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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]
In the citing paper
“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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BackgroundInterferons reshape the 3D conformation and accessibility of macrophage chromatin
Platanitis, E., Gruener, S., Geetha, A. R. S. J., Boccuni, L., Vogt, A., Novatchkova, M., Sommer, A., Barozzi, I., Müller, M. M., & Decker, T. (2022) · iScience · doi:10.1016/j.isci.2022.103840 · Cited by 45
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“The balance between loading and releasing of cohesin on chromatin controls the strength of interaction within TADs as well as their length (Gassler et al. 2017; Wutz et al. 2017).”
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Theory of chromatin organization maintained by active loop extrusion
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Lineage-specific 3D genome organization is assembled at multiple scales by IKAROS
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Self-citationWapl releases Scc1-cohesin and regulates chromosome structure and segregation in mouse oocytes
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BackgroundSingle‐cell imaging of genome organization and dynamics
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PDS5 proteins regulate the length of axial elements and telomere integrity during male mouse meiosis
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Self-citationRapid depletion of CTCF and cohesin proteins reveals dynamic features of chromosome architecturePreprint
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“Acute depletion of CTCF or cohesin leads to loss of most TAD boundaries and chromatin loops (Nora et al., 2017; Wutz et al., 2017).”
BackgroundResultInfluentialLimits of Chromosome Compaction by Loop-Extruding Motors
Banigan, E. J., & Mirny, L. A. (2019) · Physical Review X · doi:10.1103/physrevx.9.031007 · Cited by 35
DNA Repair in Space and Time: Safeguarding the Genome with the Cohesin Complex
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“Downregulation of cohesin-unloading factor WAPL and its binding partners weakened compartments but increased the size of TADs and loops [61,62].”
BackgroundLebraud, E., Pinna, G., Siberchicot, C., Dépagne, J., Busso, D., Fantini, D., Irbah, L., Robeska, E., Kratassiouk, G., Ravanat, J., et al. (2020) · Nucleic Acids Research · doi:10.1093/nar/gkaa611 · Cited by 35
“Initially identified for their role in chromosome cohesion and segregation during mitosis, cohesin also functions in the interphasic nucleus (8), where it regulates the formation and stability of DNA loops (9,10), with different cohesin ring subunit compositions proposed to have different functions (11).”
BackgroundMaksimenko, O. G., Фурсенко, Д. В., Belova, E., & Georgiev, P. G. (2021) · Acta Naturae · doi:10.32607/actanaturae.11206 · Cited by 32
Galupa, R., & Heard, É. (2017) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2017.82.035030 · Cited by 30
“…cohesin lead to loss of TADs and loops (Nora et al. 2017; Rao et al. 2017) and mutations in factors involved in the loading or release of cohesin from DNA lead to differences in the length of the loops formed (Busslinger et al. 2017; Haarhuis et al. 2017; Schwarzer et al. 2017; Wutz et al. 2017).”
BackgroundCohesin-mediated 3D contacts tune enhancer-promoter regulationPreprint
Guckelberger, P., Doughty, B. R., Munson, G., Rao, S. S. P., Tan, Y., Cai, X. S., Fulco, C. P., Nasser, J., Mualim, K. S., Bergman, D. T., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.07.12.603288 · Cited by 33
“However, the depletion of these architectural proteins have minimal impacts on gene expression, despite the loss of loops and contact domains 23–26 .”
BackgroundLoop extrusion rules: the next generation.
Corsi, F., Rusch, E., & Goloborodko, A. (2023) · Current Opinion in Genetics and Development · doi:10.1016/j.gde.2023.102061 · Cited by 27
Cohesin-independent STAG proteins interact with RNA and R-loops and promote complex loading
Porter, H., Li, Y., Neguembor, M. V., Beltran-Nebot, M., Varsally, W., Martin, L., Tavares, M., Pezić, D., Bhamra, A., Šurinová, S., et al. (2023) · eLife · doi:10.7554/elife.79386 · Cited by 32
“Previous analyses of the contribution of SA proteins to genome organization (Kojic et al., 2018; Wutz et al., 2017) were performed in cells containing cohesin rings, possibly obscuring a functional role for SA proteins themselves in genome organization.”
