Epromoters function as a hub to recruit key transcription factors required for the inflammatory response

David Santiago-Algarra, Charbel Souaid, Himanshu Singh, Lan T. M. Dao, Saadat Hussain, Alejandra Medina-Rivera, Lucia Ramirez-Navarro, Jaime A. Castro-Mondragon, Nori Sadouni, Guillaume Charbonnier and Salvatore Spicuglia ()
Additional contact information
David Santiago-Algarra: Aix-Marseille University, INSERM, TAGC
Charbel Souaid: Aix-Marseille University, INSERM, TAGC
Himanshu Singh: Aix-Marseille University, INSERM, TAGC
Lan T. M. Dao: Aix-Marseille University, INSERM, TAGC
Saadat Hussain: Aix-Marseille University, INSERM, TAGC
Alejandra Medina-Rivera: Laboratorio Internacional de Investigación sobre el Genoma Humano, Universidad Nacional Autónoma de México
Lucia Ramirez-Navarro: Laboratorio Internacional de Investigación sobre el Genoma Humano, Universidad Nacional Autónoma de México
Jaime A. Castro-Mondragon: Aix-Marseille University, INSERM, TAGC
Nori Sadouni: Aix-Marseille University, INSERM, TAGC
Guillaume Charbonnier: Aix-Marseille University, INSERM, TAGC
Salvatore Spicuglia: Aix-Marseille University, INSERM, TAGC

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: Abstract Gene expression is controlled by the involvement of gene-proximal (promoters) and distal (enhancers) regulatory elements. Our previous results demonstrated that a subset of gene promoters, termed Epromoters, work as bona fide enhancers and regulate distal gene expression. Here, we hypothesized that Epromoters play a key role in the coordination of rapid gene induction during the inflammatory response. Using a high-throughput reporter assay we explored the function of Epromoters in response to type I interferon. We find that clusters of IFNa-induced genes are frequently associated with Epromoters and that these regulatory elements preferentially recruit the STAT1/2 and IRF transcription factors and distally regulate the activation of interferon-response genes. Consistently, we identified and validated the involvement of Epromoter-containing clusters in the regulation of LPS-stimulated macrophages. Our findings suggest that Epromoters function as a local hub recruiting the key TFs required for coordinated regulation of gene clusters during the inflammatory response.

Date: 2021
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DOI: 10.1038/s41467-021-26861-0

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