Master transcription factors form interconnected circuitry and orchestrate transcriptional networks in oesophageal adenocarcinoma

Li Chen; Moli Huang; Jasmine Plummer; Jian Pan; Yan Yi Jiang; Qian Yang; Tiago Chedraoui Silva; Nicole Gull; Stephanie Chen; Ling Wen Ding; Omer An; Henry Yang; Yulan Cheng; Jonathan W. Said; Ngan Doan; Winand N.M. Dinjens; Kevin M. Waters; Richard Tuli; Simon A. Gayther; Samuel J. Klempner; Benjamin P. Berman; Stephen J. Meltzer; De Chen Lin; H. Phillip Koeffler

doi:10.1136/gutjnl-2019-318325

Master transcription factors form interconnected circuitry and orchestrate transcriptional networks in oesophageal adenocarcinoma

Li Chen^*, Moli Huang, Jasmine Plummer, Jian Pan, Yan Yi Jiang, Qian Yang, Tiago Chedraoui Silva, Nicole Gull, Stephanie Chen, Ling Wen Ding, Omer An, Henry Yang, Yulan Cheng, Jonathan W. Said, Ngan Doan, Winand N.M. Dinjens, Kevin M. Waters, Richard Tuli, Simon A. Gayther, Samuel J. KlempnerBenjamin P. Berman, Stephen J. Meltzer, De Chen Lin, H. Phillip Koeffler

^*Corresponding author for this work

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

47 Scopus citations

Abstract

Objective While oesophageal squamous cell carcinoma remains infrequent in Western populations, the incidence of oesophageal adenocarcinoma (EAC) has increased sixfold to eightfold over the past four decades. We aimed to characterise oesophageal cancer-specific and subtypes-specific gene regulation patterns and their upstream transcription factors (TFs). Design To identify regulatory elements, we profiled fresh-frozen oesophageal normal samples, tumours and cell lines with chromatin immunoprecipitation sequencing (ChIP-Seq). Mathematical modelling was performed to establish (super)-enhancers landscapes and interconnected transcriptional circuitry formed by master TFs. Coregulation and cooperation between master TFs were investigated by ChIP-Seq, circularised chromosome conformation capture sequencing and luciferase assay. Biological functions of candidate factors were evaluated both in vitro and in vivo. Results We found widespread and pervasive alterations of the (super)-enhancer reservoir in both subtypes of oesophageal cancer, leading to transcriptional activation of a myriad of novel oncogenes and signalling pathways, some of which may be exploited pharmacologically (eg, leukemia inhibitory factor (LIF) pathway). Focusing on EAC, we bioinformatically reconstructed and functionally validated an interconnected circuitry formed by four master TFs-ELF3, KLF5, GATA6 and EHF-which promoted each other's expression by interacting with each super-enhancer. Downstream, these master TFs occupied almost all EAC super-enhancers and cooperatively orchestrated EAC transcriptome. Each TF within the transcriptional circuitry was highly and specifically expressed in EAC and functionally promoted EAC cell proliferation and survival. Conclusions By establishing cancer-specific and subtype-specific features of the EAC epigenome, our findings promise to transform understanding of the transcriptional dysregulation and addiction of EAC, while providing molecular clues to develop novel therapeutic modalities against this malignancy.

Original language	American English
Pages (from-to)	630-640
Number of pages	11
Journal	Gut
Volume	69
Issue number	4
DOIs	https://doi.org/10.1136/gutjnl-2019-318325
State	Published - 1 Apr 2020
Externally published	Yes

Bibliographical note

Funding Information:
Funding This research is supported by the national research Foundation singapore under its singapore Translational research (sTar) investigator award (nMrc/sTar/0021/2014) and administered by the singapore Ministry of health’s national Medical research council (nMrc), the nMrc centre grant awarded to national University cancer institute of singapore, the national research Foundation singapore and the singapore Ministry of education under its research centres of excellence initiatives (to hPK). This research is additionally supported by the rna Biology center at the cancer science institute of singapore, nUs, as part of funding under the singapore Ministry of education’s Tier 3 grants (grant number MOe2014-T3-1-006). sJM is supported by the emerson research Foundation and nih grants DK118250, ca190040 and ca211457; he is also the harry and Betty Myerberg Professor and american cancer society clinical research Professor. D-cl is supported by the Degregorio Family Foundation, the Price Family Foundation as well as samuel Oschin comprehensive cancer institute (sOcci) at cedars-sinai Medical center through the Translational Pipeline Discovery Fund; he is member of Ucla Jonsson comprehensive cancer center, Ucla Molecular Biology institute as well as Ucla cure: Digestive Diseases research center. sJK is supported by the howard h hall fund for oesophageal cancer research.

