Large distances separate coregulated genes in living Drosophila embryos
Open accessAbstract
Significance: The prevailing model of gene activation is the looping of a distal enhancer to its target promoter, although it remains uncertain whether enhancers must come into direct contact. Recent studies suggest that clusters of RNA polymerase II are recruited to active genes, raising the possibility that enhancers cannot get too close to their target promoters due to molecular crowding. Here, we use live imaging methods to visualize genes that are simultaneously regulated by a single enhancer both in cis and in trans. We present evidence that these coregulated genes are separated by a substantial distance—at least 100–200 nm—during transcription. These observations challenge the textbook view of enhancer function and raise the possibility of an action-at-a-distance model for gene expression.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Genes regulated by a single enhancer can localise surprisingly large distances away from each other in 3D (at least 100-200 nm), and yet show coordinated bursts in transcription, which is inconsistent with their direct looping to the shared enhancer.
“In addition, using high-resolution live imaging, it was observed that genes regulated by a single enhancer can localise surprisingly large distances away from each other in 3D (at least 100–200 nm), and yet show coordinated bursts in transcription, which is inconsistent with their direct looping to the shared enhancer [409].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [409]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredIn most of the cases studied, the establishment of communication between the enhancer and the promoter correlates with a reduction in the distance between them, but this distance still remains significant (100-400 nm).
“In most of the cases studied, the establishment of communication between the enhancer and the promoter correlates with a reduction in the distance between them. However, this distance still remains significant (100–400 nm [34,101,102,103].”
From Enhancer Function in the 3D Genome (2023) · cites this paper as [101]
In the Significance passage (page unavailable), the paper reports that coregulated alleles are closer than alleles regulated by separate enhancers, yet remain 282 ± 124 nm apart during transvection. It also estimates enhancer–promoter separation of roughly 100–300 nm during transcription. These findings support substantial remaining distance in the studied system, but not the broader assertion that distance decreases in most cases studied. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Structural Basis of Transcription: RNA Polymerase II at 2.8 Ångstrom Resolution
Cramer, P., Bushnell, D. A., & Kornberg, R. D. (2001) · Science · doi:10.1126/science.1059493 · Cited by 1,247 · see citing works
Visualizing DNA folding and RNA in embryos at single-cell resolution
Mateo, L. J., Murphy, S. E., Hafner, A., Cinquini, I. S., Walker, C. A., & Boettiger, A. N. (2019) · Nature · doi:10.1038/s41586-019-1035-4 · Cited by 446 · see citing works
Rapid Rates of Pol II Elongation in the Drosophila Embryo
Fukaya, T., Lim, B., & Levine, M. (2017) · Current Biology · doi:10.1016/j.cub.2017.03.069 · Cited by 84 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 4
- W. K. Cho et al., RNA Polymerase II cluster dynamics predict mRNA output in living cells. eLife 5, e13617 (2016).
- Y. Shin et al., Liquid nuclear condensates mechanically sense and restructure the genome. Cell 175, 1481-1491.e13 (2018). Erratum in: Cell 176, 1518 (2019).
- J. M. Alexander et al., Live-cell imaging reveals enhancer-dependent Sox2 transcrip- tion in the absence of enhancer proximity. elife 8, e41769 (2019).
- J. Li et al., Single-molecule nanoscopy elucidates RNA polymerase II transcription at single genes in live cells. Cell, 10.1016/j.cell.2019.05.029 (2019). · DOI
Cited by
Sorted by citations
Enhancer selectivity in space and time: from enhancer–promoter interactions to promoter activation
Yang, J. H., & Hansen, A. S. (2024) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-024-00710-6 · Cited by 191 · see citing works
How subtle changes in 3D structure can create large changes in transcription
Xiao, J. Y., Hafner, A., & Boettiger, A. N. (2021) · eLife · doi:10.7554/elife.64320 · Cited by 162 · see citing works
A matter of time: Using dynamics and theory to uncover mechanisms of transcriptional bursting
Lammers, N. C., Kim, Y. J., Zhao, J., & Garcia, H. G. (2020) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2020.08.001 · Cited by 99 · see citing works
“In vivo measurements of enhancer-promoter separation in the Drosophila embryo have shown that this distance fluctuates with a timescale of tens of seconds to several minutes [96–98] —timescales strikingly similar to those of bursting.”
BackgroundTranscriptional enhancers and their communication with gene promoters
Ray-Jones, H., & Spivakov, M. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-021-03903-w · Cited by 81 · see citing works
Enhancer Function in the 3D Genome
Razin, S. V., Ulianov, S. V., & Iarovaia, O. V. (2023) · Genes · doi:10.3390/genes14061277 · Cited by 15 · see citing works
Live-cell imaging of enhancer-promoter dynamics reveals transient contact-driven gene activation
Yang, J. H., Pinholt, H. D., Toppen, J., Huseyin, M. K., Jusuf, J. M., Katsifis, C. C., Kæstel-Hansen, J., Mirny, L. A., Zechner, C., & Hansen, A. S. (2026) · doi:10.64898/2026.06.21.733446 · Cited by 3 · see citing works
- Authors
- Heist, T., Fukaya, T., & Levine, M.
- Affiliations
- Princeton University (US)
- Institute for Quantitative Biosciences, The University of Tokyo (JP)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2019-07-08
- Volume
- 116
- Issue
- 30
- Pages
- 15062-15067
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC6660726
- OpenAlex
- W2961406494
- Cited by
- 89
- References
- 3
- Citations by year
- 2026: 4 · 2025: 21 · 2024: 20 · 2023: 7 · 2022: 11 · 2021: 12 · 2020: 10 · 2019: 4
- FWCI
- 3.06
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | National Institutes of Health (GM118147)
- 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 › Chromatin Remodeling and Cancer
- Keywords
- enhancer-promoter interactions, co-regulated genes, Drosophila embryo, cis-regulation
- MeSH terms
- Snail Family Transcription Factors, Red Fluorescent Protein, Alleles, Animals, Drosophila melanogaster, Embryo, Nonmammalian, Enhancer Elements, Genetic, Lac Operon, Luminescent Proteins, Models, Genetic, Promoter Regions, Genetic, RNA Polymerase II, DNA-Directed RNA Polymerases, Transcription, Genetic, Genes, Reporter, Gene Expression Regulation, Developmental, Animals, Genetically Modified, Green Fluorescent Proteins, Molecular Imaging, Chromosomes, Insect
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.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
