Signal Integration by Shadow Enhancers and Enhancer Duplications Varies across the Drosophila Embryo
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Abstract
Transcription of developmental genes is controlled by multiple enhancers. Frequently, more than one enhancer can activate transcription from the same promoter in the same cells. How is regulatory information from multiple enhancers combined to determine the overall expression output? We measure nascent transcription driven by a pair of shadow enhancers, each enhancer of the pair separately, and each duplicated, using live imaging in Drosophila embryos. This set of constructs allows us to quantify the input-output function describing signal integration by two enhancers. We show that signal integration performed by these shadow enhancers and duplications varies across the expression pattern, implying that how their activities are combined depends on the transcriptional regulators bound to the enhancers in different parts of the embryo. Characterizing signal integration by multiple enhancers is a critical step in developing conceptual and computational models of gene expression at the locus level, where multiple enhancers control transcription together.
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Some deviations from enhancer additivity could potentially be explained by steric constraints arising from enhancer competition or involvement of pioneer enhancers, but these considerations may not readily explain other reported cases.
“Some deviations from enhancer additivity could potentially be explained by steric constraints arising from enhancer competition [519] or involvement of “pioneer enhancers” [525], but these considerations may not readily explain other reported cases [523, 526].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [526]
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Kapil, S., & Kaur, T. (2022) · Indian Journal of Entomology · doi:10.55446/ije.2021.371
Development and Evolution of Drosophila Chromatin Landscape in a 3D genome contextPreprint
Ali, M., Younas, L., Liu, J., & Zhou, Q. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.11.28.518159
A mathematical model clarifies the ABC Score formula used in enhancer-gene predictionPreprint
Nasser, J., Nam, K.-M., & Gunawardena, J. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.11.29.626072
A mathematical model clarifies the ABC Score formula used in enhancer-gene predictionPreprint
Nasser, J., Nam, K.-M., & Gunawardena, J. (2025) · eLife · doi:10.7554/elife.105740
Integration by parts: The multi-layered mechanisms of cis-regulatory control
Cornwall-Scoones, J., Briscoe, J., & Delàs, M. J. (2026) · Molecular Cell · doi:10.1016/j.molcel.2026.09.016
- Authors
- Scholes, C., Biette, K. M., Harden, T. T., & DePace, A. H.
- Affiliations
- Harvard University (US)
- Corresponding author
- DePace, Angela H.
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2019-02
- Volume
- 26
- Issue
- 9
- Pages
- 2407-2418.e5
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC6597254
- OpenAlex
- W2917637208
- Cited by
- 44
- References
- 59
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 5 · 2023: 6 · 2022: 6 · 2021: 12 · 2020: 7 · 2019: 1
- FWCI
- 2.15
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Science Foundation (IOS-1452557)
- NIH (4U01GM103804-04)
- Giovanni Armenise-Harvard Foundation
- Harvard Graduate Society Merit Fellowship
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- nascent transcription, input-output function, transcriptional regulation, Drosophila embryo, live imaging, gene expression patterning, transcription factors
- MeSH terms
- Animals, Drosophila melanogaster, Embryo, Nonmammalian, Enhancer Elements, Genetic, Promoter Regions, Genetic, Gene Expression Regulation, Developmental, Drosophila Proteins, Kruppel-Like Transcription Factors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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