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Topologically associating domains and chromatin loops depend on cohesin and are regulated by CTCF, WAPL, and PDS5 proteins
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Abstract
Mammalian genomes are spatially organized into compartments, topologically associating domains (TADs), and loops to facilitate gene regulation and other chromosomal functions. How compartments, TADs, and loops are generated is unknown. It has been proposed that cohesin forms TADs and loops by extruding chromatin loops until it encounters CTCF, but direct evidence for this hypothesis is missing. Here, we show that cohesin suppresses compartments but is required for TADs and loops, that CTCF defines their boundaries, and that the cohesin unloading factor WAPL and its PDS5 binding partners control the length of loops. In the absence of WAPL and PDS5 proteins, cohesin forms extended loops, presumably by passing CTCF sites, accumulates in axial chromosomal positions (vermicelli), and condenses chromosomes. Unexpectedly, PDS5 proteins are also required for boundary function. These results show that cohesin has an essential genome-wide function in mediating long-range chromatin interactions and support the hypothesis that cohesin creates these by loop extrusion, until it is delayed by CTCF in a manner dependent on PDS5 proteins, or until it is released from DNA by WAPL.
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“Contacts between convergent CTCF binding sites are established by the extrusion of chromatin loops with cohesin [42,46,48,93].”
From Enhancer Function in the 3D Genome (2023) · cites this paper as [48]
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“Convergent binding sites for the versatile transcription factor CTCF (CCCTC-binding factor) located at TAD borders [46] block the movement of loop extruders [47,48,49].”
From Enhancer Function in the 3D Genome (2023) · cites this paper as [48]
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“The CTCF Y226A F228A mutation, like CTCF depletion, only slightly affects the contact probability profile.”
From The structural basis for cohesin–CTCF-anchored loops (2020) · cites this paper as [12]
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Lüthi, B. N., Semple, J. I., Haemmerli, A., Thapliyal, S., Ghadage, K., Stojanovski, K., D’Asaro, D., Das, M., Gilbert, N., Glauser, D. A., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-67302-6 · Cited by 28
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Brca2, Pds5 and Wapl differentially control cohesin chromosome association and function
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Postmitotic differentiation of human monocytes requires cohesin-structured chromatin
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Nanoscale 3D DNA tracing in single human cells visualizes loop extrusion directly in situPreprint
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“Recent studies also showed that cohesion complex – mediated chromatin loop extrusion results in Igh locus contraction that is helpful for RAG scanning (59 – 62).”
BackgroundCohesin supercoils DNA during loop extrusion
Davidson, I. F., Barth, R., Nagasaka, K., Tang, W., Wutz, G., Horn, S., Janissen, R., Stocsits, R. R., Chlosta, E., Bauer, B. W., et al. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.115856 · Cited by 24
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The Functions and Mechanisms of Action of Insulators in the Genomes of Higher Eukaryotes
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MethodChromatin Alterations in Neurological Disorders and Strategies of (Epi)Genome Rescue
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“CTCF results in a loss (32, 33) or weakening (34) of ~80% of TADs across the genome; but 66 not all TADs depend on CTCF.”
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“Various experiments have described the relevance of the binding motif orientation for loop formation by inverting or deleting CTCF binding sites using CRISPR / Cas9 experiments (12,13).”
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“Cohesin, an essential multiprotein complex, undergoes loading and unloading onto chromosomes in a dynamic fashion during the cell cycle, mediating sister chromatid cohesion and ensuring the equal separation of the genetic material to daughter cells (18, 19).”
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Zhang, M., Huang, H., Li, J., & Wu, Q. (2024) · Cell Reports · doi:10.1016/j.celrep.2023.113663 · Cited by 20
Cohesin regulation and roles in chromosome structure and function
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PDS5B regulates cell proliferation and motility via upregulation of Ptch2 in pancreatic cancer cells
Ma, J., Cui, Y., Cao, T., Xu, H., Shi, Y., Xia, J., Tao, Y., & Wang, Z. P. (2019) · Cancer Letters · doi:10.1016/j.canlet.2019.06.014 · Cited by 19
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“This partial effect could be due to Wpl1 activity removing cohesin from DNA at this stage (Haarhuis et al., 2017; Kueng et al., 2006; Wutz et al., 2017).”
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“Pds5 proteins are also required for proper maintenance of heterochromatin [55] and participate in chromatin loop formation [56,57].”
