biostudies-literatureUnknownBower GNICHD NIH HHSNCRR NIH HHSNHGRI NIH HHSNINDS NIH HHSNCI NIH HHSNIGMS NIH HHSNIH HHSWhile most mammalian enhancers regulate their cognate promoters over moderate distances of tens of kilobases (kb), some enhancers act over distances in the megabase range. The sequence features enabling such extreme-distance enhancer-promoter interactions remain elusive. Here, we used <i>in vivo</i> enhancer replacement experiments in mice to show that short- and medium-range enhancers cannot initiate gene expression at extreme-distance range. We uncover a novel conserved <i>cis</i>-acting element, Range EXtender (REX), that confers extreme-distance regulatory activity and is located next to a long-range enhancer of <i>Sall1</i>. The REX element itself has no endogenous enhancer activity. However, addition of the REX to other short- and mid-range enhancers substantially increases their genbioRxiv : the preprint server for biology2024.05.26.595809https://www.ebi.ac.uk/biostudies/studies/S-EPMC11142232biostudies-literatureConserved <i>Cis</i>-Acting Range Extender Element Mediates Extreme Long-Range Enhancer Activity in Mammals.PMC11142232F30 HD110233T32 NS082174S10 OD021718T32 GM008620P30 CA062203F31 HD112201DP2 GM149555R01 HG003988S10 OD010794S10 RR025496Visel ACao KBardet AFDickel DELiu MClock BXu QLopez-Rios JSkowronska-Krawczyk DPennacchio LAJacinto SAlcaina-Caro AKvon EZDziulko AHollingsworth EWBower GfalseConserved <i>Cis</i>-Acting Range Extender Element Mediates Extreme Long-Range Enhancer Activity in Mammals.While most mammalian enhancers regulate their cognate promoters over moderate distances of tens of kilobases (kb), some enhancers act over distances in the megabase range. The sequence features enabling such extreme-distance enhancer-promoter interactions remain elusive. Here, we used <i>in vivo</i> enhancer replacement experiments in mice to show that short- and medium-range enhancers cannot initiate gene expression at extreme-distance range. We uncover a novel conserved <i>cis</i>-acting element, Range EXtender (REX), that confers extreme-distance regulatory activity and is located next to a long-range enhancer of <i>Sall1</i>. The REX element itself has no endogenous enhancer activity. However, addition of the REX to other short- and mid-range enhancers substantially increases their gen2024-01-01T00:00:00Z2024 May2025-08-30T03:11:42.846Z2025-04-04T12:47:42.198ZS-EPMC111422323882639410.1101/2024.05.26.595809