Loop extrusion

Depiction of the loop extrusion process where a loop extruder lands (top), extrudes a loop (middle), and unbinds (bottom).

Loop extrusion is a major mechanism of Nuclear organization. It is a dynamic process in which structural maintenance of chromosomes (SMC) protein complexes progressively grow loops of DNA or chromatin. In this process, SMC complexes, such as condensin or cohesin, bind to DNA/chromatin, use ATP-driven motor activity to reel in DNA, and as a result, extrude the collected DNA as a loop.

Background

The organization of DNA presents a remarkable biological challenge: human DNA can reach 2 meters ^[1] and is packed into the nucleus with the diameter of 5-20 μm. ^[2] At the same time, the critical cell processes involve complex processes on highly compacted DNA, such as transcription, replication, recombination, DNA repair, and cell division.

Loop extrusion is a key mechanism that organizes DNA into loops, enabling its efficient compaction and functional organization. For instance, in vitro experiments show that cohesin can compact DNA by 80%, ^[3] while condensin achieves a remarkable 10,000-fold compaction of mitotic chromosomes, as evidenced by microscopy, Hi-C, and polymer simulations. ^[4]

Another challenge lies in establishing long-range genomic communication, which can span hundreds of thousands of base pairs. ^[5] Physical encounters between genomic elements are intrinsically random and promiscuous without mechanisms to facilitate them. ^[6] Loop extrusion has been proposed to provide an effective solution to regulate contacts by bringing target elements into proximity while limiting contact with unwanted loci. ^[7]

Key components of the loop extrusion process

Key components

The key components of the loop extrusion process are

• DNA molecule that serves as the substrate for the movement of extruder
• Extruders, usually SMC complexes, that moves along DNA in ATP-dependent manner
• Accessory factors
  • Loaders of the extruder, a factor that facilitates loading of extruder on DNA (NIPBL/MAU2 usually play the key role in loading extruder on DNA ^[8] )
  • Unloaders of the extruder, the molecule that facilitates detachment of extruder from DNA (for example, WAPL ^{[9] [10] [11]} )
  • Road-blocks located on DNA that present a hindrance to extruder movement and lead to stalling of the extrusion machinery.

SMC proteins

Main article: SMC protein

Loop extrusion is performed by the SMC family of protein-complexes which includes cohesin, ^[12] condensin, ^[13] and SMC5/6 ^[14] each playing specialized roles depending on the organism, cell cycle phase, and biological context. ^{[15] [16]} Cohesin mediates chromatin loop formation and stabilization, particularly during interphase in vertebrates, where it facilitates transcriptional regulation by promoting distal enhancer-promoter interactions. During mitosis and meiosis, cohesin dissociates from chromosome arms ceding its loop extrusion role to condensin. Loop extrusion by condensin mediates large-scale chromosome compaction, creating the compact, rod-like chromosome structures required for accurate segregation. Unlike cohesin and condensin, SMC5/6 is a loop extruding factor which primarily functions in maintaining genome integrity during DNA damage repair and resolving replication stress.

Despite their distinct roles, SMC complexes share a highly conserved ring-like structure. ^{[15] [16]} Two SMC proteins (usually, SMC1 and SMC3) are connected via a hinge region and linked at their heads by a kleisin subunit, forming a closed ring. These two SMC proteins have ATPase domains at their heads, which bind together and hydrolyze ATP. Cycles of ATP binding and hydrolysis mediate conformational changes in the ring structure, ^[17] driving DNA translocation and stepwise loop extrusion. ^{[12] [13] [14]} ATP is essential for both initiating loop extrusion (e.g., loading SMC complexes onto DNA) and propagating it (growing loops by translocating along DNA). The tension within the DNA significantly influences extrusion efficiency. At low tension, SMC complexes can make larger loop-capture steps, while higher tension can lead to stalling or reversal of loop extrusion. ^{[18] [19] [20]}

Modifications and factors for loading/unloading

The dynamic nature of loop extrusion is tightly controlled by accessory factors and post-translational modifications, especially in the case of cohesin. In vertebrates, NIPBL (and orthologs like Mau2 in yeast or SCC2 and SCC4) is crucial for loading SMC complexes onto DNA, initiating and maintaining active extrusion. ^{[21] [22]} PDS5 is thought to pause the extrusion process. ^{[23] [24]} The SMC can then either restart extruding or be unloaded by the additional binding of WAPL, ^{[9] [10] [11]} which ensure proper recycling and turnover. Post-translational modifications also play a key role. Acetylation of cohesin by enzymes such as ESCO1 and ESCO2 stabilizes chromatin loops, particularly at CTCF-bound sites. ^[25] Similarly, SUMOylation, mediated by the NSE2 subunit of the SMC5/6 complex, enhances the recruitment of SMC5/6 to sites of DNA damage, supporting its role in genomic stability. ^{[26] [27]}

