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Epigenomic mapping identifies a super-enhancer repertoire that regulates cell identity in bladder cancers through distinct transcription factor networks

View ORCID ProfileHélène Neyret-Kahn, View ORCID ProfileJacqueline Fontugne, Xiang Yu Meng, View ORCID ProfileClarice S. Groeneveld, View ORCID ProfileLuc Cabel, View ORCID ProfileTao Ye, Elodie Guyon, Clémentine Krucker, View ORCID ProfileFlorent Dufour, View ORCID ProfileElodie Chapeaublanc, Audrey Rapinat, View ORCID ProfileDaniel Jeffery, Yann Neuzillet, Thierry Lebret, David Gentien, View ORCID ProfileIrwin Davidson, Yves Allory, View ORCID ProfileIsabelle Bernard-Pierrot, François Radvanyi
doi: https://doi.org/10.1101/2022.01.11.475197
Hélène Neyret-Kahn
1Molecular Oncology, PSL Research University, CNRS, UMR 144, Institut Curie, Equipe Labellisée Ligue Nationale Contre le Cancer, Paris, France
2Sorbonne Universités, UPMC Université Paris 06, CNRS, UMR144, 75005, Paris, France
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  • ORCID record for Hélène Neyret-Kahn
  • For correspondence: helene.neyret-kahn@curie.fr
Jacqueline Fontugne
1Molecular Oncology, PSL Research University, CNRS, UMR 144, Institut Curie, Equipe Labellisée Ligue Nationale Contre le Cancer, Paris, France
3Department of Pathology, Institut Curie, Saint-Cloud, France
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Xiang Yu Meng
1Molecular Oncology, PSL Research University, CNRS, UMR 144, Institut Curie, Equipe Labellisée Ligue Nationale Contre le Cancer, Paris, France
2Sorbonne Universités, UPMC Université Paris 06, CNRS, UMR144, 75005, Paris, France
5Department of Urology, Zhongnan Hospital of Wuhan University
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Clarice S. Groeneveld
1Molecular Oncology, PSL Research University, CNRS, UMR 144, Institut Curie, Equipe Labellisée Ligue Nationale Contre le Cancer, Paris, France
2Sorbonne Universités, UPMC Université Paris 06, CNRS, UMR144, 75005, Paris, France
6Université de Paris, Centre de Recherche des Cordeliers, Paris, France
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Luc Cabel
1Molecular Oncology, PSL Research University, CNRS, UMR 144, Institut Curie, Equipe Labellisée Ligue Nationale Contre le Cancer, Paris, France
2Sorbonne Universités, UPMC Université Paris 06, CNRS, UMR144, 75005, Paris, France
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Tao Ye
7Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM) U1258, Centre National de Recherche Scientifique (CNRS) UMR7104, Université de Strasbourg,1 rue Laurent Fries, 67404 Illkirch, France
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Elodie Guyon
1Molecular Oncology, PSL Research University, CNRS, UMR 144, Institut Curie, Equipe Labellisée Ligue Nationale Contre le Cancer, Paris, France
4Department of Pathology, Institut Curie, Paris, France
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Clémentine Krucker
1Molecular Oncology, PSL Research University, CNRS, UMR 144, Institut Curie, Equipe Labellisée Ligue Nationale Contre le Cancer, Paris, France
2Sorbonne Universités, UPMC Université Paris 06, CNRS, UMR144, 75005, Paris, France
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Florent Dufour
1Molecular Oncology, PSL Research University, CNRS, UMR 144, Institut Curie, Equipe Labellisée Ligue Nationale Contre le Cancer, Paris, France
2Sorbonne Universités, UPMC Université Paris 06, CNRS, UMR144, 75005, Paris, France
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Elodie Chapeaublanc
1Molecular Oncology, PSL Research University, CNRS, UMR 144, Institut Curie, Equipe Labellisée Ligue Nationale Contre le Cancer, Paris, France
2Sorbonne Universités, UPMC Université Paris 06, CNRS, UMR144, 75005, Paris, France
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Audrey Rapinat
8Department of Translational Research, Genomics Platform, Institut Curie, PSL Research University, Paris, France
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Daniel Jeffery
9Urology Medico-Scientific Program, Department of Translational Research, Institut Curie, PSL Research University, Paris, France
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Yann Neuzillet
10Urology Department, Hôpital Foch, Suresnes, France
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Thierry Lebret
10Urology Department, Hôpital Foch, Suresnes, France
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David Gentien
8Department of Translational Research, Genomics Platform, Institut Curie, PSL Research University, Paris, France
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Irwin Davidson
11Department of Functional Genomics and Cancer, Institut de Genétique et de Biologie Moleculaire et Cellulaire, CNRS/INSERM/UDS, 67404 Illkirch Cedex, France
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Yves Allory
1Molecular Oncology, PSL Research University, CNRS, UMR 144, Institut Curie, Equipe Labellisée Ligue Nationale Contre le Cancer, Paris, France
2Sorbonne Universités, UPMC Université Paris 06, CNRS, UMR144, 75005, Paris, France
3Department of Pathology, Institut Curie, Saint-Cloud, France
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Isabelle Bernard-Pierrot
1Molecular Oncology, PSL Research University, CNRS, UMR 144, Institut Curie, Equipe Labellisée Ligue Nationale Contre le Cancer, Paris, France
2Sorbonne Universités, UPMC Université Paris 06, CNRS, UMR144, 75005, Paris, France
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François Radvanyi
1Molecular Oncology, PSL Research University, CNRS, UMR 144, Institut Curie, Equipe Labellisée Ligue Nationale Contre le Cancer, Paris, France
2Sorbonne Universités, UPMC Université Paris 06, CNRS, UMR144, 75005, Paris, France
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  • Abstract
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Abstract

