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Cited by 641Genomics and Chromatin DynamicsChromatin Remodeling and CancerDevelopmental Biology and Gene Regulation

Developmental enhancers and chromosome topology

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Furlong, Eileen E. M., Levine, Michael·2018·Science
DOI 10.1126/science.aau0320PMC PMC6986801
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Abstract

Developmental enhancers mediate on/off patterns of gene expression in specific cell types at particular stages during metazoan embryogenesis. They typically integrate multiple signals and regulatory determinants to achieve precise spatiotemporal expression. Such enhancers can map quite far—one megabase or more—from the genes they regulate. How remote enhancers relay regulatory information to their target promoters is one of the central mysteries of genome organization and function. A variety of contrasting mechanisms have been proposed over the years, including enhancer tracking, linking, looping, and mobilization to transcription factories. We argue that extreme versions of these mechanisms cannot account for the transcriptional dynamics and precision seen in living cells, tissues, and embryos. We describe emerging evidence for dynamic three-dimensional hubs that combine different elements of the classical models.

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  • The generally accepted model of enhancer action is that some activator complex is assembled on the enhancer, which is then transferred in one way or another to the target promoter.

    “The generally accepted model of enhancer action is that some activator complex is assembled on the enhancer, which is then transferred in one way or another to the target promoter [21].”

    From Enhancer Function in the 3D Genome (2023) · cites this paper as [21]

    The Abstract says enhancers bind combinations of transcription factors that activate target genes. But “Models of enhancer-promoter communication” says the field has largely converged on looping, not transfer of an assembled activator complex to the promoter; “Transcription hubs” describes bridging complexes as a speculative model. The source therefore supports enhancer-bound activators and communication with promoters, but not the claimed generally accepted transfer mechanism. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • There are multiple models for how enhancers interact with their target promoters, including tracking, linking/chaining, short- or long-range looping, transcription factory and hub/condensate models, more than one of which may be correct.

    “Finally, there are multiple models for how enhancers interact with their target promoter(s), including tracking, linking/chaining, short- or long-range looping, transcription factory and hub/condensate models (reviewed in 102), more than one of which may be correct.”

    From Towards a comprehensive catalogue of validated and target-linked human enhancers (2020) · cites this paper as [102]

  • Even within the same TAD, enhancers are not always fully promiscuous and can sometimes skip nearby genes in favour of more distal targets.

    “Even within the same TAD, enhancers are not always fully promiscuous and can sometimes “skip” nearby genes, in favour of more distal targets [472, 473].”

    From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [473]

  • Most enhancers are located at a relatively short distance (up to 50 kb in mammals and up to 10 kb in Drosophila) from target promoters.

    “However, most enhancers are located at a relatively short distance (up to 50 kb in mammals and up to 10 kb in Drosophila) from target promoters [21].”

    From Enhancer Function in the 3D Genome (2023) · cites this paper as [21]

  • Enhancers can be located at a considerable distance (up to 1 Mb or more) from target promoters.

    “An analysis of the positions of enhancers in the genome showed that they can be located at a considerable distance (up to 1 Mb or more) from the target promoters.”

    From Enhancer Function in the 3D Genome (2023) · cites this paper as [21]

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Research works printed but not linked: 53

