Quantitative genome-wide enhancer activity maps for five Drosophila species show functional enhancer conservation and turnover during cis-regulatory evolution
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Phenotypic differences between closely related species are thought to arise primarily from changes in gene expression due to mutations in cis-regulatory sequences (enhancers). However, it has remained unclear how frequently mutations alter enhancer activity or create functional enhancers de novo. Here we use STARR-seq, a recently developed quantitative enhancer assay, to determine genome-wide enhancer activity profiles for five Drosophila species in the constant trans-regulatory environment of Drosophila melanogaster S2 cells. We find that the functions of a large fraction of D. melanogaster enhancers are conserved for their orthologous sequences owing to selection and stabilizing turnover of transcription factor motifs. Moreover, hundreds of enhancers have been gained since the D. melanogaster-Drosophila yakuba split about 11 million years ago without apparent adaptive selection and can contribute to changes in gene expression in vivo. Our finding that enhancer activity is often deeply conserved and frequently gained provides functional insights into regulatory evolution.
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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 [106]
The Results sections “Specific selection of transcription factor sequence motifs” and “Compensatory changes stabilize regulatory output” link conserved enhancer activity to transcription-factor motifs rather than overall sequence identity, and show that lost motifs can be replaced at different positions. The paper does not establish that binding-site orientation is often unconserved, and its findings concern the assayed Drosophila enhancers rather than enhancers generally. Page numbers are unavailable in our copy. (LLM, conf=0.85)
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- Authors
- Arnold, C. D., Gerlach, D., Spies, D., Matts, J. A., Sytnikova, Y. A., Pagani, M., Lau, N. C., & Stark, A.
- Affiliations
- Research Institute of Molecular Pathology (AT)
- Brandeis University (US)
- Corresponding author
- Stark, Alexander
- Venue
- Nature Genetics
- Published
- 2014-06-08
- Volume
- 46
- Issue
- 7
- Pages
- 685-692
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC4250274
- OpenAlex
- W2170739826
- Cited by
- 175
- References
- 46
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 11 · 2023: 15 · 2022: 17 · 2021: 13 · 2020: 18 · 2019: 14 · 2018: 14 · 2017: 11 · 2016: 19 · 2015: 23 · 2014: 5
- FWCI
- 7.93
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD057298, R00HD057298, K99HD057298)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- enhancer activity, cis-regulatory evolution, enhancer conservation, STARR-seq, Drosophila species, Drosophila melanogaster, Drosophila yakuba, transcription factor binding motifs, gene expression evolution
- MeSH terms
- Animals, Cells, Cultured, Drosophila, Enhancer Elements, Genetic, Luciferases, Transcription Factors, Genome, Evolution, Molecular, Gene Expression Profiling, Drosophila Proteins, High-Throughput Nucleotide Sequencing
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