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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 publication

DOI

10.1093/nar/gkab053

Type

Journal article

Journal

Nucleic Acids Res

Publication Date

18/03/2021

Volume

49

Pages

2488 - 2508

Keywords

Binding Sites, Cell Line, Tumor, Chromatin, Enhancer Elements, Genetic, Epigenesis, Genetic, Fos-Related Antigen-2, Gene Expression Regulation, Neoplastic, Humans, Nucleotide Motifs, Promoter Regions, Genetic, Proto-Oncogene Proteins c-fos, Transcription Factor AP-1, Triple Negative Breast Neoplasms, p300-CBP Transcription Factors