Publisher Copyright:
© 2020 Author(s).

Keywords

gene regulation
oesophageal cancer
signal transduction
transcription factor

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1136/gutjnl-2019-318325

Cite this

Chen, L., Huang, M., Plummer, J., Pan, J., Jiang, Y. Y., Yang, Q., Silva, T. C., Gull, N., Chen, S., Ding, L. W., An, O., Yang, H., Cheng, Y., Said, J. W., Doan, N., Dinjens, W. N. M., Waters, K. M., Tuli, R., Gayther, S. A., ... Koeffler, H. P. (2020). Master transcription factors form interconnected circuitry and orchestrate transcriptional networks in oesophageal adenocarcinoma. Gut, 69(4), 630-640. https://doi.org/10.1136/gutjnl-2019-318325

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title = "Master transcription factors form interconnected circuitry and orchestrate transcriptional networks in oesophageal adenocarcinoma",

abstract = "Objective While oesophageal squamous cell carcinoma remains infrequent in Western populations, the incidence of oesophageal adenocarcinoma (EAC) has increased sixfold to eightfold over the past four decades. We aimed to characterise oesophageal cancer-specific and subtypes-specific gene regulation patterns and their upstream transcription factors (TFs). Design To identify regulatory elements, we profiled fresh-frozen oesophageal normal samples, tumours and cell lines with chromatin immunoprecipitation sequencing (ChIP-Seq). Mathematical modelling was performed to establish (super)-enhancers landscapes and interconnected transcriptional circuitry formed by master TFs. Coregulation and cooperation between master TFs were investigated by ChIP-Seq, circularised chromosome conformation capture sequencing and luciferase assay. Biological functions of candidate factors were evaluated both in vitro and in vivo. Results We found widespread and pervasive alterations of the (super)-enhancer reservoir in both subtypes of oesophageal cancer, leading to transcriptional activation of a myriad of novel oncogenes and signalling pathways, some of which may be exploited pharmacologically (eg, leukemia inhibitory factor (LIF) pathway). Focusing on EAC, we bioinformatically reconstructed and functionally validated an interconnected circuitry formed by four master TFs-ELF3, KLF5, GATA6 and EHF-which promoted each other's expression by interacting with each super-enhancer. Downstream, these master TFs occupied almost all EAC super-enhancers and cooperatively orchestrated EAC transcriptome. Each TF within the transcriptional circuitry was highly and specifically expressed in EAC and functionally promoted EAC cell proliferation and survival. Conclusions By establishing cancer-specific and subtype-specific features of the EAC epigenome, our findings promise to transform understanding of the transcriptional dysregulation and addiction of EAC, while providing molecular clues to develop novel therapeutic modalities against this malignancy.",

keywords = "gene regulation, oesophageal cancer, signal transduction, transcription factor",

author = "Li Chen and Moli Huang and Jasmine Plummer and Jian Pan and Jiang, {Yan Yi} and Qian Yang and Silva, {Tiago Chedraoui} and Nicole Gull and Stephanie Chen and Ding, {Ling Wen} and Omer An and Henry Yang and Yulan Cheng and Said, {Jonathan W.} and Ngan Doan and Dinjens, {Winand N.M.} and Waters, {Kevin M.} and Richard Tuli and Gayther, {Simon A.} and Klempner, {Samuel J.} and Berman, {Benjamin P.} and Meltzer, {Stephen J.} and Lin, {De Chen} and Koeffler, {H. Phillip}",