Roadblocks of loop extrusion

Loop extruders can encounter various obstacles while extruding. For example, many of which were shown to directly interact with cohesin and hypothesized to stop its movement on DNA. However, in vivo experiments demonstrate that cohesin can frequently bypass obstacles larger than its ring size. ^[28]

1. Other cohesin and condensin molecules: Extruding cohesins and condensins has been found to be obstacle to other extruders that they encounter on the way. ^{[29] [4]} As such, they present a fundamental road-block that can be randomly encountered on the DNA.
2. CTCF: The C-terminal DNA-binding domain of CTCF has been shown to directly interact with SA2 and SCC1 subunits of cohesin to stop extrusion and retain it on DNA ^[30] with recent evidence suggesting a tension-dependence to the interaction. ^[31] CTCF stalls cohesin in a highly directional manner where cohesin can bypass CTCF in one orientation but stalls when encountering it in the opposite orientation. ^[32] This directionality allows for the creation of isolated domains on the genome called Topologically Associating Domains (TADs) which have been proposed to have a large role in gene-regulation. ^[33]
3. Polymerase : Transcribing polymerases can serve as barriers to cohesin that may not only stall extruders but also act as a motor pushing cohesin in the direction of polymerase movement. ^{[34] [35]} The size of a polymerase with an RNA transcript is usually larger than the size of the cohesin ring, and the stall force of cohesin is much smaller than that of polymerase, ^[36] allowing for effective barrier function by polymerase. Furthermore, it has been found that RNA can directly interact with cohesin subunits. ^[37]
4. Helicase : MCM helicase has been found to counteract the extrusion of cohesin on DNA. ^[38]
5. R-loops: Some evidence suggests that R-loops can also act as barriers to loop extrusion, ^[39] and R-loops have been shown to interact with cohesin subunits. ^[37] However, other evidence suggests that R-loops may instead act as cohesin loaders. ^[40]

Molecular mechanism

The molecular mechanisms of DNA-loop extrusion by SMC proteins have not yet been fully understood, but recent structural studies have made significant progress in developing several working models, like the scrunching model, ^[41] the Brownian-ratchet model, the DNA-segment capture model/DNA-pumping model, the hold-and-feed model and the swing-and-clamp model. ^[42]

Evidence for loop extrusion

Evidence for loop extruding molecules and their properties

The first direct evidence of loop extrusion came from in vitro imaging studies on fluorescently labeled DNA with condensin ^[43] or cohesin. ^{[3] [44]} Extrusion was found to be ATP-dependent and happened at ~1-3kb/s. The stall force was measured to be around 0.1-1pN ^{[45] [43]} which is small compared to other molecular motors. ^[46]

Evidence for the biological role of loop extrusion

Most work on the biological role of loop extrusion relies on inhibiting loop extruders and observing the consequences. Depletion of cohesin leads to the disappearance of TADs and some loss in transcription genome-wide. ^{[47] [48]} In more specific settings, inhibition of cohesin has been found to inhibit neuronal maturation ^[49] and differentiation and function of dendritic cells. ^[50] Depletion of either condensin I or condensin II at the entry into mitosis leads to abnormal chromosome formation and improper segregation of sister chromatids. ^[4]

Biological function

Loop extrusion has been found across the tree of life with suggested roles in immune response, DNA repair, enhancer-promoter interactions, and mitosis.

• Mitosis in eukaryotes: In mitosis, loop extrusion by condensin is critical for the segregation of sister chromatids and for providing structural rigidity after separation. Condensin I has been found to modulate the size and arrangement of nested inner loops and condensin II organizing the backbone from which loops emanate. ^[4]
• Cell division in bacteria: In bacteria, SMC proteins have been found to maintain the juxtaposition of the chromosome arms by loading at the centromere and extruding until the terminus. ^[51]
• Topologically associating domains (TADs): During interphase, chromosomes are locally compacted at the sub-megabase scale into so-called TADs. Generally, they are bordered by motifs for CTCF and completely disappear if either cohesin or CTCF is degraded. ^[52]
• V(D)J recombination: Loop extrusion by cohesin has been found to play a key role in V(D)J recombination to generate diversity in antibodies and T-cell receptors ^{[53] [54]} as depletion of cohesin inhibits V(D)J recombination. ^[55] There are CTCF motifs throughout the recombination region, and inversions of their orientation or mutation of the motifs lead to changes in recombination probabilities consistent with those predicted by loop extrusion. ^{[56] [57]}
• Protocadherin promoter choice: Protocadherins are mammalian proteins involved in cell adhesion of the neurons encoded in DNA in multiple similar genes located in the protocadherin locus. Neurons usually express only a subset of the protocadherins, enabling variability in the interactions between neurons. ^[58] The choice of protocadherins rely on cohesin, which bridges alternative promoters of protocadherin with the enhancer in a CTCF-dependent manner. ^[59] This process involves intricate regulation by CTCF ^[60] and WAPL. ^[61]

