️ Episode 77: Range Extender: Unlocking Long-Distance Enhancer Activity

In this episode of PaperCast Base by Base, we explore the discovery and functional characterization of a novel cis-acting element, termed REX, that mediates megabase-scale enhancer–promoter interactions and enables remote gene activation during limb development.

Study Highlights:

The authors performed in vivo enhancer-replacement experiments at the mouse Shh locus to demonstrate that bona fide short- and medium-range limb enhancers lack the capacity to activate target genes over megabase distances. They identified a conserved REX element adjacent to a long-range Sall1 enhancer that by itself has no enhancer activity but extends the genomic interaction range of tethered enhancers by over an order of magnitude. Addition of REX to diverse limb enhancers enabled long-distance activation up to 848 kb away, revealing its modular ability to confer remote regulatory function. Mutational analyses showed that conserved [C/T]AATTA homeodomain motifs within REX are essential for its long-range activity and are enriched in remote enhancers genome-wide.

Conclusion:

This discovery defines a sequence signature essential for long-distance enhancer–promoter communication and offers a new strategy for engineering gene regulation across large genomic distances.

Reference:

Bower G, Hollingsworth EW, Jacinto SH, Alcantara JA, Clock B, Cao K, et al. Range extender mediates long-distance enhancer activity. Nature. 2025; DOI:10.1038/s41586-025-09221-6

License:

This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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