note = "Funding Information: Funding This research is supported by the national research Foundation singapore under its singapore Translational research (sTar) investigator award (nMrc/sTar/0021/2014) and administered by the singapore Ministry of health{\textquoteright}s national Medical research council (nMrc), the nMrc centre grant awarded to national University cancer institute of singapore, the national research Foundation singapore and the singapore Ministry of education under its research centres of excellence initiatives (to hPK). This research is additionally supported by the rna Biology center at the cancer science institute of singapore, nUs, as part of funding under the singapore Ministry of education{\textquoteright}s Tier 3 grants (grant number MOe2014-T3-1-006). sJM is supported by the emerson research Foundation and nih grants DK118250, ca190040 and ca211457; he is also the harry and Betty Myerberg Professor and american cancer society clinical research Professor. D-cl is supported by the Degregorio Family Foundation, the Price Family Foundation as well as samuel Oschin comprehensive cancer institute (sOcci) at cedars-sinai Medical center through the Translational Pipeline Discovery Fund; he is member of Ucla Jonsson comprehensive cancer center, Ucla Molecular Biology institute as well as Ucla cure: Digestive Diseases research center. sJK is supported by the howard h hall fund for oesophageal cancer research. Publisher Copyright: {\textcopyright} 2020 Author(s).",

year = "2020",

month = apr,

day = "1",

doi = "10.1136/gutjnl-2019-318325",

language = "American English",

volume = "69",

pages = "630--640",

journal = "Gut",

issn = "0017-5749",

publisher = "BMJ Publishing Group",

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Chen, L, Huang, M, Plummer, J, Pan, J, Jiang, YY, Yang, Q, Silva, TC, Gull, N, Chen, S, Ding, LW, An, O, Yang, H, Cheng, Y, Said, JW, Doan, N, Dinjens, WNM, Waters, KM, Tuli, R, Gayther, SA, Klempner, SJ, Berman, BP, Meltzer, SJ, Lin, DC & Koeffler, HP 2020, 'Master transcription factors form interconnected circuitry and orchestrate transcriptional networks in oesophageal adenocarcinoma', Gut, vol. 69, no. 4, pp. 630-640. https://doi.org/10.1136/gutjnl-2019-318325

TY - JOUR

T1 - Master transcription factors form interconnected circuitry and orchestrate transcriptional networks in oesophageal adenocarcinoma

AU - Chen, Li

AU - Huang, Moli

AU - Plummer, Jasmine

AU - Pan, Jian

AU - Jiang, Yan Yi

AU - Yang, Qian

AU - Silva, Tiago Chedraoui

AU - Gull, Nicole

AU - Chen, Stephanie

AU - Ding, Ling Wen

AU - An, Omer

AU - Yang, Henry

AU - Cheng, Yulan

AU - Said, Jonathan W.

AU - Doan, Ngan

AU - Dinjens, Winand N.M.

AU - Waters, Kevin M.

AU - Tuli, Richard

AU - Gayther, Simon A.

AU - Klempner, Samuel J.

AU - Berman, Benjamin P.

AU - Meltzer, Stephen J.

AU - Lin, De Chen

AU - Koeffler, H. Phillip

N1 - Funding Information: Funding This research is supported by the national research Foundation singapore under its singapore Translational research (sTar) investigator award (nMrc/sTar/0021/2014) and administered by the singapore Ministry of health’s national Medical research council (nMrc), the nMrc centre grant awarded to national University cancer institute of singapore, the national research Foundation singapore and the singapore Ministry of education under its research centres of excellence initiatives (to hPK). This research is additionally supported by the rna Biology center at the cancer science institute of singapore, nUs, as part of funding under the singapore Ministry of education’s Tier 3 grants (grant number MOe2014-T3-1-006). sJM is supported by the emerson research Foundation and nih grants DK118250, ca190040 and ca211457; he is also the harry and Betty Myerberg Professor and american cancer society clinical research Professor. D-cl is supported by the Degregorio Family Foundation, the Price Family Foundation as well as samuel Oschin comprehensive cancer institute (sOcci) at cedars-sinai Medical center through the Translational Pipeline Discovery Fund; he is member of Ucla Jonsson comprehensive cancer center, Ucla Molecular Biology institute as well as Ucla cure: Digestive Diseases research center. sJK is supported by the howard h hall fund for oesophageal cancer research. Publisher Copyright: © 2020 Author(s).

