Functional and topological characteristics of mammalian regulatory domains
Open accessAbstract
Long-range regulatory interactions play an important role in shaping gene-expression programs. However, the genomic features that organize these activities are still poorly characterized. We conducted a large operational analysis to chart the distribution of gene regulatory activities along the mouse genome, using hundreds of insertions of a regulatory sensor. We found that enhancers distribute their activities along broad regions and not in a gene-centric manner, defining large regulatory domains. Remarkably, these domains correlate strongly with the recently described TADs, which partition the genome into distinct self-interacting blocks. Different features, including specific repeats and CTCF-binding sites, correlate with the transition zones separating regulatory domains, and may help to further organize promiscuously distributed regulatory influences within large domains. These findings support a model of genomic organization where TADs confine regulatory activities to specific but large regulatory domains, contributing to the establishment of specific gene expression profiles.
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TADs appear to restrict the areas of enhancer action.
“Second, it was demonstrated that eukaryotic chromosomes are partitioned into so-called topologically associated domains (TADs) [35,36,37], which appear to restrict the areas of enhancer action [38,39,40,41].”
From Enhancer Function in the 3D Genome (2023) · cites this paper as [38]
The ability to establish contacts between enhancers and promoters is partially controlled at the level of chromosome organization into TADs, which in many cases limit the scope of enhancers.
“The ability to establish contacts between enhancers and promoters is partially controlled at the level of chromosome organization into topologically associated domains, which in many cases limit the scope of enhancers [38,41,130,131].”
From Enhancer Function in the 3D Genome (2023) · cites this paper as [38]
Chromatin domains span >90% of the genome and are thought to create insulated neighborhoods demarcating the search space of specific long-range interactions between enhancers and their target genes.
“Such chromatin domains span >90% of the genome and are thought to create insulated neighborhoods demarcating the search space of specific long-range interactions between enhancers and their target genes (Dowen et al., 2014; Narendra et al., 2015; Symmons et al., 2014).”
From Disease-Associated Short Tandem Repeats Co-localize with Chromatin Domain Boundaries (2018) · cites this paper as Symmons et al., 2014
TADs correspond to functional regulatory domains by primarily restricting contact between enhancers and promoters to occur within the same TAD.
“A large body of evidence suggests that TADs correspond to functional regulatory domains by primarily restricting contact between enhancers and promoters to occur within the same TAD3,21–25”
From Recent evidence that TADs and chromatin loops are dynamic structures (2018) · cites this paper as [24]
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Formation of chromosomal domains by loop extrusion
Fudenberg, G., Imakaev, M., Lu, C., Goloborodko, A., Abdennur, N., & Mirny, L. A. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.04.085 · Cited by 2,003 · see citing works
Two independent modes of chromatin organization revealed by cohesin removal
Schwarzer, W., Abdennur, N., Goloborodko, A., Pekowska, A., Fudenberg, G., Loe-Mie, Y., Fonseca, N. A., Huber, W., Haering, C. H., Mirny, L., et al. (2017) · Nature · doi:10.1038/nature24281 · Cited by 1,196 · see citing works
Self-citationLong-range enhancer–promoter contacts in gene expression control
Schoenfelder, S., & Fraser, P. (2019) · Nature Reviews Genetics · doi:10.1038/s41576-019-0128-0 · Cited by 1,102 · see citing works
The 3D Genome as Moderator of Chromosomal Communication
Dekker, J., & Mirny, L. (2016) · Cell · doi:10.1016/j.cell.2016.02.007 · Cited by 937 · see citing works
Mapping Nucleosome Resolution Chromosome Folding in Yeast by Micro-C
Hsieh, T.-H. S., Weiner, A., Lajoie, B., Dekker, J., Friedman, N., & Rando, O. J. (2015) · Cell · doi:10.1016/j.cell.2015.05.048 · Cited by 788 · see citing works
CTCF Binding Polarity Determines Chromatin Looping
de Wit, E., Vos, E. S. M., Holwerda, S. J. B., Valdes-Quezada, C., Verstegen, M. J. A. M., Teunissen, H., Splinter, E., Wijchers, P. J., Krijger, P. H. L., & de Laat, W. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.09.023 · Cited by 641 · see citing works
Formation of new chromatin domains determines pathogenicity of genomic duplications
Franke, M., Ibrahim, D. M., Andrey, G., Schwarzer, W., Heinrich, V., Schöpflin, R., Kraft, K., Kempfer, R., Jerković, I., Chan, W.-L., et al. (2016) · Nature · doi:10.1038/nature19800 · Cited by 673 · see citing works
Self-citationVisualizing 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
The 3D genome in transcriptional regulation and pluripotency
Gorkin, D. U., Leung, D., & Ren, B. (2014) · Cell Stem Cell · doi:10.1016/j.stem.2014.05.017 · Cited by 391 · see citing works
Nonlinear control of transcription through enhancer–promoter interactions
Zuin, J., Roth, G., Zhan, Y., Cramard, J., Redolfi, J., Piskadlo, E., Mach, P., Kryzhanovska, M., Tihanyi, G., Kohler, H., et al. (2022) · Nature · doi:10.1038/s41586-022-04570-y · Cited by 415 · see citing works
Weischenfeldt, J., Dubash, T., Drainas, A. P., Mardin, B. R., Chen, Y., Stütz, A. M., Waszak, S. M., Bosco, G., Halvorsen, A. R., Raeder, B., et al. (2017) · Nature Genetics · doi:10.1038/ng.3722 · Cited by 404 · see citing works
Hsieh, T.-H. S., Cattoglio, C., Slobodyanyuk, E., Hansen, A. S., Darzacq, X., & Tjian, R. (2022) · Nature Genetics · doi:10.1038/s41588-022-01223-8 · Cited by 406 · see citing works
YY1 and CTCF orchestrate a 3D chromatin looping switch during early neural lineage commitment
Beagan, J. A., Duong, M. T., Titus, K. R., Zhou, L., Cao, Z., Ma, J., Lachanski, C. V., Gillis, D. R., & Phillips-Cremins, J. E. (2017) · Genome Research · doi:10.1101/gr.215160.116 · Cited by 299 · see citing works
“A leading hypothesis is that sub-TAD/TAD boundaries, anchored by constitutive CTCF, might constrain developmentally regulated enhancers from aberrantly looping to off-target genes (Dowen et al. 2014; Symmons et al. 2014; Lupiáñez et al. 2015; Flavahan et al. 2016; Hnisz et al. 2016).”
