Shadow enhancer

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Shadow enhancers are groups of two or more enhancers that control the same target gene and work together to stabilize gene expression. [1] [2] [3] Shadow enhancers are found in a wide range of organisms, from insects to plants to mammals. [4] [5] [6] [7] Shadow enhancers modulate distinct aspects of gene expression, including transcriptional activation strength, timing and location. [8] They stabilize gene expression levels under changing conditions or stress, and act as a buffer against mutations to ensure proper development. [9] [1]

Contents

Discovery of shadow enhancers

Shadow enhancers were first described in 2008 by Mike Levine and his research group at the University of California, Berkeley. Their research in Drosophila investigated the transcription factor Dorsal and its target genes. Through characterization of enhancers, other than the primary enhancer, they found that these enhancers appeared to produce gene expression patterns that overlap with those produced by the primary enhancer. Initially, shadow enhancers were believed to act redundantly to the function of the primary enhancer to ensure proper gene expression, despite environmental or genetic variability. [2]

Shadow enhancers vs primary enhancers

Although both primary enhancers and shadow enhancers are regulatory components of a gene, they each have distinct roles that are crucial to proper gene expression patterns. Primary enhancers drive gene expression, while shadow enhancers work together to ensure stable gene expression and minimize variability. [10] [11] This ensures that even with mutation or damage to the primary enhancer, shadow enhancers can compensate for this and ensure proper gene expression patterns. [12] Although they are both types of enhancers, shadow enhancers and primary enhancers are quite distinct in terms of their locations within the genome, their regulatory strategies and their importance in changing environments.

References

  1. 1 2 Waymack, Rachel; Fletcher, Alvaro; Enciso, German; Wunderlich, Zeba (2020-08-17). Wittkopp, Patricia J; Crocker, Justin (eds.). "Shadow enhancers can suppress input transcription factor noise through distinct regulatory logic". eLife. 9: e59351. doi: 10.7554/eLife.59351 . ISSN   2050-084X. PMC   7556877 . PMID   32804082. Creative Commons by small.svg  This article incorporates text available under the CC BY 4.0 license.
  2. 1 2 Hong, Joung-Woo; Hendrix, David A.; Levine, Michael S. (2008-09-05). "Shadow Enhancers as a Source of Evolutionary Novelty". Science. 321 (5894): 1314. Bibcode:2008Sci...321.1314H. doi:10.1126/science.1160631. ISSN   0036-8075. PMC   4257485 . PMID   18772429.
  3. ↑ Barolo, Scott (2012). "Shadow enhancers: Frequently asked questions about distributed cis-regulatory information and enhancer redundancy". BioEssays. 34 (2): 135–141. doi:10.1002/bies.201100121. ISSN   1521-1878. PMC   3517143 . PMID   22083793.
  4. ↑ Cannavò, Enrico; Khoueiry, Pierre; Garfield, David A.; Geeleher, Paul; Zichner, Thomas; Gustafson, E. Hilary; Ciglar, Lucia; Korbel, Jan O.; Furlong, Eileen E.M. (January 2016). "Shadow Enhancers Are Pervasive Features of Developmental Regulatory Networks". Current Biology. 26 (1): 38–51. Bibcode:2016CBio...26...38C. doi:10.1016/j.cub.2015.11.034. ISSN   0960-9822. PMC   4712172 . PMID   26687625.
  5. ↑ Osterwalder, Marco; Barozzi, Iros; Tissières, Virginie; Fukuda-Yuzawa, Yoko; Mannion, Brandon J.; Afzal, Sarah Y.; Lee, Elizabeth A.; Zhu, Yiwen; Plajzer-Frick, Ingrid; Pickle, Catherine S.; Kato, Momoe (February 2018). "Enhancer redundancy provides phenotypic robustness in mammalian development". Nature. 554 (7691): 239–243. Bibcode:2018Natur.554..239O. doi:10.1038/nature25461. ISSN   1476-4687. PMC   5808607 . PMID   29420474.
  6. ↑ Garnett, Aaron T.; Square, Tyler A.; Medeiros, Daniel M. (2012-11-15). "BMP, Wnt and FGF signals are integrated through evolutionarily conserved enhancers to achieve robust expression of Pax3 and Zic genes at the zebrafish neural plate border". Development. 139 (22): 4220–4231. doi:10.1242/dev.081497. ISSN   0950-1991. PMC   4074300 . PMID   23034628.
  7. ↑ Bomblies, Kirsten; Dagenais, Nicole; Weigel, Detlef (1999-12-01). "Redundant Enhancers Mediate Transcriptional Repression of AGAMOUS by APETALA2". Developmental Biology. 216 (1): 260–264. doi: 10.1006/dbio.1999.9504 . ISSN   0012-1606. PMID   10588876.
  8. ↑ Whitney, Peter H.; Shrestha, Bikhyat; Xiong, Jiahan; Zhang, Tom; Rushlow, Christine A. (2022-11-01). "Shadow enhancers modulate distinct transcriptional parameters that differentially effect downstream patterning events". Development. 149 (21): dev200940. doi:10.1242/dev.200940. ISSN   0950-1991. PMC   9687063 . PMID   36264246.
  9. ↑ Wunderlich, Zeba; Bragdon, Meghan D. J.; Vincent, Ben J.; White, Jonathan A.; Estrada, Javier; DePace, Angela H. (2015-09-22). "Krüppel Expression Levels Are Maintained through Compensatory Evolution of Shadow Enhancers". Cell Reports. 12 (11): 1740–1747. doi:10.1016/j.celrep.2015.08.021. ISSN   2211-1247. PMC   4581983 .
  10. ↑ Fletcher, Alvaro; Wunderlich, Zeba; Enciso, German (2023-05-19). "Shadow enhancers mediate trade-offs between transcriptional noise and fidelity". PLOS Computational Biology. 19 (5): e1011071. Bibcode:2023PLSCB..19E1071F. doi: 10.1371/journal.pcbi.1011071 . ISSN   1553-7358. PMC   10234526 . PMID   37205714.
  11. ↑ Dresch, Jacqueline M; Nourie, Luke L; Conrad, Regan D; Carlson, Lindsay T; Tchantouridze, Elizabeth I; Tesfaye, Biruck; Verhagen, Eleanor; Gupta, Mahima; Borges-Rivera, Diego; Drewell, Robert A (2025-01-01). "Two coacting shadow enhancers regulate twin of eyeless expression during early Drosophila development". Genetics. 229 (1): 1–43. doi:10.1093/genetics/iyae176. ISSN   1943-2631. PMC   11708921 . PMID   39607769.
  12. ↑ Perry, Michael W.; Boettiger, Alistair N.; Bothma, Jacques P.; Levine, Michael (September 2010). "Shadow Enhancers Foster Robustness of Drosophila Gastrulation". Current Biology. 20 (17): 1562–1567. Bibcode:2010CBio...20.1562P. doi:10.1016/j.cub.2010.07.043. ISSN   0960-9822. PMC   4257487 . PMID   20797865.


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