PY - 2020/4/1

Y1 - 2020/4/1

N2 - Objective While oesophageal squamous cell carcinoma remains infrequent in Western populations, the incidence of oesophageal adenocarcinoma (EAC) has increased sixfold to eightfold over the past four decades. We aimed to characterise oesophageal cancer-specific and subtypes-specific gene regulation patterns and their upstream transcription factors (TFs). Design To identify regulatory elements, we profiled fresh-frozen oesophageal normal samples, tumours and cell lines with chromatin immunoprecipitation sequencing (ChIP-Seq). Mathematical modelling was performed to establish (super)-enhancers landscapes and interconnected transcriptional circuitry formed by master TFs. Coregulation and cooperation between master TFs were investigated by ChIP-Seq, circularised chromosome conformation capture sequencing and luciferase assay. Biological functions of candidate factors were evaluated both in vitro and in vivo. Results We found widespread and pervasive alterations of the (super)-enhancer reservoir in both subtypes of oesophageal cancer, leading to transcriptional activation of a myriad of novel oncogenes and signalling pathways, some of which may be exploited pharmacologically (eg, leukemia inhibitory factor (LIF) pathway). Focusing on EAC, we bioinformatically reconstructed and functionally validated an interconnected circuitry formed by four master TFs-ELF3, KLF5, GATA6 and EHF-which promoted each other's expression by interacting with each super-enhancer. Downstream, these master TFs occupied almost all EAC super-enhancers and cooperatively orchestrated EAC transcriptome. Each TF within the transcriptional circuitry was highly and specifically expressed in EAC and functionally promoted EAC cell proliferation and survival. Conclusions By establishing cancer-specific and subtype-specific features of the EAC epigenome, our findings promise to transform understanding of the transcriptional dysregulation and addiction of EAC, while providing molecular clues to develop novel therapeutic modalities against this malignancy.

AB - Objective While oesophageal squamous cell carcinoma remains infrequent in Western populations, the incidence of oesophageal adenocarcinoma (EAC) has increased sixfold to eightfold over the past four decades. We aimed to characterise oesophageal cancer-specific and subtypes-specific gene regulation patterns and their upstream transcription factors (TFs). Design To identify regulatory elements, we profiled fresh-frozen oesophageal normal samples, tumours and cell lines with chromatin immunoprecipitation sequencing (ChIP-Seq). Mathematical modelling was performed to establish (super)-enhancers landscapes and interconnected transcriptional circuitry formed by master TFs. Coregulation and cooperation between master TFs were investigated by ChIP-Seq, circularised chromosome conformation capture sequencing and luciferase assay. Biological functions of candidate factors were evaluated both in vitro and in vivo. Results We found widespread and pervasive alterations of the (super)-enhancer reservoir in both subtypes of oesophageal cancer, leading to transcriptional activation of a myriad of novel oncogenes and signalling pathways, some of which may be exploited pharmacologically (eg, leukemia inhibitory factor (LIF) pathway). Focusing on EAC, we bioinformatically reconstructed and functionally validated an interconnected circuitry formed by four master TFs-ELF3, KLF5, GATA6 and EHF-which promoted each other's expression by interacting with each super-enhancer. Downstream, these master TFs occupied almost all EAC super-enhancers and cooperatively orchestrated EAC transcriptome. Each TF within the transcriptional circuitry was highly and specifically expressed in EAC and functionally promoted EAC cell proliferation and survival. Conclusions By establishing cancer-specific and subtype-specific features of the EAC epigenome, our findings promise to transform understanding of the transcriptional dysregulation and addiction of EAC, while providing molecular clues to develop novel therapeutic modalities against this malignancy.

KW - gene regulation

KW - oesophageal cancer

KW - signal transduction

KW - transcription factor

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U2 - 10.1136/gutjnl-2019-318325

DO - 10.1136/gutjnl-2019-318325

M3 - Article

C2 - 31409603

AN - SCOPUS:85070773955

SN - 0017-5749

VL - 69

SP - 630

EP - 640

JO - Gut

JF - Gut

IS - 4

ER -

Master transcription factors form interconnected circuitry and orchestrate transcriptional networks in oesophageal adenocarcinoma

Abstract

Bibliographical note

Keywords

UN SDGs

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