Theoretical models of loop extrusion

In mathematical models of loop extrusion, the two legs of a loop-extruding factor (LEF) are represented as points on a one-dimensional line, evolving according to different extrusion policies:

• LEF Translocation: These dictate how LEFs move along the chromatin. These include symmetric extrusion—where both legs move in opposite directions—and one-sided extrusion—where one leg remains stalled while the other moves. Cohesin is often modeled with symmetric extrusion, while condensin is thought to follow a one-sided extrusion mechanism. ^[62]
• Stochastic Binding and Unbinding: LEFs bind to chromatin at a random time and position along the chain, and unbind after a characteristic time.
• LEF-LEF interactions: When LEFs encounter one another, different interaction policies can be implemented. LEFs may halt upon collision, or bypass each other, as observed in some contexts. ^{[29] [4]}
• Extrusion Barriers: Bound proteins such as CTCF or RNA polymerase II can act as obstacles, stalling or halting LEF motion.

Since the exact modalities of LEF dynamics remain uncertain, these models provide a flexible framework to explore different hypothetical behaviors of LEFs.

In these models, the statistics of LEFs are characterized by two key physical parameters: ^[29]

• Processivity (${\textstyle \lambda =2v\tau }$): Average size of a loop extruded by an unobstructed LEF before dissociating. This characteristic loop size depends on the extrusion speed ${\displaystyle v}$ and the residence time ${\displaystyle \tau }$ of the LEF on the chromatin.
• Separation (${\displaystyle d=L/N}$): Average distance between LEFs on the chromatin fiber. It is determined by the total number of LEFs ${\displaystyle N}$ and the length of the chromatin ${\displaystyle L}$. A shorter separation results in denser packing of loops, while larger separation leaves gaps between loops.

The interplay of these two parameters, encapsulated by the dimensionless parameter ${\displaystyle \lambda /d}$, defines two states of chromatin organization:

• Sparse State (${\displaystyle \lambda /d\ll 1}$): LEFs operate independently, forming isolated loops with large gaps between them. This state results in minimal compaction of the chromatin fiber.
• Dense State (${\displaystyle \lambda /d\gg 1}$): LEFs are abundant enough to form a continuous, gapless array of loops. This leads to significant chromatin compaction, as seen during mitosis.