BackgroundKant, A., Guo, Z., Vinayak, V., Neguembor, M. V., Li, W. S., Agrawal, V., Pujadas-Liwag, E. M., Almassalha, L. M., Backman, V., Lakadamyali, M., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-48698-z · Cited by 31
CTCF depletion decouples enhancer-mediated gene activation from chromatin hub formation
Karpińska, M. A., Zhu, Y., Ghazvini, Z. F., Ramasamy, S., Barbieri, M., Cao, T. B. N., Varahram, N., Aljahani, A., Lidschreiber, M., Papantonis, A., et al. (2025) · Nature Structural & Molecular Biology · doi:10.1038/s41594-025-01555-z · Cited by 35
Towards a Better Understanding of Cohesin Mutations in AML
Cuartero, S., Innes, A. J., & Merkenschlager, M. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.00867 · Cited by 33
Dynamic Runx1 chromatin boundaries affect gene expression in hematopoietic development
Owens, D. D. G., Anselmi, G., Oudelaar, A. M., Downes, D. J., Cavallo, A., Harman, J. R., Schweßinger, R., Bucakci, A., Greder, L. V., Ornellas, S. D., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-28376-8 · Cited by 33
“Although studies in cell lines indicate that CTCF sites are required for TAD formation (Nora et al. 2017, Rao et al. 2017, Schwarzer et al. 2017, Wutz et al. 2017), interestingly, promoter-proximal CTCF sites have been suggested to play a role in E-P interactions and gene transcription (Canzio et…”
BackgroundGualdrini, F., Polletti, S., Simonatto, M., Prosperini, E., Pileri, F., & Natoli, G. (2022) · Genes & Development · doi:10.1101/gad.349282.121 · Cited by 35
“This is a consequence of CTCF blocking the loop extrusion activity of the cohesin complex (Sanborn et al. 2015; Fudenberg et al. 2016; Wutz et al. 2017), which eventually determines the boundaries of topologically associating domains (TADs) (Dixon et al. 2012; Nora et al. 2012; for reviews, see…”
Backgroundp53 rapidly restructures 3D chromatin organization to trigger a transcriptional response
Serra, F., Nieto-Aliseda, A., Fanlo, L., Rovirosa, L., Cabrera-Pasadas, M., Lazarenkov, A., Urmeneta, B., Alcalde-Merino, A., Nola, E., Okorokov, A. L., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-46666-1 · Cited by 30
Self-citationLi, H., Dalgleish, J. L. T., Lister, G., Maristany, M. J., Huertas, J., Dopico-Fernandez, A. M., Hamley, J. C., Denny, N., Bloye, G., Zhang, W., et al. (2025) · Cell · doi:10.1016/j.cell.2025.10.013 · Cited by 35
Cohesin: building loops, but not compartments
Haarhuis, J. H. I., & Rowland, B. D. (2017) · The EMBO Journal · doi:10.15252/embj.201798654 · Cited by 27
“Three studies have now tested this hypothesis in different ways (Gassler et al , 2017; Haarhuis et al , 2017; Wutz et al , 2017).”
InfluentialCohesin mutations are synthetic lethal with stimulation of WNT signaling
Chin, C. V., Antony, J., Ketharnathan, S., Labudina, A. A., Gimenez, G., Parsons, K. M., He, J.-S., George, A. J., Pallotta, M. M., Musio, A., et al. (2020) · eLife · doi:10.7554/elife.61405 · Cited by 30
Ing‐Simmons, E., Rigau, M., & Vaquerizas, J. M. (2022) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2021.12.004 · Cited by 33
Barton, R. E., Massari, L. F., Robertson, D., & Marston, A. L. (2022) · eLife · doi:10.7554/elife.74447 · Cited by 33
Predicting genome organisation and function with mechanistic modelling
Chiang, M., Brackley, C. A., Marenduzzo, D., & Gilbert, N. (2021) · Trends in Genetics · doi:10.1016/j.tig.2021.11.001 · Cited by 35
“Domains are also affected by degradation of CTCF [44], cohesin [45,46], and complexes involved in cohesin loading and unloading [47,48].”
