TY - JOUR
T1 - Fra-1 regulates its target genes via binding to remote enhancers without exerting major control on chromatin architecture in triple negative breast cancers
AU - Bejjani, Fabienne
AU - Tolza, Claire
AU - Boulanger, Mathias
AU - Downes, Damien
AU - Romero, Raphaël
AU - Maqbool, Muhammad Ahmad
AU - Zine El Aabidine, Amal
AU - Andrau, Jean Christophe
AU - Lebre, Sophie
AU - Brehelin, Laurent
AU - Parrinello, Hughes
AU - Rohmer, Marine
AU - Kaoma, Tony
AU - Vallar, Laurent
AU - Hughes, Jim R.
AU - Zibara, Kazem
AU - Lecellier, Charles Henri
AU - Piechaczyk, Marc
AU - Jariel-Encontre, Isabelle
N1 - Publisher Copyright:
© 2021 The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.
PY - 2021/3/18
Y1 - 2021/3/18
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85103229064&partnerID=8YFLogxK
UR - https://pubmed.ncbi.nlm.nih.gov/33533919
U2 - 10.1093/nar/gkab053
DO - 10.1093/nar/gkab053
M3 - Article
C2 - 33533919
AN - SCOPUS:85103229064
SN - 0305-1048
VL - 49
SP - 2488
EP - 2508
JO - Nucleic Acids Research
JF - Nucleic Acids Research
IS - 5
ER -