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Cohesin is positioned in mammalian genomes by transcription, CTCF and Wapl
Open accessAbstract
Mammalian genomes are spatially organized by CCCTC-binding factor (CTCF) and cohesin into chromatin loops and topologically associated domains, which have important roles in gene regulation and recombination. By binding to specific sequences, CTCF defines contact points for cohesin-mediated long-range chromosomal cis-interactions. Cohesin is also present at these sites, but has been proposed to be loaded onto DNA elsewhere and to extrude chromatin loops until it encounters CTCF bound to DNA. How cohesin is recruited to CTCF sites, according to this or other models, is unknown. Here we show that the distribution of cohesin in the mouse genome depends on transcription, CTCF and the cohesin release factor Wings apart-like (Wapl). In CTCF-depleted fibroblasts, cohesin cannot be properly recruited to CTCF sites but instead accumulates at transcription start sites of active genes, where the cohesin-loading complex is located. In the absence of both CTCF and Wapl, cohesin accumulates in up to 70 kilobase-long regions at 3'-ends of active genes, in particular if these converge on each other. Changing gene expression modulates the position of these 'cohesin islands'. These findings indicate that transcription can relocate mammalian cohesin over long distances on DNA, as previously reported for yeast cohesin, that this translocation contributes to positioning cohesin at CTCF sites, and that active genes can be freed from cohesin either by transcription-mediated translocation or by Wapl-mediated release.
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“Since cohesin can remain topologically engaged and slide on both naked DNA42–44 and chromatin,45,46”
From Recent evidence that TADs and chromatin loops are dynamic structures (2018) · cites this paper as [46]
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“Supporting this idea, recent results showed that cohesin is recruited at transcription start sites and positioned to CTCF sites by transcription-mediated translocation (56).”
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The Dynamic 3D Genome in Gametogenesis and Early Embryonic Development
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“In both yeast and mouse, transcription can relocate cohesin over long distances on DNA [53,54].”
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“31,32 To test this hypothesis, we evaluated all single-nucleotide mutations in the 300 bp on either side of the transcription start site (TSS) of the 1,789 highest expressed protein-coding genes in HFFc6 29 and compared disruption scores with expression level in regions where CTCF motifs are…”
MethodLoss of cohesin regulator PDS5A reveals repressive role of Polycomb loops
Bsteh, D., Moussa, H. F., Michlits, G., Yelagandula, R., Wang, J.-K., Elling, U., & Bell, O. (2021) · bioRxiv · doi:10.1038/s41467-023-43869-w · Cited by 19
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“Moreover, in concert with cohesin, CTCF mediates DNA looping to distal CTCF-binding sites (44, 45), suggesting the potential for various types of regulatory interactions among the CTCF-binding regions of HSV (46, 47).”
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Sawyer, I. A., & Dundr, M. (2017) · Chromosoma · doi:10.1007/s00412-017-0632-y · Cited by 20
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The Interplay of Cohesin and the Replisome at Processive and Stressed DNA Replication Forks
van Schie, J. J. M., & de Lange, J. (2021) · Cells · doi:10.3390/cells10123455 · Cited by 22
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Genome organization via loop extrusion, insights from polymer physics models
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Pereira, M. C. F., Brackley, C. A., Michieletto, D., Annunziatella, C., Bianco, S., Chiariello, A. M., Nicodemi, M., & Marenduzzo, D. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/305359 · Cited by 19
A functional overlap between actively transcribed genes and chromatin boundary elementsPreprint
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“can affect 3D genome structure independently of CTCF (36-38).”
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TAD border deletion at the Kit locus causes tissue-specific ectopic activation of a neighboring gene
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Fursova, N. A., & Larson, D. R. (2024) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2024.102920 · Cited by 18
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The dynamic role of cohesin in maintaining human genome architecture
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BackgroundDefining a core configuration for human centromeres during mitosis
Gupta, A. S., Seidel, C. W., Tsuchiya, D., McKinney, S., Yu, Z., Smith, S. E., Unruh, J. R., & Gerton, J. L. (2023) · Nature Communications · doi:10.1038/s41467-023-42980-2 · Cited by 16
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A CTCF-dependent mechanism underlies the Hox timer: relation to a segmented body plan
Rekaik, H., & Duboule, D. (2024) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2024.102160 · Cited by 16
“Concomitantly with the early activation, an enrichment of cohesin loading is observed over this CTCT-free segment, likely due to its transcriptional activity [12].”
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Understanding transcription across scales: From base pairs to chromosomes
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Engineering three-dimensional genome folding
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“Also, in mammalian cells, formation of “cohesin islands” at 3′ ends of active genes was seen in CTCF/ Wapl double- knockout cells (Busslinger et al., 2017).”