Rec8 Cohesin-mediated Axis-loop chromatin architecture is required for meiotic recombination
Sakuno, T., Tashiro, S., Tanizawa, H., Iwasaki, O., Ding, D., Haraguchi, T., Noma, K.-I., & Hiraoka, Y. (2022) · Nucleic Acids Research · doi:10.1093/nar/gkac183 · Cited by 29
Transcription regulates the spatio-temporal dynamics of genes through micro-compartmentalization
Salari, H., Fourel, G., & Jost, D. (2024) · Nature Communications · doi:10.1038/s41467-024-49727-7 · Cited by 35
“17).”
Dynamics of microcompartment formation at the mitosis-to-G1 transition
Goel, V. Y., Aboreden, N. G., Jusuf, J. M., Zhang, H., Mori, L., Mirny, L. A., Blobel, G. A., Banigan, E. J., & Hansen, A. S. (2025) · Nature Structural & Molecular Biology · doi:10.1038/s41594-025-01687-2 · Cited by 35
“%) are inter-A/B interactions. f , Saddle plots of progressive compartmentalization across the 0-h, 1-h and A/B compartments, which can be erased by extrusive cohesin with a long residence time (for example, because of WAPL loss) 45,51,52 .”
InfluentialESA1 regulates meiotic chromosome axis and crossover frequency via acetylating histone H4
Wang, Y., Zhai, B., Tan, T., Xiao, Y., Zhang, J., Song, M., Tan, Y., Yang, X., Chu, T., Zhang, S., et al. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab722 · Cited by 30
Liu, Y., Zhao, N., Kanemaki, M. T., Yamamoto, Y., Sadamura, Y., Ito, Y., Tokunaga, M., Stasevich, T. J., & Kimurâ, H. (2021) · Genes to Cells · doi:10.1111/gtc.12893 · Cited by 29
“This is because CTCF depletion disrupts cohesion-anchoring at specific sites and WAPL depletion leads to an extended loop formation that increases the size of topologically associating domains (Wutz et al., 2017).”
InfluentialNucleome programming is required for the foundation of totipotency in mammalian germline development
Nagano, M., Hu, B., Yokobayashi, S., Yamamura, A., Umemura, F., Coradin, M., Ohta, H., Yabuta, Y., Ishikura, Y., Okamoto, I., et al. (2022) · The EMBO Journal · doi:10.15252/embj.2022110600 · Cited by 27
“Chromatin fractionation was performed as previously described (Wutz et al , 2017).”
Self-citationCTCF blocks antisense transcription initiation at divergent promoters
Luan, J. Y., Vermunt, M. W., Syrett, C. M., Coté, A., Tome, J. M., Zhang, H., Huang, A., Luppino, J. M., Keller, C. A., Giardine, B. M., et al. (2022) · Nature Structural & Molecular Biology · doi:10.1038/s41594-022-00855-y · Cited by 29
Loop formation by SMC complexes: turning heads, bending elbows, and fixed anchors
Sedeño Cacciatore, Á., & Rowland, B. D. (2019) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2019.04.010 · Cited by 24
Sister chromatid cohesion halts DNA loop expansion
Bastié, N., Chapard, C., Cournac, A., Nejmi, S., Mboumba, H., Gadal, O., Thierry, A., Beckouët, F., & Koszul, R. (2024) · Molecular Cell · doi:10.1016/j.molcel.2024.02.004 · Cited by 27
All eukaryotic SMC proteins induce a twist of −0.6 at each DNA loop extrusion step
Janissen, R., Barth, R., Davidson, I., Taschner, M., Gruber, S., Peters, J.-M., & Dekker, C. (2024) · bioRxiv · doi:10.1126/sciadv.adt1832 · Cited by 26
Self-citationDynamic chromatin organization in the cell
Prieto, E., & Maeshima, K. (2019) · Essays in Biochemistry · doi:10.1042/ebc20180054 · Cited by 26
Single cell analysis pushes the boundaries of TAD formation and function
Luppino, J. M., & Joyce, E. F. (2020) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2020.03.005 · Cited by 29
“Importantly, these results are consistent with the widespread yet modest effect on gene expression observed following depletion of either cohesin or CTCF (Nora et al., 2017; Rao et al., 2017; Schwarzer et al., 2017; Wutz et al., 2017).”
