Range extender mediates long-distance enhancer activity

• 成果类型: Article
• 署名作者: Bower, Grace; Hollingsworth, Ethan W.; Jacinto, Sandra H.; Alcantara, Joshua A.; Clock, Benjamin; Cao, Kaitlyn; Liu, Mandy; Dziulko, Adam; Alcaina-Caro, Ana; Xu, Qianlan; Skowronska-Krawczyk, Dorota; Lopez-Rios, Javier; Dickel, Diane E.; Bardet, Anais F.; Pennacchio, Len A.; Visel, Axel; Kvon, Evgeny Z.
• 署名单位: University of California System; University of California Irvine; University of California System; University of California Irvine; United States Department of Energy (DOE); Lawrence Berkeley National Laboratory; Consejo Superior de Investigaciones Cientificas (CSIC); Universidad Pablo de Olavide; CSIC - Andalusian Center for Developmental Biology (CABD); University of California System; University of California Irvine; University of California System; University of California Irvine; University of California System; University of California Irvine; Universidad Loyola Andalucia; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); Institut National de la Sante et de la Recherche Medicale (Inserm); Universites de Strasbourg Etablissements Associes; Universite de Strasbourg; United States Department of Energy (DOE); Lawrence Berkeley National Laboratory; University of California System; University of California Berkeley; University of California System; University of California Merced
• 刊物名称: Nature
• ISSN/ISSBN: 0028-3388
• DOI: 10.1038/s41586-025-09221-6
• 发表日期: 2025-07-17
• 关键词: transcription factors; promoter specificity; regulatory landscapes; gene-regulation; limb enhancer; chromatin; expression; ELEMENTS; domains; cohesin

摘要

Although most mammalian transcriptional enhancers regulate their cognate promoters over distances of tens of kilobases, some enhancers act over distances in the megabase range1. The sequence features that enable such long-distance enhancer-promoter interactions remain unclear. Here we used in vivo enhancer-replacement experiments at the mouse Shh locus to show that short- and medium-range limb enhancers cannot initiate gene expression at long-distance range. We identify a cis-acting element, range extender (REX), that confers long-distance regulatory activity and is located next to a long-range limb enhancer of Sall1. The REX element has no endogenous enhancer activity. However, addition of the REX to other short- and mid-range limb enhancers substantially increases their genomic interaction range. In the most extreme example observed, addition of REX increased the range of an enhancer by an order of magnitude from its native 73 kb to 848 kb. The REX element contains highly conserved [C/T]AATTA homeodomain motifs that are critical for its activity. These motifs are enriched in long-range limb enhancers genome-wide, including the ZRS (zone of polarizing activity (ZPA) regulatory sequence), a benchmark long-range limb enhancer of Shh2. The ZRS enhancer with mutated [C/T]AATTA motifs maintains limb activity at short range, but loses its long-range activity, resulting in severe limb reduction in knock-in mice. In summary, we identify a sequence signature associated with long-range enhancer-promoter interactions and describe a prototypical REX element that is necessary and sufficient to confer long-distance activation by remote enhancers.