BackgroundStructure-function relationships of SMC protein complexes for DNA loop extrusion
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Yu, G., Xu, K., Xia, W., Zhang, K., Xu, Q., Li, L., Lin, Z., Liu, L., Liu, B., Du, Z., et al. (2025) · Nature · doi:10.1038/s41586-025-09400-5 · Cited by 16
“RNA polymerase is thought to push cohesin or hinder it from sliding along chromatin 13,14,18,32 .”
A Cohesin Traffic Pattern Genetically Linked to Gene Regulation
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Multi-Dimensional Gene Regulation in Innate and Adaptive Lymphocytes: A View From Regulomes
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Principles of Meiotic Chromosome AssemblyPreprint
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“The latter effect is more perplexing, but agrees with NIPBL binding active gene promoters before cohesin does following mitotic exit (Zuin et al, 2014; Busslinger et al, 2017) – and, thus, raises three key questions.”
BackgroundA cohesin traffic pattern genetically linked to gene regulationPreprint
Valton, A.-L., Venev, S. V., Mair, B., Khokhar, E. S., Tong, A. H. Y., Ušaj, M., Chan, K. S. K., Pai, A. A., Moffat, J., & Dekker, J. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.07.29.454218 · Cited by 15
“Previous studies had shown that in cells depleted for CTCF and the cohesin unloading factor WAPL, cohesin accumulates at 3’ ends of active genes and especially at sites of convergent transcription (Busslinger et al., 2017).”
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“Generally, the nucleotide translocation might disrupt the transcription of itself or nearby genes by affecting the cis/trans-acting regulatory factors from the transcription units and consequently deleterious changes in the expression and protein level (89, 104).”
BackgroundThe α-globin super-enhancer acts in an orientation-dependent manner
Kassouf, M. T., Francis, H. S., Gosden, M. E., Suciu, M., Downes, D. J., Harrold, C. L., Larke, M., Oudelaar, A. M., Cornell, L., Blayney, J., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-56380-1 · Cited by 13
High-resolution CTCF footprinting reveals impact of chromatin state on cohesin extrusion
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“Several studies hinted that cohesin may facilitate transcriptional activity by genome-wide correlation or by testing at a selected few loci 7,15,23,24,49,50 , but lack systematic evidence.”
Analysis of high-resolution 3D intrachromosomal interactions aided by Bayesian network modeling
Zhang, X., Branciamore, S., Gogoshin, G., Rodin, A. S., & Riggs, A. D. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1620425114 · Cited by 12
“Very recently, while our manuscript was under review, Busslinger et al. (51) and Haarhuis et al. (52) reported that the distribution and directionality of movement of cohesin in the mouse genome is influenced by transcription.”
BackgroundPeltier, D., & Reddy, P. R. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01110 · Cited by 13
One ring to bind them – Cohesin’s interaction with chromatin fibers
Gines, M. M., van Staveren, T., & Wendt, K. S. (2019) · Essays in Biochemistry · doi:10.1042/ebc20180064 · Cited by 14
Cohesin as an essential disruptor of chromosome organization
Bird, A. P. (2025) · Molecular Cell · doi:10.1016/j.molcel.2025.01.010 · Cited by 13
Sun, T., Xu, Y., Angel, N., Chen, L., Zhang, K., Hoffman, B. D., Ou, J., Meng, Z., Varghese, S., & Diao, Y. (2025) · Nature Cell Biology · doi:10.1038/s41556-025-01770-2 · Cited by 12
Two CTCF motifs impede cohesin-mediated DNA loop extrusion
Barth, R., Janissen, R., Muras, L., van der Torre, J., Litos, G., van der Sluis, E. O., van den Berg, A., Davidson, I. F., Peters, J., & Dekker, C. (2025) · Molecular Cell · doi:10.1016/j.molcel.2025.11.001 · Cited by 14
Self-citationCohesin-Mediated Chromatin Interactions and Autoimmunity
Chandrasekaran, V., Oparina, N. Y., García-Bonete, M.-J., Wasén, C., Erlandsson, M. C., Malmhäll-Bah, E., Andersson, K., Jensen, M., Silfverswärd, S. T., Katona, G., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.840002 · Cited by 13
“CTCF is essential for the insulation activity of cohesin on chromatin (13).”
BackgroundInfluentialCostea, J., Schoeberl, U. E., Malzl, D., von der Linde, M., Fitz, J., Gupta, A., Makharova, M., Goloborodko, A. A., & Pavri, R. (2022) · Molecular Cell · doi:10.1016/j.molcel.2023.01.014 · Cited by 12
Alpsoy, A., Sood, S., & Dykhuizen, E. C. (2021) · Biology · doi:10.3390/biology10040272 · Cited by 13
“The motor for this movement might simply result from transcription-induced supercoiling [78,88], passive diffusion coupled with transcription [89], or other processive enzymes moving along the DNA during transcription [90].”