Distinct Classes of Chromatin Loops Revealed by Deletion of an RNA-Binding Region in CTCF
Hansen, A. S., Hsieh, T.-H. S., Cattoglio, C., Pustova, I., Saldaña-Meyer, R., Reinberg, D., Darzacq, X., & Tjian, R. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.07.039 · Cited by 279 · see citing works
Recent evidence that TADs and chromatin loops are dynamic structures
Hansen, A. S., Cattoglio, C., Darzacq, X., & Tjian, R. (2018) · Nucleus · doi:10.1080/19491034.2017.1389365 · Cited by 266 · see citing works
Disease-Associated Short Tandem Repeats Co-localize with Chromatin Domain Boundaries
Sun, J. H., Zhou, L., Emerson, D. J., Phyo, S. A., Titus, K. R., Gong, W., Gilgenast, T. G., Beagan, J. A., Davidson, B. L., Tassone, F., et al. (2018) · Cell · doi:10.1016/j.cell.2018.08.005 · Cited by 249 · see citing works
“Such chromatin domains span >90% of the genome and are thought to create insulated neighborhoods demarcating the search space of specific long-range interactions between enhancers and their target genes (Dowen et al., 2014; Narendra et al., 2015; Symmons et al., 2014).”
BackgroundTranscription in Living Cells: Molecular Mechanisms of Bursting
Rodriguez, J., & Larson, D. R. (2020) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-011520-105250 · Cited by 224 · see citing works
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
Hi-C analyses with GENOVA: a case study with cohesin variants
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Aljahani, A., Hua, P., Karpinska, M. A., Quililan, K., Davies, J. O. J., & Oudelaar, A. M. (2022) · Nature Communications · doi:10.1038/s41467-022-29696-5 · Cited by 121 · see citing works
Stochastic motion and transcriptional dynamics of pairs of distal DNA loci on a compacted chromosome
Brückner, D. B., Chen, H., Barinov, L., Zoller, B., & Gregor, T. (2023) · Science · doi:10.1126/science.adf5568 · Cited by 112 · see citing works
Gain of CTCF-Anchored Chromatin Loops Marks the Exit from Naive Pluripotency
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Nonlinear control of transcription through enhancer-promoter interactions
Zuin, J., Roth, G., Zhan, Y., Cramard, J., Redolfi, J., Piskadlo, E., Mach, P., Kryzhanovska, M., Tihanyi, G., Kohler, H., et al. (2021) · doi:10.1101/2021.04.22.440891 · Cited by 67 · see citing works
Crossed wires: 3D genome misfolding in human disease
Norton, H. K., & Phillips-Cremins, J. E. (2017) · Journal of Cell Biology · doi:10.1083/jcb.201611001 · Cited by 57 · see citing works
Long-range regulation of transcription scales with genomic distance in a gene-specific manner
Jensen, C. L., Chen, L.-F., Swigut, T., Crocker, O. J., Yao, D., Bassik, M. C., Ferrell, J. E., Boettiger, A. N., & Wysocka, J. (2025) · Molecular Cell · doi:10.1016/j.molcel.2024.10.021 · Cited by 39 · see citing works
Narducci, D. N., & Hansen, A. S. (2025) · Molecular Cell · doi:10.1016/j.molcel.2024.11.032 · Cited by 25 · 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
Between form and function: the complexity of genome folding
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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
- Symmons, O., Uslu, V. V., Tsujimura, T., Ruf, S., Nassari, S., Schwarzer, W., Ettwiller, L., & Spitz, F.
- Affiliations
- European Molecular Biology Laboratory (DE)
- Heidelberg University (DE)
- Corresponding author
- Spitz, François
- ORCID
- Venue
- Genome Research
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2014-01-07
- Volume
- 24
- Issue
- 3
- Pages
- 390-400
- ISSN
- 1088-9051 (ISSN-L)
- PMC
- PMC3941104
- OpenAlex
- W2107866789
- Cited by
- 455
- References
- 86
- Citations by year
- 2026: 16 · 2025: 30 · 2024: 32 · 2023: 39 · 2022: 41 · 2021: 43 · 2020: 42 · 2019: 45 · 2018: 39 · 2017: 47 · 2016: 39 · 2015: 31 · 2014: 10
- Type
- posted content
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Genome Research (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Uehara Memorial Foundation
- European Molecular Biology Laboratory
- European Commission (223210)
- Louis-Jeantet Foundation
- Darwin Trust of Edinburgh
- Japan Society for the Promotion of Science
- 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
- topologically associating domains, enhancers, CTCF binding sites, chromatin looping, mouse genome, genome organization, gene expression regulation
- MeSH terms
- CCCTC-Binding Factor, Cohesins, Animals, Binding Sites, Chromosomal Proteins, Non-Histone, Embryo, Mammalian, Enhancer Elements, Genetic, Regulatory Sequences, Nucleic Acid, Repetitive Sequences, Nucleic Acid, Repressor Proteins, Genome, Cell Cycle Proteins, Mice
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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.
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