The Energetics and Physiological Impact of Cohesin Extrusion
Open accessAbstract
Cohesin extrusion is thought to play a central role in establishing the architecture of mammalian genomes. However, extrusion has not been visualized in vivo, and thus, its functional impact and energetics are unknown. Using ultra-deep Hi-C, we show that loop domains form by a process that requires cohesin ATPases. Once formed, however, loops and compartments are maintained for hours without energy input. Strikingly, without ATP, we observe the emergence of hundreds of CTCF-independent loops that link regulatory DNA. We also identify architectural "stripes," where a loop anchor interacts with entire domains at high frequency. Stripes often tether super-enhancers to cognate promoters, and in B cells, they facilitate Igh transcription and recombination. Stripe anchors represent major hotspots for topoisomerase-mediated lesions, which promote chromosomal translocations and cancer. In plasmacytomas, stripes can deregulate Igh-translocated oncogenes. We propose that higher organisms have coopted cohesin extrusion to enhance transcription and recombination, with implications for tumor development.
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Stripe domains tend to anchor at a single CTCF binding site, which points towards a nearby site for the cohesin-loading factor NIPBL.
“Stripe domains tend to anchor at a single CTCF binding site (as opposed to two divergent CTCF sites in the classic case for TADs), which points towards a nearby site for the cohesin-loading factor NIPBL [456, 457].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [456]
The presence of so-called stripes or flames on Hi-C maps indicates that unidirectional extrusion from an enhancer is quite common.
“The presence of so-called stripes or flames on Hi-C maps indicates that unidirectional extrusion from an enhancer is quite common [116,117,118].”
From Enhancer Function in the 3D Genome (2023) · cites this paper as [116]
Stripes were enriched in super enhancers.
“The stripes were enriched in super enhancers (Extended Data Fig. 8a-8b), consistent with previous findings 34.”
From Subtype-specific 3D genome alteration in acute myeloid leukaemia (2022) · cites this paper as [34]
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“Recent studies have suggested critical and distinct roles of the cohesin complex in compartmentalization versus formation of TADs (Rao et al., 2017; Schwarzer et al., 2017; Vian et al., 2018).”
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- Authors
- Vian, L., Pękowska, A., Rao, S. S. P., Kieffer-Kwon, K.-R., Jung, S., Baranello, L., Huang, S.-C., El Khattabi, L., Dose, M., Pruett, N., Sanborn, A. L., Canela, A., Maman, Y., Oksanen, A., Resch, W., Li, X., Lee, B., Kovalchuk, A. L., Tang, Z., Nelson, S., Di Pierro, M., Cheng, R. R., Machol, I., St Hilaire, B. G., Durand, N. C., Shamim, M. S., Stamenova, E. K., Onuchic, J. N., Ruan, Y., Nussenzweig, A., Levens, D., Aiden, E. L., & Casellas, R.
- Affiliations
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (US)
- Baylor College of Medicine (US)
- National Institutes of Health (US)
- University of Connecticut (US)
- Center for Theoretical Biological Physics (US)
- Corresponding author
- Aiden, Erez Lieberman
- Casellas, Rafael
- ORCID
- Pękowska, Aleksandra
- Rao, Suhas S.P.
- Jung, Seolkyoung
- Baranello, Laura
- Dose, Marei
- Pruett, Nathanael
- Sanborn, Adrian L.
- Maman, Yaakov
- Resch, Wolfgang
- Li, Xingwang
- Lee, Byoungkoo
- Kovalchuk, Alexander L.
- Tang, Zhonghui
- Cheng, Ryan R.
- Machol, Ido
- Durand, Neva C.
- Shamim, Muhammad S.
- Onuchic, José N.
- Ruan, Yijun
- Levens, David
- Aiden, Erez Lieberman
- Casellas, Rafael
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2018-05
- Volume
- 173
- Issue
- 5
- Pages
- 1165-1178.e20
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC6251724
- OpenAlex
- W2800216985
- Cited by
- 581
- References
- 57
- Citations by year
- 2026: 48 · 2025: 57 · 2024: 63 · 2023: 65 · 2022: 68 · 2021: 90 · 2020: 78 · 2019: 80 · 2018: 32
- FWCI
- 25.16
- Type
- journal article
- Language
- en
- Update notices
- erratum (2018-09-20)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- UWA Profiles and Research Repository (UWA) (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
- Funders
- NIAMS, NCI
- NIAID
- NIH Helix Systems
- Paul and Daisy Soros Fellowship
- Fannie and John Hertz Foundation Fellowship
- Cornelia de Lange Syndrome Foundation
- NIH New Innovator Award (1DP2OD008540-01)
- NSF Physics Frontiers Center Award (PHY-1427654)
- NHGRI Center for Excellence for Genomic Sciences (HG006193)
- Welch Foundation (Q-1866, C-1792)
- NVIDIA Research Center Award
- IBM University Challenge Award
- Google Research Award
- Cancer Prevention Research Institute of Texas Scholar Award (R1304)
- USDA Agriculture and Food Research Initiative Grant (2017-05741)
- McNair Medical Institute Scholar Award
- NIH Encyclopedia of DNA Elements Mapping Center Award (UM1HG009375)
- President’s Early Career Award in Science and Engineering
- NSF (PHY-1427654, CHE-1614101)
- 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
- 3D genome organization, super-enhancers, chromosomal translocation, plasmacytoma, oncogene deregulation
- MeSH terms
- CCCTC-Binding Factor, Cohesins, Adenosine Triphosphate, Animals, B-Lymphocytes, Cell Line, Chromatin, Chromosomal Proteins, Non-Histone, Chromosomes, DNA-Binding Proteins, Humans, Nuclear Proteins, Phosphoproteins, Chondroitin Sulfate Proteoglycans, Transcription Factors, Transcription, Genetic, Mutagenesis, Genome, Cell Cycle Proteins, Mice
About these checks
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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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