BackgroundCTCF supports preferentially short lamina-associated domains
Kaczmarczyk, L. S., Levi, N., Segal, T., Salmon‐Divon, M., & Gerlitz, G. (2022) · Chromosome Research · doi:10.1007/s10577-022-09686-5 · Cited by 12
“Since cohesin position is also determined by CTCF (Davidson et al. 2016; Busslinger et al. 2017; Racko et al. 2018), we decided to evaluate if CTCF importance for the LADs landscape is increased upon inhibition of RNA polymerase II.”
BackgroundJones, B. G., Sealy, R. E., Penkert, R. R., Surman, S. L., Birshtein, B. K., Xu, B., Neale, G. A. M., Maul, R. W., Gearhart, P. J., & Hurwitz, J. L. (2020) · Viral Immunology · doi:10.1089/vim.2019.0144 · Cited by 12
“In contrast, CCCTC-binding factor (CTCF) and the subunits of cohesin (SMC1, SMC3) (93) are preferentially bound farther downstream in the insulator region (6).”
RNA interactions with CTCF are essential for its proper functionPreprint
Saldaña-Meyer, R., Rodriguez-Hernaez, J., Nishana, M., Jácome-López, K., Nora, E. P., Bruneau, B. G., Furlan-Magaril, M., Skok, J. A., & Reinberg, D. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/530014 · Cited by 12
“…a positive-feedback loop that contributes to the stability of gene expression programs” (Sigova et al., 2015) and 5) highly expressed genes can sometimes displace CTCF and push cohesin to intergenic CTCF sites where they can form chromatin loops (Busslinger et al., 2017; Heinz et al., 2018).”
BackgroundPDS5 proteins control genome architecture by limiting the lifetime of cohesin-NIPBL complexes
Wutz, G., Davidson, I. F., Banigan, E. J., Stocsits, R. R., Kawasumi, R., Tang, W., Nagasaka, K., Costantino, L., Jansen, R., Hirota, K., et al. (2026) · Molecular Cell · doi:10.1016/j.molcel.2026.03.025 · Cited by 12
Self-citationLocus folding mechanisms determine modes of antigen receptor gene assembly
Allyn, B. M., Hayer, K. E., Oyeniran, C., Nganga, V. K., Lee, K. D., Mishra, B., Saçan, A., Oltz, E. M., & Bassing, C. H. (2023) · The Journal of Experimental Medicine · doi:10.1084/jem.20230985 · Cited by 10
“Additional impediments to cohesin can anchor loops, including active transcription and chromatin-bound proteins other than CTCF (Busslinger et al., 2017; Jeppsson et al., 2022; Wutz et al., 2017; Zhang et al., 2019).”
BackgroundFrom compartments to loops: understanding the unique chromatin organization in neuronal cells
Zagirova, D., Kononkova, A. D., Vaulin, N., & Khrameeva, E. E. (2024) · Epigenetics & Chromatin · doi:10.1186/s13072-024-00538-6 · Cited by 12
“These modifications are known to be associated with transcription start sites (TSSs), which are important sites for cohesin recruitment [32].”
BackgroundQi, S., Shi, Z., & Yu, H. (2025) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2025.102310 · Cited by 13
Datta, S., Sherva, R., Cruz, M. D., Long, M. T., Roy, P., Backman, V., Chowdhury, S., & Roy, H. K. (2018) · Neoplasia · doi:10.1016/j.neo.2018.01.003 · Cited by 11
Redundant and specific roles of cohesin STAG subunits in chromatin looping and transcription controlPreprint
Casà, V., Gines, M. M., Gusmao, E. G., Slotman, J. A., Zirkel, A., Josipović, N., Oole, E., van IJcken, W. F. J., Houtsmuller, A. B., Papantonis, A., et al. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/642959 · Cited by 11
Transcription Pause and Escape in Neurodevelopmental Disorders
Eigenhuis, K. N., Somsen, H. B., & van den Berg, D. L. C. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.846272 · Cited by 8
“Widespread NIPBL binding in the absence of cohesin was detected at active promoters and enhancers in mouse embryonic fibroblasts, neural progenitor cells, and lymphoblastoid cells (Zuin et al., 2014; Busslinger et al., 2017; van den Berg et al., 2017).”
BackgroundGenome folding dynamics during the M-to-G1-phase transition
Zhang, H., & Blobel, G. A. (2023) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2023.102036 · Cited by 13
Genome Organization: Cohesin on the Move
Richterova, J., Huraiová, B., & Gregáň, J. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.05.002 · Cited by 10
“Busslinger et al. (2017) reveal that transcription moves cohesin along DNA to CTCF-binding sites, providing insights into how cohesin and CTCF mediate chromosomal interactions by formation of chromatin loops.”
