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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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Weak interactions in higher-order chromatin organization
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“Although there is clear evidence for the role of active DNA loop extrusion in mammalian TAD formation (41,42,148,156), the mechanisms underlying the formation of contact chromatin domains in other taxa remain less clear.”
BackgroundCohesin: behind dynamic genome topology and gene expression reprogramming
Perea-Resa, C., Wattendorf, L., Marzouk, S., & Blower, M. D. (2021) · Trends in Cell Biology · doi:10.1016/j.tcb.2021.03.005 · Cited by 63
Chang, L., Ghosh, S., Papale, A., Luppino, J. M., Miranda, M., Piras, V., Degrouard, J., Edouard, J., Poncelet, M., Lecouvreur, N., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-41265-y · Cited by 63
CTCF organizes inter-A compartment interactions through RYBP-dependent phase separation
Wei, C., Jia, L., Huang, X., Tan, J., Wang, M., Niu, J., Hou, Y., Sun, J.-Y., Zeng, P., Wang, J., et al. (2022) · Cell Research · doi:10.1038/s41422-022-00676-0 · Cited by 55
LDB1 establishes multi-enhancer networks to regulate gene expression
Aboreden, N. G., Lam, J. C., Goel, V. Y., Wang, S., Wang, X., Midla, S. C., Quijano, A., Keller, C. A., Giardine, B. M., Hardison, R. C., et al. (2025) · Molecular Cell · doi:10.1016/j.molcel.2024.11.037 · Cited by 61
Spatial Organization of Chromatin: Emergence of Chromatin Structure During Development
Ghosh, R. P., & Meyer, B. J. (2021) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-032321-035734 · Cited by 60
Gambetta, M. C., & Furlong, E. E. M. (2018) · Genetics · doi:10.1534/genetics.118.301350 · Cited by 61
CTCF–CTCF loops and intra-TAD interactions show differential dependence on cohesin ring integrity
Liu, Y., & Dekker, J. (2022) · Nature Cell Biology · doi:10.1038/s41556-022-00992-y · Cited by 74
Full circle: a brief history of cohesin and the regulation of gene expression
Horsfield, J. A. (2022) · FEBS Journal · doi:10.1111/febs.16362 · Cited by 57
Bakr, A., Corte, G., Veselinov, O., Kelekçi, S., Chen, M.-J. M., Lin, Y.-Y., Sigismondo, G., Iacovone, M., Cross, A., Syed, R., et al. (2024) · Nucleic Acids Research · doi:10.1093/nar/gkae233 · Cited by 71
“Loss of cohesin and CTCF resulted in failure of chromatin loop formation and disruption of the boundaries of chromatin loops, respectively ( 88 ).”
BackgroundHigher-Order Chromosomal Structures Mediate Genome Function
Jerković, I., Szabo, Q., Bantignies, F., & Cavalli, G. (2019) · Journal of Molecular Biology · doi:10.1016/j.jmb.2019.10.014 · Cited by 57
Defining Functionally Relevant Spatial Chromatin Domains: It is a TAD Complicated
Sikorska, N., & Sexton, T. (2019) · Journal of Molecular Biology · doi:10.1016/j.jmb.2019.12.006 · Cited by 65
The multifaceted roles of cohesin in cancer
Nardo, M. D., Pallotta, M. M., & Musio, A. (2022) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-022-02321-5 · Cited by 62
“In the absence of WAPL, PDS5A and PDS5B proteins, cohesin forms extended loops, presumably by passing CTCF sites [74, 83].”
BackgroundWAPL functions as a rheostat of Protocadherin isoform diversity that controls neural wiring
Kiefer, L., Chiosso, A., Langen, J., Buckley, A., Gaudin, S., Rajkumar, S. M., Servito, G., Cha, E. S., Vijay, A., Yeung, A. K. W., et al. (2023) · Science · doi:10.1126/science.adf8440 · Cited by 59
Engineering 3D genome organization
Wang, H., Han, M., & Qi, L. S. (2021) · Nature Reviews Genetics · doi:10.1038/s41576-020-00325-5 · Cited by 62
Chromatin Conformation in Development and Disease
Boltsis, I., Grosveld, F. G., Giraud, G., & Kolovos, P. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.723859 · Cited by 59
“, 2017), while TADs dramatically disappear after depletion of cohesion and compartmentalization is increased (Haarhuis et al., 2017; Rao et al., 2017; Schwarzer et al., 2017; Wutz et al., 2017).”
BackgroundInfluentialChromosome disentanglement driven via optimal compaction of loop-extruded brush structures
Brahmachari, S., & Marko, J. F. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1906355116 · Cited by 54
Topologically Associating Domains and Regulatory Landscapes in Development, Evolution and Disease
Tena, J. J., & Santos-Pereira, J. M. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.702787 · Cited by 65
“, 2017), as well as the depletion of factors regulating cohesin loading on chromatin, which leads to differences in the length of loops formed (Busslinger et al., 2017; Haarhuis et al., 2017; Schwarzer et al., 2017; Wutz et al., 2017).”
