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; Patrick Tan

doi:10.1038/ncomms12983

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. DaviesWai 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, Patrick Tan

Department of Internal Medicine

Research output: Contribution to journal › Article › peer-review

92 Citations (Scopus)

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.

Original language	English
Article number	12983
Journal	Nature communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms12983
Publication status	Published - 2016 Sept 28

Bibliographical note

Funding Information:
We thank the Sequencing and Scientific Computing teams at the Genome Institute of Singapore for sequencing services and data management capabilities, and the Duke-NUS Genome Biology Facility for sequencing services. We also thank Ioana Cutcutache, Huang Kie Kyon, Longyu Hu, Niantao Deng, Simeen Malik and Nisha Padmanabhan for helpful discussions. This work was supported by core funding from the Genome Institute of Singapore under the Agency for Science, Technology and Research, Biomedical Research Council Young Investigator Grant 1510851024, National Medical Research Council grants TCR/009-NUHS/2013 and NMRC/STaR/0026/2015, Ministry of Education Academic Research Fund (AcRF) Tier 2 (MOE2014-T2-1-138), and by the National Research Foundation Singapore through an NRF Fellowship awarded to M.J.F (NRF-NRFF2012-054). J.R.H. was supported by a Wellcome Trust Strategic Award (reference 106130/Z/14/Z) and Medical Research Council (MRC) Core funding. J.O.J.D. was funded byWellcome Trust Clinical Research Training Fellowship ref 098931/Z/12/Z. Other sources of support include the RNA Biology Center at the Cancer Science Institute of Singapore, NUS, as part of funding under the Singapore Ministry of Education Academic Research Fund Tier 3, and by the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiative.

Publisher Copyright:
© 2016 The Author(s).

All Science Journal Classification (ASJC) codes

Physics and Astronomy(all)
Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)

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Ooi, W. F., Xing, M., Xu, C., Yao, X., Ramlee, M. K., Lim, M. C., Cao, F., Lim, K., Babu, D., Poon, L. F., Lin Suling, J., Qamra, A., Irwanto, A., Qu Zhengzhong, J., Nandi, T., Lee-Lim, A. P., Chan, Y. S., Tay, S. T., Lee, M. H., ... Tan, P. (2016). Epigenomic profiling of primary gastric adenocarcinoma reveals super-enhancer heterogeneity. Nature communications, 7, Article 12983. https://doi.org/10.1038/ncomms12983

@article{3d43cdd6326442aa9891fd49f549732e,

title = "Epigenomic profiling of primary gastric adenocarcinoma reveals super-enhancer heterogeneity",

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.",

author = "Ooi, {Wen Fong} and Manjie Xing and Chang Xu and Xiaosai Yao and Ramlee, {Muhammad Khairul} and Lim, {Mei Chee} and Fan Cao and Kevin Lim and Deepak Babu and Poon, {Lai Fong} and {Lin Suling}, Joyce and Aditi Qamra and Astrid Irwanto and {Qu Zhengzhong}, James and Tannistha Nandi and Lee-Lim, {Ai Ping} and Chan, {Yang Sun} and Tay, {Su Ting} and Lee, {Ming Hui} and Davies, {James O.J.} and Wong, {Wai Keong} and Soo, {Khee Chee} and Chan, {Weng Hoong} and Ong, {Hock Soo} and Pierce Chow and Wong, {Chow Yin} and Rha, {Sun Young} and Jianjun Liu and Hillmer, {Axel M.} and Hughes, {Jim R.} and Steve Rozen and Teh, {Bin Tean} and Fullwood, {Melissa Jane} and Shang Li and Patrick Tan",

note = "Funding Information: We thank the Sequencing and Scientific Computing teams at the Genome Institute of Singapore for sequencing services and data management capabilities, and the Duke-NUS Genome Biology Facility for sequencing services. We also thank Ioana Cutcutache, Huang Kie Kyon, Longyu Hu, Niantao Deng, Simeen Malik and Nisha Padmanabhan for helpful discussions. This work was supported by core funding from the Genome Institute of Singapore under the Agency for Science, Technology and Research, Biomedical Research Council Young Investigator Grant 1510851024, National Medical Research Council grants TCR/009-NUHS/2013 and NMRC/STaR/0026/2015, Ministry of Education Academic Research Fund (AcRF) Tier 2 (MOE2014-T2-1-138), and by the National Research Foundation Singapore through an NRF Fellowship awarded to M.J.F (NRF-NRFF2012-054). J.R.H. was supported by a Wellcome Trust Strategic Award (reference 106130/Z/14/Z) and Medical Research Council (MRC) Core funding. J.O.J.D. was funded byWellcome Trust Clinical Research Training Fellowship ref 098931/Z/12/Z. Other sources of support include the RNA Biology Center at the Cancer Science Institute of Singapore, NUS, as part of funding under the Singapore Ministry of Education Academic Research Fund Tier 3, and by the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiative. Publisher Copyright: {\textcopyright} 2016 The Author(s).",

