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

David Santiago-Algarra,Saadat Hussain,Himanshu Singh,Lucia Ramirez-Navarro,Jaime A Castro-Mondragon,Salvatore Spicuglia,Nori Sadouni,Lan T M Dao,Alejandra Medina-Rivera,Charbel Souaid,Guillaume Charbonnier

doi:10.1038/s41467-021-26861-0

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.

Highlights

Gene expression is controlled by the involvement of gene-proximal and distal regulatory elements
By systematically assessing gene expression and enhancer activity of coding gene promoters in response to type I interferon stimulation we found that a subset of IFNa response genes was associated with Epromoters
IFNa-induced Epromoters associated with an induced gene were found to preferentially recruit the key interferon response factors (STAT1/2, IRF1/9) and to be required for the efficient induction of neighbor genes within the same cluster

Summary

Introduction

Gene expression is controlled by the involvement of gene-proximal (promoters) and distal (enhancers) regulatory elements. 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. 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. The classical definition of enhancers implies the property to activate gene expression at a distance, while promoters induce local gene expression. Using high-throughput reporter assays in different cellular contexts from drosophila to humans, it was found that a subset of gene-promoters, termed Epromoters, displays enhancer activity when tested in vitro[5,6,7,8,9]. Epromoters have a broad role in the induction of co-regulated genes during the mammalian inflammatory response

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