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Modulation of the high-order chromatin structure by Polycomb complexes
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“cohesin complex, a multi-subunit ring-like motor protein machinery, uses the ATP hydrolysis-generated energy to extrude DNA and progressively enlarge DNA loops until it is stalled by the CCCTC-binding factor (CTCF) (Sanborn et al., 2015; Fudenberg et al., 2016; Merkenschlager and Nora, 2016; Wutz et al., 2017; Rowley…”
BackgroundATM signaling modulates cohesin behavior in meiotic prophase and proliferating cells
Yu, Z., Kim, H. J., & Dernburg, A. F. (2023) · Nature Structural & Molecular Biology · doi:10.1038/s41594-023-00929-5 · Cited by 18
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“In this context, depletion of WAPL in nonlymphoid cells extends genome-wide loop extrusion by increasing cohesin density, allowing it to bypass CBEs and potentially other impediments (45–47).”
EMF1 functions as a 3D chromatin modulator in Arabidopsis
Shu, J., Sun, L., Wang, D., Yin, X., Yang, M., Yang, Z., Gao, Z., He, Y., Calonje, M., Lai, J., et al. (2024) · Molecular Cell · doi:10.1016/j.molcel.2024.10.031 · Cited by 20
Condensin II inactivation in interphase does not affect chromatin folding or gene expressionPreprint
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Cohesin is required for long-range enhancer action
Kane, L., Williamson, I., Flyamer, I. M., Kumar, Y., Hill, R. E., Lettice, L. A., & Bickmore, W. A. (2021) · doi:10.1101/2021.06.24.449812 · Cited by 23
Mechanisms of Enhancer-Mediated Gene Activation in the Context of the 3D Genome
Papantonis, A., & Oudelaar, A. M. (2025) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev-genom-120423-012301 · Cited by 19
Chromatin structure changes during various processes from a DNA sequence view
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“Wutz, G.; Varnai, C.; Nagasaka, K.; Cisneros, D.A.; Stocsits, R.R.; Tang, W.; Schoenfelder, S.; Jessberger, G.; Muhar, M.; Hossain, M.J.; et al. Topologically associating domains and chromatin loops depend on cohesin and are regulated by CTCF, WAPL, and PDS5 proteins.”
BackgroundInfluentialRegulation of cohesin‐mediated chromosome folding by PDS5 in mammals
Yu, D., Chen, G., Wang, Y., Wang, Y., Lin, R., Liu, N., Zhu, P., Liu, H., Hu, T., Feng, R., et al. (2022) · EMBO Reports · doi:10.15252/embr.202254853 · Cited by 15
Three‐dimensional genome structure and function
Liu, H., Tsai, H., Yang, M., Li, G., Bian, Q., Ding, G., Wu, D., & Dai, J. (2023) · MedComm · doi:10.1002/mco2.326 · Cited by 25
The dynamic role of cohesin in maintaining human genome architecture
Agarwal, A., Korsak, S., Choudhury, A., & Plewczyński, D. (2023) · BioEssays · doi:10.1002/bies.202200240 · Cited by 14
“[20,46] For example, with the depletion of the RAD21 subunit, many Hox genes ( HOXA11AS , HOXA-AS3) are downregulated, affecting 48 other linked genes.”
BackgroundNuclear filaments: role in chromosomal positioning and gene expression
Bera, M., & Sengupta, K. (2020) · Nucleus · doi:10.1080/19491034.2020.1769445 · Cited by 17
“[84] Wutz G, Várnai C, Nagasaka K, et al.”
BackgroundFunctional organization of the maternal and paternal human 4D Nucleome
Lindsly, S., Jia, W., Chen, H., Liu, S., Ronquist, S., Chen, C., Wen, X., Stansbury, C. M., Dotson, G. A., Ryan, C., et al. (2021) · iScience · doi:10.1016/j.isci.2021.103452 · Cited by 17
Shah, R., Tortora, M. M. C., Louafi, N., Rahmaninejad, H., Hansen, K. L., Anderson, E. C., Wen, D., Giorgetti, L., Fudenberg, G., & Nora, E. P. (2025) · doi:10.1101/2025.08.14.667581 · Cited by 15
Chromatin Organization and Function in Drosophila
Llorens‐Giralt, P., Camilleri‐Robles, C., Corominas, M., & Climent‐Cantó, P. (2021) · Cells · doi:10.3390/cells10092362 · Cited by 16
Cummings, C. T., & Rowley, M. J. (2022) · Genes · doi:10.3390/genes13040583 · Cited by 15
“Addition of the AID tag to CTCF or cohesin resulted in partial depletion by about half, even in the absence of auxin addition [18,33,35,36].”
BackgroundMethodArruda, N. L., Bryan, A. F., & Dowen, J. M. (2022) · Epigenetics & Chromatin · doi:10.1186/s13072-022-00463-6 · Cited by 17
“These results are consistent with a model where PDS5A, but not PDS5B, interacts with CTCF at insulator sites before the core cohesin complex arrives via DNA extrusion [19, 20].”