BackgroundResultContessoto, V. G., Dudchenko, O., Aiden, E. L., Wolynes, P. G., Onuchic, J. N., & Pierro, M. D. (2023) · Nature Communications · doi:10.1038/s41467-023-35909-2 · Cited by 27
Hill, L., Wutz, G., Jaritz, M., Tagoh, H., Calderón, L., Peters, J., Goloborodko, A. A., & Busslinger, M. (2023) · Nature Communications · doi:10.1038/s41467-023-37994-9 · Cited by 30
“The generation of TADs and their chromatin loops depends on the ring-shaped cohesin complex 8 – 10 , which is enriched at the DNA-bound zinc fi nger protein CTCF in the genome 11,12 .”
Self-citationCTCF and Its Multi-Partner Network for Chromatin Regulation
Moral‐Morales, A. D., Salgado-Albarrán, M., Sánchez-Pérez, Y., Wenke, N. K., Baumbach, J., & Soto‐Reyes, E. (2023) · Cells · doi:10.3390/cells12101357 · Cited by 30
Cohesin‐mediated DNA loop extrusion resolves sister chromatids in G2 phase
Batty, P., Langer, C. C. H., Takács, Z., Tang, W., Blaukopf, C., Peters, J., & Gerlich, D. W. (2023) · The EMBO Journal · doi:10.15252/embj.2023113475 · Cited by 28
Self-citationThree‐dimensional chromatin re‐organization during muscle stem cell aging
Yang, B. A., Larouche, J. A., Sabin, K., Fraczek, P. M., Parker, S. C. J., & Aguilar, C. A. (2023) · Aging Cell · doi:10.1111/acel.13789 · Cited by 27
Protein degradation in auxin response
de Roij, M., Borst, J. W., & Weijers, D. (2024) · The Plant Cell · doi:10.1093/plcell/koae125 · Cited by 28
“For example, precisely timed depletion of condensins and cohesins through AID revealed distinct roles for both complexes during specific mitotic phases ( Rao et al. 2017; Wutz et al. 2017; Gibcus et al. 2018; Rhodes et al. 2020; Thiecke et al. 2020).”
BackgroundExtrusion fountains are restricted by WAPL-dependent cohesin release and CTCF barriers
Liu, N. Q., Magnitov, M. D., Schijns, M. M. G. A., van Schaik, T., Teunissen, H., van Steensel, B., & de Wit, E. (2025) · Nucleic Acids Research · doi:10.1093/nar/gkaf549 · Cited by 33
Xu, D., Ma, R., Zhang, J., Liu, Z., Wu, B., Peng, J., Zhai, Y., Gong, Q., Shi, Y., Wu, J., et al. (2018) · The Journal of Physical Chemistry Letters · doi:10.1021/acs.jpclett.8b01440 · Cited by 25
Spatial Organization of Chromatin: Transcriptional Control of Adaptive Immune Cell Development
Pongubala, J. M. R., & Murre, C. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.633825 · Cited by 29
“Consistent with this function, deletion of cohesin releasing factor, WAPL, causes prolonged cohesin retention resulting in the enrichment of larger CTCF loops and decreased intra-TAD chromatin interactions (109, 110).”
BackgroundDevenish, L. P., Mhlanga, M. M., & Negishi, Y. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.662565 · Cited by 27
Non-Coding Variants in Cancer: Mechanistic Insights and Clinical Potential for Personalized Medicine
Lange, M., Begolli, R., & Giakountis, A. (2021) · Non-Coding RNA · doi:10.3390/ncrna7030047 · Cited by 26
Bansal, K., Michelson, D. A., Ramírez, R. N., Viny, A. D., Levine, R. L., Benoist, C. O., & Mathis, D. J. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2110991118 · Cited by 26
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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