BackgroundInfluentialUSP13 interacts with cohesin and regulates its ubiquitination in human cells
He, X., Kim, J.-S., Díaz-Martínez, L. A., Han, C., Lane, W. S., Budnik, B., & Waldman, T. A. (2021) · Journal of Biological Chemistry · doi:10.1074/jbc.ra120.015762 · Cited by 10
“Chromatin-associated proteins and total soluble proteins were prepared as described (30).”
BackgroundDysregulation of the cohesin subunit RAD21 by Hepatitis C virus mediates host–virus interactions
Perez, S., Gevor, M., Davidovich, A., Kaspi, A., Yamin, K., Domovich, T., Meirson, T., Matityahu, A., Brody, Y., Stemmer, S. M., et al. (2019) · Nucleic Acids Research · doi:10.1093/nar/gkz052 · Cited by 10
“In WAPL depleted MEF cells, cohesin relocalizes and accumulates at sites of convergent transcription (23,24).”
BackgroundCohesin positions the epigenetic reader Phf2 within the genome
Tang, W., Costantino, L., Stocsits, R. R., Wutz, G., Ladurner, R., Hudecz, O., Mechtler, K., & Peters, J. (2025) · The EMBO Journal · doi:10.1038/s44318-024-00348-2 · Cited by 9
“To test this hypothesis further, we performed Phf2 ChIP-seq experiments using MEFs depleted of either Wapl or of Wapl and CTCF, in which cohesin accumulates in different regions than in wild type cells (Busslinger et al, 2017; Tedeschi et al, 2013).”
InfluentialSelf-citationMetelova, M., Vigh, M. L., & Krietenstein, N. (2025) · Nature Communications · doi:10.1038/s41467-025-64350-w · Cited by 11
“Despite extensive evidence supporting the role of chromatin architectural proteins in E-P/P-P interactions 14,16,54,55 , recent high-resolution studies report minimal alterations in the E-P/P-P connectome following their depletion 2,22,48 .”
Under the magnifying glass: The ups and downs of rDNA copy number
Kindelay, S. M., & Maggert, K. A. (2022) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2022.05.006 · Cited by 11
RNAP II antagonizes mitotic chromatin folding and chromosome segregation by condensin
Lebreton, J., Colin, L., Chatre, E., & Bernard, P. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.113901 · Cited by 10
Cohesin — bridging the gap among gene transcription, genome stability, and human diseases
Nardo, M. D., & Musio, A. (2024) · FEBS Letters · doi:10.1002/1873-3468.14949 · Cited by 10
Zhou, Y., Jay, A., Burget, N. G., Friedrich, T., Yoon, S., Alsing, J., Nir, G., Grosschedl, R., Vahedi, G., & Faryabi, R. B. (2025) · Nature Cell Biology · doi:10.1038/s41556-025-01827-2 · Cited by 8
Emerging regulatory mechanisms of noncoding RNAs in topologically associating domains
Yeo, S. J., Chen, Y., Fullwood, M. J., & Tergaonkar, V. (2023) · Trends in Genetics · doi:10.1016/j.tig.2022.12.003 · Cited by 7
Loop extrusion drives very different dynamics for Rouse chains in bulk solutions and at interfaces
Yamamoto, T., Sakaue, T., & Schießel, H. (2019) · Europhysics Letters (EPL) · doi:10.1209/0295-5075/127/38002 · Cited by 8
Metadata
- Authors
- Busslinger, G. A., Stocsits, R. R., van der Lelij, P., Axelsson, E., Tedeschi, A., Galjart, N., & Peters, J.-M.
- Affiliations
- Research Institute of Molecular Pathology (AT)
- Erasmus MC (NL)
- Corresponding author
- Peters, Jan-Michael
- ORCID
- Venue
- Nature
- Published
- 2017-04
- Volume
- 544
- Issue
- 7651
- Pages
- 503-507
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6080695
- OpenAlex
- W2607008467
- Cited by
- 468
- References
- 51
- Citations by year
- 2026: 30 · 2025: 36 · 2024: 36 · 2023: 45 · 2022: 58 · 2021: 52 · 2020: 59 · 2019: 67 · 2018: 50 · 2017: 35
- FWCI
- 23.91
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- 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
- cohesin, CTCF, WAPL, transcription, cohesin loading, chromatin looping, topologically associating domains, 3D genome organization, transcription start sites, mouse genome, cis-interactions, gene expression regulation, recombination, mouse fibroblasts
- MeSH terms
- CCCTC-Binding Factor, Cohesins, Animals, Binding Sites, Cells, Cultured, Chromatin, Chromosomal Proteins, Non-Histone, DNA, Female, Fibroblasts, Male, Proteins, Chondroitin Sulfate Proteoglycans, Repressor Proteins, Transcription, Genetic, Genome, Cell Cycle Proteins, Protein Transport, Transcription Initiation Site, Chromosomes, Mammalian, Mice
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