  1. [1]Lettice LA, Development 141, 1715– 1725 (2014). 24715461 PMC3978833
  2. [2]Frankel N, Nature 466, 490– 493 (2010). 20512118 PMC2909378
  3. [3]Kvon EZ, Nature 512, 91– 95 (2014). 24896182
  4. [4]Ghavi-Helm Y, Nature 512, 96– 100 (2014). 25043061
  5. [5]Cannavò E, Nature 541, 402– 406 (2017). 28024300
  6. [6]Dixon JR, Gorkin DU, Ren B, Mol. Cell 62, 668– 680 (2016). 27259200 PMC5371509
  7. [7]Dekker J, Heard E, FEBS Lett. 589 (20PartA), 2877– 2884 (2015). 26348399 PMC4598308
  8. [8]Sanyal A, Lajoie BR, Jain G, Dekker J, Nature 489, 109– 113 (2012). 22955621 PMC3555147
  9. [9]Phillips-Cremins JE, Cell 153, 1281– 1295 (2013). 23706625 PMC3712340
  10. [10]Rao SS, Cell 159, 1665– 1680 (2014). 25497547 PMC5635824
  11. [11]Fudenberg G, Cell Rep. 15, 2038– 2049 (2016). 27210764 PMC4889513
  12. [12]Hansen AS, Pustova I, Cattoglio C, Tjian R, Darzacq X, eLife 6, e25776 (2017). 28467304 PMC5446243
  13. [13]Gambetta MC, Furlong EEM, Genetics 210, 129– 136 (2018). 30021792 PMC6116963
  14. [14]Ganji M, Science 360, 102– 105 (2018). 29472443 PMC6329450
  15. [15]Symmons O, Genome Res. 24, 390– 400 (2014). 24398455 PMC3941104
  16. [16]Lupiáñez DG, Cell 161, 1012– 1025 (2015). 25959774 PMC4791538
  17. [17]Narendra V, Science 347, 1017– 1021 (2015). 25722416 PMC4428148
  18. [18]Guo Y, Cell 162, 900– 910 (2015). 26276636 PMC4642453
  19. [19]Franke M, Nature 538, 265– 269 (2016). 27706140
  20. [20]Nora EP, Cell 169, 930– 944.e22 (2017). 28525758 PMC5538188
  21. [22]Schwarzer W, Nature 551, 51– 56 (2017). 29094699 PMC5687303
  22. [23]Juven-Gershon T, Hsu JY, Kadonaga JT, Genes Dev. 22, 2823– 2830 (2008). 18923080 PMC2569877
  23. [24]Chang TH, Dev. Biol 269, 595– 608 (2004). 15110722
  24. [25]Cho SW, Cell 173, 1398– 1412.e22 (2018). 29731168 PMC5984165
  25. [26]Symmons O, Dev. Cell 39, 529– 543 (2016). 27867070 PMC5142843
  26. [27]Kong S, Bohl D, Li C, Tuan D, Mol. Cell. Biol 17, 3955– 3965 (1997). 9199330 PMC232248
  27. [28]Morcillo P, Rosen C, Baylies MK, Dorsett D, Genes Dev. 11, 2729– 2740 (1997). 9334334 PMC316608
  28. [29]Deng W, Cell 149, 1233– 1244 (2012). 22682246 PMC3372860
  29. [30]Dunn TM, Hahn S, Ogden S, Schleif RF, Proc. Natl. Acad. Sci. U.S.A. 81, 5017– 5020 (1984). 6089170 PMC391628
  30. [31]Rollins RA, Morcillo P, Dorsett D, Genetics 152, 577– 593 (1999). 10353901 PMC1460629
  31. [32]Wendt KS, Nature 451, 796– 801 (2008). 18235444
  32. [33]Splinter E, Genes Dev. 20, 2349– 2354 (2006). 16951251 PMC1560409
  33. [34]Bell AC, West AG, Felsenfeld G, Cell 98, 387– 396 (1999). 10458613
  34. [35]de Wit E, Mol. Cell 60, 676– 684 (2015). 26527277
  35. [36]Weintraub AS, Cell 171, 1573– 1588.e28 (2017). 29224777 PMC5785279
  36. [37]Schoenfelder S, Nat. Genet 42, 53– 61 (2010). 20010836 PMC3237402
  37. [38]Krivega I, Dean A, Nucleic Acids Res. 45, 8255– 8268 (2017). 28520978 PMC5737898
  38. [39]Bonev B, Cell 171, 557– 572.e24 (2017). 29053968 PMC5651218
  39. [40]Palstra RJ, Nat. Genet 35, 190– 194 (2003). 14517543
  40. [41]Spilianakis CG, Flavell RA, Nat. Immunol 5, 1017– 1027 (2004). 15378057
  41. [42]Andrey G, Science 340, 1234167 (2013). 23744951
  42. [43]Rubin AJ, Nat. Genet 49, 1522– 1528 (2017). 28805829 PMC5715812
  43. [44]Chen H, Nat. Genet 50, 1296– 1303 (2018). 30038397 PMC6119122
  44. [45]Lim B, Heist T, Levine M, Fukaya T, Mol. Cell 70, 287– 296.e6 (2018). 29606591 PMC6092965
  45. [46]Williamson I, Lettice LA, Hill RE, Bickmore WA, Development 143, 2994– 3001 (2016). 27402708 PMC5004883
  46. [47]Lucas JS, Zhang Y, Dudko OK, Murre C, Cell 158, 339– 352 (2014). 24998931 PMC4113018
  47. [48]Jackson DA, Iborra FJ, Manders EM, Cook PR, Mol. Biol. Cell 9, 1523– 1536 (1998). 9614191 PMC25378
  48. [49]Osborne CS, Nat. Genet 36, 1065– 1071 (2004). 15361872
  49. [50]Cisse II, Science 341, 664– 667 (2013). 23828889
  50. [51]Hnisz D, Shrinivas K, Young RA, Chakraborty AK, Sharp PA, Cell 169, 13– 23 (2017). 28340338 PMC5432200
  51. [52]Brangwynne CP, Science 324, 1729– 1732 (2009). 19460965
  52. [55]Cho WK, Science 361, 412– 415 (2018). 29930094 PMC6543815
  53. [56]Gu B, Science 359, 1050– 1055 (2018). 29371426 PMC6590518

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Authors
Furlong, E. E. M., & Levine, M.
Affiliations
  • European Molecular Biology Laboratory (DE)
  • Princeton University (US)
Corresponding author
  • Furlong, Eileen E. M.
  • Levine, Michael
ORCID
Venue
Science
Publisher
American Association for the Advancement of Science (AAAS)
Published
2018-09-28
Volume
361
Issue
6409
Pages
1341-1345
ISSN
  • 0036-8075 (ISSN-L)
  • 1095-9203
DOI
10.1126/science.aau0320
PMC
PMC6986801
OpenAlex
W2894289085
Cited by
641
References
15
Citations by year
2026: 56 · 2025: 70 · 2024: 94 · 2023: 96 · 2022: 87 · 2021: 97 · 2020: 77 · 2019: 58 · 2018: 6
FWCI
5.84
Type
journal article
Language
en
Open access
Locations
  • Science (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute on Drug Abuse (U01DA047730)
  • National Institute of General Medical Sciences (R35GM118147)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Keywords
developmental enhancers, chromosome topology, 3D genome organization, enhancer-promoter looping, transcription factories, gene expression regulation, embryonic development, chromatin structure
MeSH terms
Protein Domains, Animals, Chromatin, Chromosomes, Enhancer Elements, Genetic, Humans, Promoter Regions, Genetic, Transcription, Genetic, Gene Expression Regulation, Developmental, Embryonic Development, Mice

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