Range extender mediates long-distance enhancer activity

Grace Bower, Ethan W. Hollingsworth, Sandra H. Jacinto, Joshua A. Alcantara, Benjamin Clock, Kaitlyn Cao, Mandy Liu, Adam Dziulko, Ana Alcaina-Caro, Qianlan Xu, Dorota Skowronska-Krawczyk, Javier Lopez-Rios, Diane E. Dickel, Anaïs F. Bardet, Len A. Pennacchio, Axel Visel and Evgeny Z. Kvon ()
Additional contact information
Grace Bower: University of California Irvine
Ethan W. Hollingsworth: University of California Irvine
Sandra H. Jacinto: University of California Irvine
Joshua A. Alcantara: University of California Irvine
Benjamin Clock: University of California Irvine
Kaitlyn Cao: University of California Irvine
Mandy Liu: University of California Irvine
Adam Dziulko: Lawrence Berkeley National Laboratory
Ana Alcaina-Caro: CSIC-Universidad Pablo de Olavide-Junta de Andalucía
Qianlan Xu: University of California
Dorota Skowronska-Krawczyk: University of California
Javier Lopez-Rios: CSIC-Universidad Pablo de Olavide-Junta de Andalucía
Diane E. Dickel: Lawrence Berkeley National Laboratory
Anaïs F. Bardet: INSERM U1258
Len A. Pennacchio: Lawrence Berkeley National Laboratory
Axel Visel: Lawrence Berkeley National Laboratory
Evgeny Z. Kvon: University of California Irvine

Nature, 2025, vol. 643, issue 8072, 830-838

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41586-025-09221-6

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