year = "2016",

month = sep,

day = "28",

doi = "10.1038/ncomms12983",

language = "English",

volume = "7",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

Ooi, WF, Xing, M, Xu, C, Yao, X, Ramlee, MK, Lim, MC, Cao, F, Lim, K, Babu, D, Poon, LF, Lin Suling, J, Qamra, A, Irwanto, A, Qu Zhengzhong, J, Nandi, T, Lee-Lim, AP, Chan, YS, Tay, ST, Lee, MH, Davies, JOJ, Wong, WK, Soo, KC, Chan, WH, Ong, HS, Chow, P, Wong, CY, Rha, SY, Liu, J, Hillmer, AM, Hughes, JR, Rozen, S, Teh, BT, Fullwood, MJ, Li, S & Tan, P 2016, 'Epigenomic profiling of primary gastric adenocarcinoma reveals super-enhancer heterogeneity', Nature communications, vol. 7, 12983. https://doi.org/10.1038/ncomms12983

TY - JOUR

T1 - Epigenomic profiling of primary gastric adenocarcinoma reveals super-enhancer heterogeneity

AU - Ooi, Wen Fong

AU - Xing, Manjie

AU - Xu, Chang

AU - Yao, Xiaosai

AU - Ramlee, Muhammad Khairul

AU - Lim, Mei Chee

AU - Cao, Fan

AU - Lim, Kevin

AU - Babu, Deepak

AU - Poon, Lai Fong

AU - Lin Suling, Joyce

AU - Qamra, Aditi

AU - Irwanto, Astrid

AU - Qu Zhengzhong, James

AU - Nandi, Tannistha

AU - Lee-Lim, Ai Ping

AU - Chan, Yang Sun

AU - Tay, Su Ting

AU - Lee, Ming Hui

AU - Davies, James O.J.

AU - Wong, Wai Keong

AU - Soo, Khee Chee

AU - Chan, Weng Hoong

AU - Ong, Hock Soo

AU - Chow, Pierce

AU - Wong, Chow Yin

AU - Rha, Sun Young

AU - Liu, Jianjun

AU - Hillmer, Axel M.

AU - Hughes, Jim R.

AU - Rozen, Steve

AU - Teh, Bin Tean

AU - Fullwood, Melissa Jane

AU - Li, Shang

AU - Tan, Patrick

N1 - Funding Information: We thank the Sequencing and Scientific Computing teams at the Genome Institute of Singapore for sequencing services and data management capabilities, and the Duke-NUS Genome Biology Facility for sequencing services. We also thank Ioana Cutcutache, Huang Kie Kyon, Longyu Hu, Niantao Deng, Simeen Malik and Nisha Padmanabhan for helpful discussions. This work was supported by core funding from the Genome Institute of Singapore under the Agency for Science, Technology and Research, Biomedical Research Council Young Investigator Grant 1510851024, National Medical Research Council grants TCR/009-NUHS/2013 and NMRC/STaR/0026/2015, Ministry of Education Academic Research Fund (AcRF) Tier 2 (MOE2014-T2-1-138), and by the National Research Foundation Singapore through an NRF Fellowship awarded to M.J.F (NRF-NRFF2012-054). J.R.H. was supported by a Wellcome Trust Strategic Award (reference 106130/Z/14/Z) and Medical Research Council (MRC) Core funding. J.O.J.D. was funded byWellcome Trust Clinical Research Training Fellowship ref 098931/Z/12/Z. Other sources of support include the RNA Biology Center at the Cancer Science Institute of Singapore, NUS, as part of funding under the Singapore Ministry of Education Academic Research Fund Tier 3, and by the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiative. Publisher Copyright: © 2016 The Author(s).

PY - 2016/9/28

Y1 - 2016/9/28

N2 - 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.

AB - 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.

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UR - http://www.scopus.com/inward/citedby.url?scp=84989246398&partnerID=8YFLogxK

U2 - 10.1038/ncomms12983

DO - 10.1038/ncomms12983

M3 - Article

AN - SCOPUS:84989246398

SN - 2041-1723

VL - 7

JO - Nature communications

JF - Nature communications

M1 - 12983

ER -

Epigenomic profiling of primary gastric adenocarcinoma reveals super-enhancer heterogeneity

Abstract

Bibliographical note

All Science Journal Classification (ASJC) codes

UN SDGs

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