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Cited by 235Genomics and Chromatin DynamicsDevelopmental Biology and Gene RegulationGene Regulatory Network Analysis

Shadow Enhancers Are Pervasive Features of Developmental Regulatory Networks

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Cannavò, Enrico, Khoueiry, Pierre, Garfield, David A., Geeleher, Paul, Zichner, Thomas, Gustafson, E. Hilary, Ciglar, Lucia, Korbel, Jan O. +1 more·2016·Current Biology
DOI 10.1016/j.cub.2015.11.034PMC PMC4712172
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Abstract

Embryogenesis is remarkably robust to segregating mutations and environmental variation; under a range of conditions, embryos of a given species develop into stereotypically patterned organisms. Such robustness is thought to be conferred, in part, through elements within regulatory networks that perform similar, redundant tasks. Redundant enhancers (or "shadow" enhancers), for example, can confer precision and robustness to gene expression, at least at individual, well-studied loci. However, the extent to which enhancer redundancy exists and can thereby have a major impact on developmental robustness remains unknown. Here, we systematically assessed this, identifying over 1,000 predicted shadow enhancers during Drosophila mesoderm development. The activity of 23 elements, associated with five genes, was examined in transgenic embryos, while natural structural variation among individuals was used to assess their ability to buffer against genetic variation. Our results reveal three clear properties of enhancer redundancy within developmental systems. First, it is much more pervasive than previously anticipated, with 64% of loci examined having shadow enhancers. Their spatial redundancy is often partial in nature, while the non-overlapping function may explain why these enhancers are maintained within a population. Second, over 70% of loci do not follow the simple situation of having only two shadow enhancers-often there are three (rols), four (CadN and ade5), or five (Traf1), at least one of which can be deleted with no obvious phenotypic effects. Third, although shadow enhancers can buffer variation, patterns of segregating variation suggest that they play a more complex role in development than generally considered.

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  • Sub-additivity may underlie some cases of functional enhancer redundancy, such as for Drosophila shadow enhancers that can back up important developmental enhancers and enable them to accumulate deleterious mutations.

    “Sub-additivity may also underlie some cases of functional enhancer redundancy, such as for Drosophila “shadow enhancers” that can “back up” important developmental enhancers and enable them to accumulate deleterious mutations [520–522].”

    From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [522]

    The Results section (“Shadow Enhancers Can Buffer the Effects of Natural Sequence Variation”; page unavailable) says redundant enhancers can compensate for mutations that disable a partner, supporting the backup role. Our copy does not link that role to sub-additivity or establish that backup enables important developmental enhancers to accumulate deleterious mutations; the Discussion (“How Are Redundant Enhancers Maintained during Evolution?”; page unavailable) instead reports no support for a related hypothesis that shadow enhancers accumulate mutations under relaxed constraint. (LLM, conf=0.84)

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Cited by

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Authors
Cannavò, E., Khoueiry, P., Garfield, D. A., Geeleher, P., Zichner, T., Gustafson, E. H., Ciglar, L., Korbel, J. O., & Furlong, E. E. M.
Affiliations
European Molecular Biology Laboratory (DE)
Corresponding author
Furlong, Eileen E.M.
ORCID
Venue
Current Biology
Publisher
Elsevier BV
Published
2016-01
Volume
26
Issue
1
Pages
38-51
ISSN
0960-9822 (ISSN-L)
DOI
10.1016/j.cub.2015.11.034
PMC
PMC4712172
OpenAlex
W2194390873
Cited by
235
References
5
Citations by year
2026: 8 · 2025: 7 · 2024: 37 · 2023: 29 · 2022: 18 · 2021: 26 · 2020: 27 · 2019: 18 · 2018: 27 · 2017: 24 · 2016: 12 · 2015: 1
FWCI
9.27
Type
journal article
Language
en
Open access
Licence
Locations
  • Current Biology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
Keywords
enhancer redundancy, developmental robustness, gene regulatory networks, embryonic patterning
MeSH terms
Animals, Drosophila, Enhancer Elements, Genetic, Transcription, Genetic, Gene Expression Regulation, Developmental, Embryonic Development

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