction profiles, expression patterns correlated with patient outcome and dense co-occupancy of the transcription factors CDX2 and HNF4α. Somatic super-enhancers are also enriched in genetic risk SNPs associated with cancer predisposition. Our results reveal a genome-wide reprogramming of the GC enhancer and super-enhancer landscape during tumorigenesis, contributing to dysregulated local and regional cancer gene expression.

Date: 2016
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DOI: 10.1038/ncomms12983

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