Range Extender (REX) DNA element
 | This article may be too technical for most readers to understand. (November 2025) |
The Range Extender (REX) is a conserved cis-acting DNA element which was identified in 2025. REX confers extreme long-range regulatory functions to gene enhancers in mammalian genomes. The addition of the REX to short- and mid-range enhancers significantly enhance their range of interaction and by one order of magnitude. The REX sequence by itself has no inherent enhancer activity. The activity conferred to other promoters is reported to depend on highly conserved [C/T]AATTA sequences.[1] With the description of a REX a sequence for long-range enhancer-promoter interactions has been found. It has been proposed to molecularly explain how such long-range interactions control developmental genes in mammalian.[1] Mutations in such a REX motif has been shown to abolish the long-distance activity.[1] The element's function or disruption has significant implications as several developmental anomalies are explainable.
Background
[edit]Enhancers are regulatory DNA sequences that can alter the transcription of a target gene by interacting with the promoter.[2] An example of such long-range cis-acting regulatory elements is the misregulation of Sonic hedgehog (Shh) within the LMBR1 gene.[3] Further research demonstrated that a conserved non-coding sequence can act as an essential cis-regulatory element and that its deletion resulted in loss of Shh expression.[4] Through this remodelling a high order topology can be established, thereby illustrating the mechanistic principles of REX within chromosome architecture.[5] A more recent study revealed that REX contains a conserved binding domain to enable enhancer action over extreme genomic distances thereby increasing the enhancer-promoter interaction thereby differentiating between long-range and cell-type enhancer functions.[6] Before REX was discovered, it was proposed that such specialized DNA sequence elements might be required for long-range interactions over megabase distances.
Discovery
[edit]REX was discovered by in vivo enhancer-replacement in mice. In those experiments, REX motifs were mutated which abolished long-range interactions while short-range activities remained intact.[1]
Sequence features and binding preferences
[edit]REX contains highly conserved domain motifs, such as [C/T]AATTA. The TAAT core has been shown a key determinant of DNA binding specificity. This variation in the flanking bases suggests REX to function by recruiting homeodomain transcription factors.[7]
Mechanistic 3D genome organization
[edit]Three-dimensional organisation with chromatin loop extrusion provides the basis for topologically associated domains (TADs). TADs are an architectural feature of genome organization.[8] TADs and loops are organized by the protein cohesin, while their positioning and stability is modulated by effectors such as CTCF and WAPL.[9] Through spatial and temporal imaging it was shown that long-range transcriptional regulation might be dependent on transient physical interaction.[10]
References
[edit]- ^ a b c d Bower (2025). "Range extender mediates long-distance enhancer activity". Nature. 643 (8072): 830–838. Bibcode:2025Natur.643..830B. doi:10.1038/s41586-025-09221-6. PMC 12267059. PMID 40604280.
- ^ Serebreni (2021). "Insights into gene regulation: From regulatory genomic elements to DNA-protein and protein-protein interactions". Current Opinion in Cell Biology. 70: 58–66. doi:10.1016/j.ceb.2020.11.009. PMID 33385708.
- ^ Lettice (2002). "Disruption of a long-range cis-acting regulator for Shh causes preaxial polydactyly". PNAS. 99 (11): 7548–7553. Bibcode:2002PNAS...99.7548L. doi:10.1073/pnas.112212199. PMC 124279. PMID 12032320.
- ^ Sagai (2005). "Elimination of a long-range cis-regulatory module causes complete loss of limb-specific Shh expression and truncation of the mouse limb". Development. 132 (4): 797–803. doi:10.1242/dev.01613. PMID 15677727.
- ^ Dixon (2012). "Topological domains in mammalian genomes identified by analysis of chromatin interactions". Nature. 485 (7398): 376–380. Bibcode:2012Natur.485..376D. doi:10.1038/nature11082. PMC 3356448. PMID 22495300.
- ^ Weischenfeldt (2023). "When 3D genome changes cause disease: the impact of structural variations in congenital disease and cancer". Current Opinion in Genetics & Development. 80 102048. doi:10.1016/j.gde.2023.102048. PMID 37156210.
- ^ Catron (1993). "Nucleotides flanking a conserved TAAT core dictate the DNA binding specificity of three murine homeodomain proteins". MCB. 13 (4): 2354–2365. doi:10.1128/mcb.13.4.2354-2365.1993. PMC 359556. PMID 8096059.
- ^ Sanborn (2015). "Chromatin extrusion explains key features of loop and domain formation in wild-type and engineered genomes". PNAS. 112 (47). Bibcode:2015PNAS..112E6456S. doi:10.1073/pnas.1518552112. PMID 26499245.
- ^ Wutz (2017). "Topologically associating domains and chromatin loops depend on cohesin and are regulated by CTCF, WAPL, and PDS5 proteins". The EMBO Journal. 36 (24): 3573–3599. doi:10.15252/embj.201798004. PMC 5730888. PMID 29217591.
- ^ Mach (2022). "Cohesin and CTCF control the dynamics of chromosome folding". Nature Genetics. 54 (12): 1907–1918. doi:10.1038/s41588-022-01232-7. PMC 9729113. PMID 36471076.