BackgroundResultInfluentialCondensin I folds the Caenorhabditis elegans genome
Das, M., Semple, J. I., Haemmerli, A., Volodkina, V., Scotton, J., Gitchev, T., Annan, A., Campos, J., Statzer, C., Dakhovnik, A., et al. (2024) · Nature Genetics · doi:10.1038/s41588-024-01832-5 · Cited by 24
“By analogy with observations made in mammalian cells on depletion of cohesin, a consequence of condensin I/I DC cleavage should be the reinforcement of A and B compartments 11–13 .”
Wang, Z., Tian, W.-H., Guo, Y.-L., Wang, D.-D., Zhang, Y., Zhi, Y.-H., Li, D.-H., Li, W.-T., Li, Z.-J., Jiang, R., et al. (2024) · Communications Biology · doi:10.1038/s42003-024-06599-3 · Cited by 16
Are SMC Complexes Loop Extruding Factors? Linking Theory With Fact
Baxter, J., Oliver, A. W., & Schalbetter, S. A. (2018) · BioEssays · doi:10.1002/bies.201800182 · Cited by 18
Emerging strategies to target the dysfunctional cohesin complex in cancer
Mintzas, K., & Heuser, M. (2019) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2019.1609943 · Cited by 18
Understanding transcription across scales: From base pairs to chromosomes
Vos, S. M. (2021) · Molecular Cell · doi:10.1016/j.molcel.2021.03.002 · Cited by 18
Engineering three-dimensional genome folding
Zhang, D., Lam, J. C., & Blobel, G. A. (2021) · Nature Genetics · doi:10.1038/s41588-021-00860-9 · Cited by 17
Interplay between regulatory elements and chromatin topology in cellular lineage determination
Shukla, V., Cetnarowska, A., Hyldahl, M., & Mandrup, S. (2022) · Trends in Genetics · doi:10.1016/j.tig.2022.05.011 · Cited by 15
Liu, Y., & Dekker, J. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.08.24.457555 · Cited by 16
Enhancer Function in the 3D Genome
Razin, S. V., Ulianov, S. V., & Iarovaia, O. V. (2023) · Genes · doi:10.3390/genes14061277 · Cited by 15
“Contacts between convergent CTCF binding sites are established by the extrusion of chromatin loops with cohesin [42,46,48,93].”
BackgroundPopay, T. M., Pant, A., Munting, F. W., Tastemel, M., Black, M. E., Haghani, N. K., & Dixon, J. R. (2026) · Nature Genetics · doi:10.1038/s41588-026-02516-y · Cited by 19
3D Genome Organization: Causes and Consequences for DNA Damage and Repair
Simon, À. C., & Fabre, E. (2021) · Genes · doi:10.3390/genes13010007 · Cited by 15
“Upon depletion of Wpl1 in mammals, an accumulation of cohesins has also been observed but in elongated chromatin structures called “vermicelli” that would form the base of the loops [28,30,52].”
BackgroundJain, R., & Epstein, J. A. (2024) · Advances in experimental medicine and biology · doi:10.1007/978-3-031-44087-8_18 · Cited by 16
Dynamics of transcriptional enhancers and chromosome topology in gene regulation
Yokoshi, M., & Fukaya, T. (2019) · Development Growth & Differentiation · doi:10.1111/dgd.12597 · Cited by 14
“…factor Wapl is depleted from cells, cohesin complex more stably associates with chromatin during loop extrusion and starts to form extended loops (Gassler et al., 2017; Haarhuis et al., 2017; Wutz et al., 2017), implicating that duration of extruding cohesin is dynamically regulated by Wapl.”
BackgroundMethodDeep Learning of Sequence Patterns for CCCTC-Binding Factor-Mediated Chromatin Loop Formation
Kuang, S., & Wang, L. (2020) · Journal of Computational Biology · doi:10.1089/cmb.2020.0225 · Cited by 15
“Recent studies suggest that, besides CTCF and cohesin, some other proteins such as BRD2, PDS5, and WAPL may also play important roles in establishing chromatin loop boundaries (Hsu et al., 2017; Wutz et al., 2017).”
Structure-function relationships of SMC protein complexes for DNA loop extrusion
Lee, H., Noh, H., & Ryu, J. (2021) · Korean Society for Structural Biology · doi:10.34184/kssb.2021.9.1.1 · Cited by 15
Induction of a chromatin boundary in vivo upon insertion of a TAD border
Willemin, A., Lopez‐Delisle, L., Bolt, C. C., Gadolini, M.-L., Duboule, D., & Rodríguez-Carballo, E. (2021) · PLoS Genetics · doi:10.1371/journal.pgen.1009691 · Cited by 14
Li, D., Mosbruger, T., Verma, D., & Swaminathan, S. (2019) · Journal of Virology · doi:10.1128/jvi.01279-19 · Cited by 15
“The specificity of cohesin localization is complex and likely mediated by multiple proteins, including NIPBL, mediator, transcription factors, and CTCF (21, 22).”
