Uncoupling evolutionary changes in DNA sequence, transcription factor occupancy and enhancer activity
Open accessAbstract
Sequence variation within enhancers plays a major role in both evolution and disease, yet its functional impact on transcription factor (TF) occupancy and enhancer activity remains poorly understood. Here, we assayed the binding of five essential TFs over multiple stages of embryogenesis in two distant Drosophila species (with 1.4 substitutions per neutral site), identifying thousands of orthologous enhancers with conserved or diverged combinatorial occupancy. We used these binding signatures to dissect two properties of developmental enhancers: (1) potential TF cooperativity, using signatures of co-associations and co-divergence in TF occupancy. This revealed conserved combinatorial binding despite sequence divergence, suggesting protein-protein interactions sustain conserved collective occupancy. (2) Enhancer in-vivo activity, revealing orthologous enhancers with conserved activity despite divergence in TF occupancy. Taken together, we identify enhancers with diverged motifs yet conserved occupancy and others with diverged occupancy yet conserved activity, emphasising the need to functionally measure the effect of divergence on enhancer activity.
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Enhancer conservation is typically modular, commonly preserving the sets of binding sites for the required transcription factors, but often not their exact sequence and orientation.
“Instead, enhancer conservation is typically “modular”, commonly preserving the sets of binding sites for the required TFs, but often not their exact sequence and orientation [101–109].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [109]
The Results section, “Conserved enhancer occupancy is associated with enhancer function” (page unavailable), says evolutionary constraints likely select for overall enhancer composition rather than the positions of individual binding sites. The Results section, “TF binding site divergence is tolerated in the context of collective TF binding” (page unavailable), also reports conserved Tin occupancy despite motif divergence in enhancers bound by many factors. These findings support flexibility in some enhancers, but do not establish that enhancer conservation is typically modular or that exact binding-site orientation is often not preserved. (LLM, conf=0.83)
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- Authors
- Khoueiry, P., Girardot, C., Ciglar, L., Peng, P.-C., Gustafson, E. H., Sinha, S., & Furlong, E. E.
- Affiliations
- European Molecular Biology Laboratory (DE)
- University of Illinois Urbana-Champaign (US)
- Corresponding author
- Furlong, Eileen EM
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2017-08-09
- Volume
- 6
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC5550276
- OpenAlex
- W2744132129
- Cited by
- 44
- References
- 92
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 4 · 2023: 2 · 2022: 3 · 2021: 13 · 2020: 7 · 2019: 4 · 2018: 6 · 2017: 1
- FWCI
- 2.12
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Marie Curie (ITN EvoNet)
- Deutsche Forschungsgemeinschaft (DFG FU750)
- National Institutes of Health (R01GM114341)
- European Molecular Biology Organization (Long-term fellowship)
- 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 › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
- Keywords
- enhancer evolution, transcription factor occupancy, enhancer activity, sequence divergence, protein-protein interaction, Drosophila, embryonic development
- MeSH terms
- Animals, DNA, Drosophila, Enhancer Elements, Genetic, Protein Binding, Transcription Factors, Evolution, Molecular
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