Fra-1 regulates its target genes via binding to remote enhancers without exerting major control on chromatin architecture in triple negative breast cancers

Fabienne Bejjani, Claire Tolza, Mathias Boulanger, Damien Downes, Raphaël Romero, Muhammad Ahmad Maqbool, Amal Zine El Aabidine, Jean Christophe Andrau, Sophie Lebre, Laurent Brehelin, Hughes Parrinello, Marine Rohmer, Tony Kaoma, Laurent Vallar, Jim R. Hughes, Kazem Zibara, Charles Henri Lecellier, Marc Piechaczyk, Isabelle Jariel-Encontre*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

7 Citations (Scopus)

Abstract

The ubiquitous family of dimeric transcription factors AP-1 is made up of Fos and Jun family proteins. It has long been thought to operate principally at gene promoters and how it controls transcription is still ill-understood. The Fos family protein Fra-1 is overexpressed in triple negative breast cancers (TNBCs) where it contributes to tumor aggressiveness. To address its transcriptional actions in TNBCs, we combined transcriptomics, ChIP-seqs, machine learning and NG Capture-C. Additionally, we studied its Fos family kin Fra-2 also expressed in TNBCs, albeit much less. Consistently with their pleiotropic effects, Fra-1 and Fra-2 up-and downregulate individually, together or redundantly many genes associated with a wide range of biological processes. Target gene regulation is principally due to binding of Fra-1 and Fra-2 at regulatory elements located distantly from cognate promoters where Fra-1 modulates the recruitment of the transcriptional co-regulator p300/CBP and where differences in AP-1 variant motif recognition can underlie preferential Fra-1-or Fra-2 bindings. Our work also shows no major role for Fra-1 in chromatin architecture control at target gene loci, but suggests collaboration between Fra-1-bound and-unbound enhancers within chromatin hubs sometimes including promoters for other Fra-1-regulated genes. Our work impacts our view of AP-1.

Original languageEnglish
Pages (from-to)2488-2508
Number of pages21
JournalNucleic Acids Research
Volume49
Issue number5
DOIs
Publication statusPublished - 18 Mar 2021

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