Epigenomic mapping identifies a super-enhancer repertoire that regulates cell identity in bladder cancers through distinct transcription factor networks - Archive ouverte HAL Access content directly
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Epigenomic mapping identifies a super-enhancer repertoire that regulates cell identity in bladder cancers through distinct transcription factor networks

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Hélène Neyret-Kahn
Jacqueline Fontugne
Xiang Yu Meng
  • Function : Author
Clarice Groeneveld
Luc Cabel
Tao Ye
Elodie Guyon
  • Function : Author
Clémentine Krucker
  • Function : Author
Florent Dufour
Elodie Chapeaublanc
Audrey Rapinat
  • Function : Author
Daniel Jeffery
Yann Neuzillet
  • Function : Author
Thierry Lebret
  • Function : Author
David Gentien
  • Function : Author
Irwin Davidson
Yves Allory
  • Function : Author
Isabelle Bernard-Pierrot
François Radvanyi
  • Function : Author

Abstract

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.

Dates and versions

hal-03854062 , version 1 (15-11-2022)

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Hélène Neyret-Kahn, Jacqueline Fontugne, Xiang Yu Meng, Clarice Groeneveld, Luc Cabel, et al.. Epigenomic mapping identifies a super-enhancer repertoire that regulates cell identity in bladder cancers through distinct transcription factor networks. 2022. ⟨hal-03854062⟩
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