BackgroundControlling gene activation by enhancers through a drug-inducible topological insulator
Tsujimura, T., Takase, O., Yoshikawa, M., Sano, E., Hayashi, M., Hoshi, K., Takato, T., Toyoda, A., Okano, H., & Hishikawa, K. (2020) · eLife · doi:10.7554/elife.47980 · Cited by 17
“Loss of cohesin or CTCF resulted in disappearance of contact domains (Gassler et al., 2017; Nora et al., 2017; Rao et al., 2017; Schwarzer et al., 2017; Wutz et al., 2017).”
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“The cohesin complex has been identified as a major molecular determinant of loops and TADs, since depletion of its subunit RAD21 or its chromatin loader NIPBL leads to near-complete loss of these Hi-C features in various human cell types and across species [7 – 10].”
BackgroundAre the processes of DNA replication and DNA repair reading a common structural chromatin unit?
Mamberti, S., & Cardoso, M. C. (2020) · Nucleus · doi:10.1080/19491034.2020.1744415 · Cited by 12
“[49] Wutz G, Varnai C, Nagasaka K, et al.”
BackgroundMutations of PDS5 genes enhance TAD-like domain formation in Arabidopsis thaliana
Göbel, A.-M., Zhou, S., Wang, Z., Tzourtzou, S., Himmelbach, A., Zheng, S., Pradillo, M., Liu, C., & Jiang, H. L. (2024) · Nature Communications · doi:10.1038/s41467-024-53760-x · Cited by 17
“5a – d and Supplementary Data 8).”
A common molecular mechanism underlying Cornelia de Lange and CHOPS syndromes
Sakata, T., Tei, S., Izumi, K., Krantz, I. D., Bando, M., & Shirahige, K. (2025) · Current Biology · doi:10.1016/j.cub.2025.01.044 · Cited by 12
RNA-binding proteins mediate the maturation of chromatin topology during differentiation
Dehingia, B., Milewska, M., Janowski, M., Rafiee, M., Abbas, M., Piotrowska, A., Senge, J. F., Blaut, P., Walsh, D., Severino, J., et al. (2025) · Nature Cell Biology · doi:10.1038/s41556-025-01735-5 · Cited by 17
Organization of replicated chromosomes by DNA loops and sister chromatid cohesion
Ochs, F., & Gerlich, D. W. (2026) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-025-00933-1 · Cited by 16
Wang, R., Xu, Q., Wang, C., Tian, K., Wang, H., & Ji, X. (2023) · Nucleic Acids Research · doi:10.1093/nar/gkad401 · Cited by 13
Metadata
- Authors
- Wutz, G., Várnai, C., Nagasaka, K., Cisneros, D. A., Stocsits, R. R., Tang, W., Schoenfelder, S., Jessberger, G., Muhar, M., Hossain, M. J., Walther, N., Koch, B., Kueblbeck, M., Ellenberg, J., Zuber, J., Fraser, P., & Peters, J.
- Affiliations
- Research Institute of Molecular Pathology (AT)
- Babraham Institute (GB)
- European Molecular Biology Laboratory (DE)
- Florida State University (US)
- Corresponding author
- Peters, Jan‐Michael
- ORCID
- Venue
- The EMBO Journal
- Published
- 2017-12-07
- Volume
- 36
- Issue
- 24
- Pages
- 3573-3599
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC5730888
- OpenAlex
- W2775505403
- Cited by
- 864
- References
- 97
- Citations by year
- 2026: 83 · 2025: 77 · 2024: 102 · 2023: 97 · 2022: 119 · 2021: 127 · 2020: 112 · 2019: 87 · 2018: 49 · 2017: 11
- FWCI
- 29.61
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- The EMBO Journal (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- ePrints Soton (University of Southampton) (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Funders
- Boehringer Ingelheim
- Austrian Research Promotion Agency (FFG‐834223)
- UK Biotechnology and Biological Sciences Research Council (BB/J004480/1)
- European Research Council Advanced Grant (DEVOCHROMO)
- EMBO Long Term Fellowship (ALTF 1335‐2016)
- Austrian Science Fund (SFB F34, Z196‐B20)
- Human Frontier Science Program (LT001527/2017)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Keywords
- topologically associating domains, chromatin looping, cohesin, CTCF, WAPL, Pds5, loop extrusion, chromatin compartments, long-range chromatin interactions, chromosome condensation, vermicelli, 3D genome organization
- MeSH terms
- CCCTC-Binding Factor, Cohesins, Carrier Proteins, Chromatin, Chromosomal Proteins, Non-Histone, Chromosomes, DNA-Binding Proteins, HeLa Cells, Humans, Nuclear Proteins, Proto-Oncogene Proteins, Transcription Factors, Genome, Human, Cell Cycle Proteins
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