Muscle-invasive bladder cancer (BLCA) is an aggressive disease. Consensus BLCA transcriptomic subtypes have been proposed, with two major Luminal and Basal subgroups, presenting distinct molecular and clinical characteristics. However, how these distinct subtypes are regulated remains unclear. We hypothesized that epigenetic activation of distinct super-enhancers could drive the transcriptional programs of BLCA subtypes.

Through integrated RNA-sequencing and epigenomic profiling of histone marks in primary tumours, cancer cell lines, and normal human urothelia, we established the first integrated epigenetic map of BLCA and demonstrated the link between subtype and epigenetic control. We identified the repertoire of activated super-enhancers and highlighted Basal, Luminal and Normal-associated SEs. We revealed the super-enhancer-regulated networks of candidate master transcription factors for Luminal and Basal subgroups including FOXA1 and ZBED2 respectively. FOXA1 CRISPR-Cas9 mutation triggered a shift from Luminal to Basal phenotype, confirming its role in Luminal identity regulation and induced ZBED2 overexpression. In parallel, we showed that both FOXA1 and ZBED2 play concordant roles in preventing inflammatory response in cancer cells through STAT2 inhibition.

Our study furthers the understanding of epigenetic regulation of muscle-invasive BLCA and identifies a co-regulated network of super-enhancers and associated transcription factors providing potential targets for the treatment of this aggressive disease.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵# These authors co-supervised this work

  • Abbreviation

    SE
    Super-enhancer
    TF
    Transcription Factor
    NMIBC
    non-muscle-invasive bladder carcinoma
    MIBC
    muscle-invasive bladder carcinoma
    BLCA
    Bladder Cancer Carcinoma
    Ba/Sq
    basal/squamous
    LumU
    luminal unstable
    LumNS
    luminal non-specified
    LumP
    luminal papillary
  • Copyright 
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    Epigenomic mapping identifies a super-enhancer repertoire that regulates cell identity in bladder cancers through distinct transcription factor networks
    Hélène Neyret-Kahn, Jacqueline Fontugne, Xiang Yu Meng, Clarice S. Groeneveld, Luc Cabel, Tao Ye, Elodie Guyon, Clémentine Krucker, Florent Dufour, Elodie Chapeaublanc, Audrey Rapinat, Daniel Jeffery, Yann Neuzillet, Thierry Lebret, David Gentien, Irwin Davidson, Yves Allory, Isabelle Bernard-Pierrot, François Radvanyi
    bioRxiv 2022.01.11.475197; doi: https://doi.org/10.1101/2022.01.11.475197
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    Epigenomic mapping identifies a super-enhancer repertoire that regulates cell identity in bladder cancers through distinct transcription factor networks
    Hélène Neyret-Kahn, Jacqueline Fontugne, Xiang Yu Meng, Clarice S. Groeneveld, Luc Cabel, Tao Ye, Elodie Guyon, Clémentine Krucker, Florent Dufour, Elodie Chapeaublanc, Audrey Rapinat, Daniel Jeffery, Yann Neuzillet, Thierry Lebret, David Gentien, Irwin Davidson, Yves Allory, Isabelle Bernard-Pierrot, François Radvanyi
    bioRxiv 2022.01.11.475197; doi: https://doi.org/10.1101/2022.01.11.475197

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