BackgroundChromosome architecture and homologous recombination in meiosis
Ito, M., & Shinohara, A. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.1097446 · Cited by 57
NIPBL and cohesin: new take on a classic tale
Gil, D. A., & Losada, A. (2023) · Trends in Cell Biology · doi:10.1016/j.tcb.2023.03.006 · Cited by 56
Račko, D., Benedetti, F., Dorier, J., & Stasiak, A. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky1091 · Cited by 58
Activation of Clustered IFNγ Target Genes Drives Cohesin-Controlled Transcriptional Memory
Siwek, W., Tehrani, S., Mata, J. F., & Jansen, L. E. T. (2020) · Molecular Cell · doi:10.1016/j.molcel.2020.10.005 · Cited by 60
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Folding of cohesin’s coiled coil is important for Scc2/4-induced association with chromosomes
Petela, N. J., Llamazares, A. G., Dixon, S. E., Hu, B., Lee, B., Metson, J., Seo, H., Ferrer-Harding, A., Voulgaris, M., Gligoris, T. G., et al. (2021) · eLife · doi:10.7554/elife.67268 · Cited by 54
Amat, R., Böttcher, R., Dily, F. L., Vidal, E., Quilez, J., Cuartero, Y., Beato, M., de Nadal, E., & Posas, F. (2018) · Genome Research · doi:10.1101/gr.238527.118 · Cited by 58
“S1F; Nora et al. 2017; Schwarzer et al. 2017; Wutz et al. 2017).”
3D genome organization: a role for phase separation and loop extrusion?
Stam, M. E., Tark‐Dame, M., & Fransz, P. F. (2019) · Current Opinion in Plant Biology · doi:10.1016/j.pbi.2019.03.008 · Cited by 54
Masamsetti, V. P., Low, R. R. J., Mak, K. S., O’Connor, A., Riffkin, C. D., Lamm, N., Crabbé, L., Karlseder, J., Huang, D. C. S., Hayashi, M., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-12255-w · Cited by 56
de Wit, E. (2019) · Journal of Molecular Biology · doi:10.1016/j.jmb.2019.09.026 · Cited by 57
Cohesin mediates DNA loop extrusion and sister chromatid cohesion by distinct mechanisms
Nagasaka, K., Davidson, I. F., Stocsits, R. R., Tang, W., Wutz, G., Batty, P., Panarotto, M., Litos, G., Schleiffer, A., Gerlich, D. W., et al. (2023) · Molecular Cell · doi:10.1016/j.molcel.2023.07.024 · Cited by 53
Self-citationCondensins and cohesins – one of these things is not like the other!
Skibbens, R. V. (2019) · Journal of Cell Science · doi:10.1242/jcs.220491 · Cited by 52
Function and regulation of chromatin insulators in dynamic genome organization
Chen, D., & Lei, E. P. (2019) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2019.02.001 · Cited by 52
Chromatin Remodelers in the 3D Nuclear Compartment
Magaña‐Acosta, M., & Valadéz-Graham, V. (2020) · Frontiers in Genetics · doi:10.3389/fgene.2020.600615 · Cited by 58
“…there are reports showing that depletion of cohesin, CTCF, or the cohesin-loader protein, NIPBL, causes disruption of the chromatin loop domains (Nora et al., 2012; Wutz et al., 2017), whereas depletion of WAPL (a cohesin release factor) causes reinforcement of the stability of the loops.”
BackgroundChatzidaki, E. E., Powell, S. T., Dequeker, B. J. H., Gassler, J., Silva, M. C. C., & Tachibana, K.-E. K. (2021) · Current Biology · doi:10.1016/j.cub.2021.06.076 · Cited by 53
High-throughput Oligopaint screen identifies druggable 3D genome regulators
Park, D. S., Nguyen, S. C., Isenhart, R. L., Shah, P. P., Kim, W., Barnett, R. J., Chandra, A., Luppino, J. M., Harke, J., Wai, M., et al. (2023) · Nature · doi:10.1038/s41586-023-06340-w · Cited by 56
Dynamics of sister chromatid resolution during cell cycle progression
Stanytė, R., Nuebler, J., Blaukopf, C., Hoefler, R., Stocsits, R. R., Peters, J., & Gerlich, D. W. (2018) · The Journal of Cell Biology · doi:10.1083/jcb.201801157 · Cited by 49
“Cohesin enriches at the boundaries of TADs and is required for their formation (Rao et al., 2014; Schwarzer et al., 2016; Wutz et al., 2017; Gassler et al., 2017; Zuin et al., 2014a; Rao et al., 2017).”
BackgroundSelf-citationThe emergence of genome architecture and zygotic genome activation
Vallot, A., & Tachibana, K.-E. K. (2020) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2020.02.002 · Cited by 53
The role of loop extrusion in enhancer-mediated gene activation
Karpińska, M. A., & Oudelaar, A. M. (2023) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2023.102022 · Cited by 53
“In contrast to the global loss of TADs and CTCF ‘loops’ in the absence of Cohesin [18–20], enhancer–promoter interactions are not completely abolished [24••,28,31•,32].”
BackgroundMethodInfluential
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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