范围扩展器介导长距离增强活动，这一成果由加州大学Evgeny Z. Kvon团队经过不懈努力而取得。该研究于2025年7月2日发表于国际一流学术期刊《自然》杂志上。

在这里，该研究团队在motheme Shh位点进行了体内增强子替换实验，以证明短距离和中距离肢体增强子不能启动长距离的基因表达。课题组人员发现了一个顺式作用元件，范围扩展器（REX），它具有长距离调控活性，位于Sall1的远程肢体增强子旁边。REX元件没有内源性增强活性。

然而，将REX添加到其他中短程肢体增强子中，大大增加了它们的基因组相互作用范围。在观察到的最极端的例子中，REX的加入使增强子的范围比原来的73KB到848kb。REX元件含有高度保守的[C/T]AATTA同源域基序，这些基序对其活性至关重要。这些基序在全基因组的远端肢体增强子中都很丰富，包括Shh的基准远端肢体增强子ZRS （zone of polarization activity， ZPA）调控序列。具有突变的[C/T]AATTA基序的ZRS增强子维持短距离肢体活动，但失去其远程活动，导致敲入小鼠的严重肢体减少。总之，课题组确定了一个与远程增强子-启动子相互作用相关的序列特征，并描述了一个典型的REX元件，该元件是远程增强子远程激活的必要和充分条件。

据了解，尽管大多数哺乳动物的转录增强子对其同源启动子的调控距离为数万个碱基，但有些增强子的调控距离仅为100个碱基。导致这种长距离增强子-启动子相互作用的序列特征尚不清楚。

附：英文原文

Title: Range extender mediates long-distance enhancer activity

Author: 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, Anas F., Pennacchio, Len A., Visel, Axel, Kvon, Evgeny Z.

Issue&Volume: 2025-07-02

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 73kb to 848kb. 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.

DOI: 10.1038/s41586-025-09221-6

Source: https://www.nature.com/articles/s41586-025-09221-6