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Original article
Master transcription factors form interconnected circuitry and orchestrate transcriptional networks in oesophageal adenocarcinoma
  1. Li Chen1,
  2. Moli Huang2,
  3. Jasmine Plummer3,
  4. Jian Pan4,
  5. Yan Yi Jiang5,
  6. Qian Yang1,
  7. Tiago Chedraoui Silva3,
  8. Nicole Gull3,
  9. Stephanie Chen3,
  10. Ling Wen Ding5,
  11. Omer An5,
  12. Henry Yang5,
  13. Yulan Cheng6,
  14. Jonathan W Said7,
  15. Ngan Doan7,
  16. Winand NM Dinjens8,
  17. Kevin M Waters9,
  18. Richard Tuli10,
  19. Simon A Gayther3,
  20. Samuel J Klempner11,12,
  21. Benjamin P Berman3,
  22. Stephen J Meltzer6,
  23. De-Chen Lin1,
  24. H Phillip Koeffler1,5
  1. 1 Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
  2. 2 School of Biology and Basic Medical Sciences, Soochow University, Suzhou, China
  3. 3 Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, California, USA
  4. 4 Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, China
  5. 5 Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
  6. 6 Departments of Medicine and Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA
  7. 7 Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
  8. 8 Department of Pathology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
  9. 9 Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
  10. 10 Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, California, USA
  11. 11 The Angeles Clinic and Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
  12. 12 Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
  1. Correspondence to Dr De-Chen Lin, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles 90048, CA 90048-0750, USA; dchlin11{at}gmail.com; Dr Moli Huang, School of Biology and Basic Medical Sciences, Soochow University, Suzhou, 215123, China; huangml{at}suda.edu.cn

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.

  • transcription factor
  • gene regulation
  • signal transduction
  • oesophageal cancer
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Footnotes

  • LC, MH, JP, JP and YYJ contributed equally.

  • Contributors D-CL conceived and devised the study. D-CL, LC and MH designed the experiments and analysis. LC, JaP, JiP, YYJ, SC, WDL, JWS and ND performed the experiments. MH, TCS, OA, QY, HY and BB performed the bioinformatics and statistical analysis. YC, WNMD, KW, RT, SG, SJK and SJM contributed reagents and materials. LC, MH, JaP, D-CL and HPK analysed the data. D-CL and HPK supervised the research and wrote the manuscript.

  • 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.

  • Competing interests None declared.

  • Patient consent for publication Obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available in a public, open access repository.

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