Evidence map›Paper›PMID 31409603›Full record

ArticleGut2020

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 and 14 more

Open access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Gut, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 63 papers.

0numbers the graph read from it
0cells of the map it votes in
63citing papers in PubMed
4.0field-weighted citation impact, top 5% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

63 citing papers in PubMed, 102 citations in OpenAlex.

  1. Article
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  7. Acta pharmaceutica Sinica. B · 2025
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  16. A druggable cascade links methionine metabolism to epigenomic reprogramming in squamous cell carcinoma.Proceedings of the National Academy of Sciences of the United States of America · 2024
    Article
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  20. Article

3 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

24 authors at 6 institutions in 4 countries.

Li Chen *Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA.ORCID 0000-0003-1148-1359
Moli Huang *School of Biology and Basic Medical Sciences, Soochow University, Suzhou, China dchlin11@gmail.com huangml@suda.edu.cn.
Jasmine Plummer *Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Jian Pan *Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, China.
Yan Yi Jiang *Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
Qian YangDepartment of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Tiago Chedraoui SilvaCenter for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Nicole GullCenter for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, California, USA.ORCID 0000-0002-1956-5648
Stephanie ChenCenter for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Ling Wen DingCancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
Omer AnCancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
Henry YangCancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
Yulan ChengDepartments of Medicine and Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA.
Jonathan W SaidDepartment of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
Ngan DoanDepartment of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
Winand Nm DinjensDepartment of Pathology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
Kevin M WatersDepartment of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Richard TuliDepartment of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Simon A GaytherCenter for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Samuel J KlempnerThe Angeles Clinic and Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.ORCID 0000-0002-4062-0808
Benjamin P BermanCenter for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Stephen J MeltzerDepartments of Medicine and Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA.
De-Chen LinDepartment of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA dchlin11@gmail.com huangml@suda.edu.cn.
H Phillip KoefflerDepartment of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Cedars-Sinai Medical Center · USNational University of Singapore · SGJohns Hopkins University · USSoochow University · CNUniversity of California, Los Angeles · USErasmus MC · NL

Funding

Academic-Industrial Partnership for Non-invasive Barrett's Esophagus DetectionR01DK118250 · NIDDK · JOHNS HOPKINS UNIVERSITY · PI MELTZER, STEPHEN J · 2018 to 2022
$3.8M
Facile screening for esophageal cancer in LMICsUH3CA211457 · NCI · JOHNS HOPKINS UNIVERSITY · PI MELTZER, STEPHEN J, WANG, TZA-HUEI JEFF · 2019 to 2021
$2.8M
(PQC-1) Driver Events In IBD-Associated Neoplastic ProgressionR01CA190040 · NCI · JOHNS HOPKINS UNIVERSITY · PI MELTZER, STEPHEN J, SELARU, FLORIN · 2014 to 2017
$2.5M
Connecting Genomic Alterations in Liposarcomas with Drug Responses and Identification of New Therapeutic ApproachesR01CA200992 · NCI · CEDARS-SINAI MEDICAL CENTER · PI KOEFFLER, HAROLD PHILLIP · 2016 to 2020
$1.8M
Software Tools For Regulatory Analysis of Large Cancer Methylome DatasetsU01CA184826 · NCI · UNIVERSITY OF SOUTHERN CALIFORNIA · PI BERMAN, BENJAMIN P · 2014 to 2016
$1.1M
Facile screening for esophageal cancer in LMICsUG3CA211457 · NCI · JOHNS HOPKINS UNIVERSITY · PI MELTZER, STEPHEN J, WANG, TZA-HUEI JEFF · 2017 to 2018
$861k
NCI NIH HHS R01 CA190040NCI NIH HHS R01 CA200992NCI NIH HHS U01 CA184826NCI NIH HHS UG3 CA211457NCI NIH HHS UH3 CA211457NIDDK NIH HHS R01 DK118250
6 · The paper itself

Abstract

objectiveWhile 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). 

designTo 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.

resultsWe 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.

conclusionsBy 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.

Indexed as

AdenocarcinomaCase-Control StudiesCell Line, TumorCell ProliferationDNA-Binding ProteinsEsophageal NeoplasmsEsophageal Squamous Cell CarcinomaGATA6 Transcription FactorGene Regulatory NetworksHumansKruppel-Like Transcription FactorsProto-Oncogene Proteins c-etsTranscription FactorsDNA-Binding ProteinsEHF protein, humanELF3 protein, humanGATA6 protein, humanGATA6 Transcription FactorKLF5 protein, humanKruppel-Like Transcription FactorsProto-Oncogene Proteins c-etsTranscription Factorsgene regulationoesophageal cancersignal transductiontranscription factor

Identifiers

PMID31409603
PMCPMC8108390
OpenAlexW2968336221

What OpenQuestion holds

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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.