Transcription factors mediate long-range enhancer-promoter interactions

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 106; no. 48; pp. 20222 - 20227
• Main Authors: Nolis, Ilias K, McKay, Daniel J, Mantouvalou, Eva, Lomvardas, Stavros, Merika, Menie, Thanos, Dimitris
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 01-12-2009; National Acad Sciences
• Subjects: Binding sites; Biological Sciences; Chromatin; Chromatin Immunoprecipitation; Deoxyribonucleic acid; DNA; DNA - metabolism; DNA Primers - genetics; Enhancer Elements, Genetic - physiology; Gene expression; Gene Expression Regulation - physiology; Gene loci; Genes; HeLa Cells; Humans; Infections; Interferon-beta - genetics; Plasmids; Polymerase Chain Reaction; Promoter Regions, Genetic - physiology; Proteins; Transcription factors; Transcription Factors - metabolism; Transcription, Genetic - physiology; Viruses
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0902454106

We examined how remote enhancers establish physical communication with target promoters to activate gene transcription in response to environmental signals. Although the natural IFN-β enhancer is located immediately upstream of the core promoter, it also can function as a classical enhancer element conferring virus infection-dependent activation of heterologous promoters, even when it is placed several kilobases away from these promoters. We demonstrated that the remote IFN-β enhancer "loops out" the intervening DNA to reach the target promoter. These chromatin loops depend on sequence-specific transcription factors bound to the enhancer and the promoter and thus can explain the specificity observed in enhancer-promoter interactions, especially in complex genetic loci. Transcription factor binding sites scattered between an enhancer and a promoter can work as decoys trapping the enhancer in nonproductive loops, thus resembling insulator elements. Finally, replacement of the transcription factor binding sites involved in DNA looping with those of a heterologous prokaryotic protein, the λ repressor, which is capable of loop formation, rescues enhancer function from a distance by re-establishing enhancer-promoter loop formation.