References

1. Piovesan, Allison; Pelleri, Maria Chiara; Antonaros, Francesca; Strippoli, Pierluigi; Caracausi, Maria; Vitale, Lorenza (2019-02-27). "On the length, weight and GC content of the human genome". BMC Research Notes. 12 (1): 106. doi: 10.1186/s13104-019-4137-z . ISSN   1756-0500. PMC   6391780 . PMID   30813969.
2. Lammerding, J. (2011-01-31). Prakash, Y. S. (ed.). Comprehensive Physiology. Vol. 1 (1 ed.). Wiley. pp. 783–807. doi:10.1002/cphy.c100038. ISBN   978-0-470-65071-4. PMC   4600468 . PMID   23737203.
3. Kim, Yoori; Shi, Zhubing; Zhang, Hongshan; Finkelstein, Ilya J.; Yu, Hongtao (2019-12-13). "Human cohesin compacts DNA by loop extrusion". Science. 366 (6471): 1345–1349. Bibcode:2019Sci...366.1345K. doi:10.1126/science.aaz4475. PMC   7387118 . PMID   31780627.
4. Gibcus, Johan H.; Samejima, Kumiko; Goloborodko, Anton; Samejima, Itaru; Naumova, Natalia; Nuebler, Johannes; Kanemaki, Masato T.; Xie, Linfeng; Paulson, James R.; Earnshaw, William C.; Mirny, Leonid A.; Dekker, Job (2018-02-09). "A pathway for mitotic chromosome formation". Science. 359 (6376): –6135. doi:10.1126/science.aao6135. PMC   5924687 . PMID   29348367.
5. Lancho, Olga; Herranz, Daniel (December 2018). "The MYC Enhancer-ome: Long-Range Transcriptional Regulation of MYC in Cancer". Trends in Cancer. 4 (12): 810–822. doi:10.1016/j.trecan.2018.10.003. ISSN   2405-8033. PMC   6260942 . PMID   30470303.
6. Yang, Jin H.; Hansen, Anders S. (July 2024). "Enhancer selectivity in space and time: from enhancer–promoter interactions to promoter activation". Nature Reviews Molecular Cell Biology. 25 (7): 574–591. doi:10.1038/s41580-024-00710-6. ISSN   1471-0080. PMC   11574175 . PMID   38413840.
7. Karpinska, Magdalena A; Oudelaar, Aukje Marieke (2023-04-01). "The role of loop extrusion in enhancer-mediated gene activation". Current Opinion in Genetics & Development. 79: 102022. doi: 10.1016/j.gde.2023.102022 . ISSN   0959-437X. PMID   36842325.
8. Alonso-Gil, Dácil; Losada, Ana (October 2023). "NIPBL and cohesin: new take on a classic tale". Trends in Cell Biology. 33 (10): 860–871. doi: 10.1016/j.tcb.2023.03.006 . PMID   37062615.
9. Kueng, Stephanie; Hegemann, Björn; Peters, Beate H.; Lipp, Jesse J.; Schleiffer, Alexander; Mechtler, Karl; Peters, Jan-Michael (December 2006). "Wapl Controls the Dynamic Association of Cohesin with Chromatin". Cell. 127 (5): 955–967. doi: 10.1016/j.cell.2006.09.040 . PMID   17113138.
10. Gandhi, Rita; Gillespie, Peter J.; Hirano, Tatsuya (December 2006). "Human Wapl Is a Cohesin-Binding Protein that Promotes Sister-Chromatid Resolution in Mitotic Prophase". Current Biology. 16 (24): 2406–2417. Bibcode:2006CBio...16.2406G. doi:10.1016/j.cub.2006.10.061. PMC   1850625 . PMID   17112726.
11. Tedeschi, Antonio; Wutz, Gordana; Huet, Sébastien; Jaritz, Markus; Wuensche, Annelie; Schirghuber, Erika; Davidson, Iain Finley; Tang, Wen; Cisneros, David A.; Bhaskara, Venugopal; Nishiyama, Tomoko; Vaziri, Alipasha; Wutz, Anton; Ellenberg, Jan; Peters, Jan-Michael (September 2013). "Wapl is an essential regulator of chromatin structure and chromosome segregation". Nature. 501 (7468): 564–568. Bibcode:2013Natur.501..564T. doi:10.1038/nature12471. PMC   6080692 . PMID   23975099.
12. Davidson, Iain F.; Bauer, Benedikt; Goetz, Daniela; Tang, Wen; Wutz, Gordana; Peters, Jan-Michael (2019-12-13). "DNA loop extrusion by human cohesin" . Science. 366 (6471): 1338–1345. Bibcode:2019Sci...366.1338D. doi:10.1126/science.aaz3418. PMID   31753851.
13. Ganji, Mahipal; Shaltiel, Indra A.; Bisht, Shveta; Kim, Eugene; Kalichava, Ana; Haering, Christian H.; Dekker, Cees (2018-04-06). "Real-time imaging of DNA loop extrusion by condensin". Science. 360 (6384): 102–105. Bibcode:2018Sci...360..102G. doi:10.1126/science.aar7831. PMC   6329450 . PMID   29472443.
14. Pradhan, Biswajit; Kanno, Takaharu; Umeda Igarashi, Miki; Loke, Mun Siong; Baaske, Martin Dieter; Wong, Jan Siu Kei; Jeppsson, Kristian; Björkegren, Camilla; Kim, Eugene (April 2023). "The Smc5/6 complex is a DNA loop-extruding motor". Nature. 616 (7958): 843–848. Bibcode:2023Natur.616..843P. doi:10.1038/s41586-023-05963-3. ISSN   1476-4687. PMC   10132971 . PMID   37076626.
15. Hoencamp, Claire; Rowland, Benjamin D. (September 2023). "Genome control by SMC complexes" . Nature Reviews Molecular Cell Biology. 24 (9): 633–650. doi:10.1038/s41580-023-00609-8. ISSN   1471-0080. PMID   37231112.
16. Kim, Eugene; Barth, Roman; Dekker, Cees (2023-06-20). "Looping the Genome with SMC Complexes". Annual Review of Biochemistry. 92: 15–41. doi: 10.1146/annurev-biochem-032620-110506 . ISSN   0066-4154. PMID   37137166.
17. Gomes, Marina Vitoria; Landwerlin, Pauline; Diebold-Durand, Marie-Laure; Shaik, Tajith B.; Durand, Alexandre; Troesch, Edouard; Weber, Chantal; Brillet, Karl; Lemée, Marianne Victoria; Decroos, Christophe; Dulac, Ludivine; Antony, Pierre; Watrin, Erwan; Ennifar, Eric; Golzio, Christelle (2024-09-24). "The cohesin ATPase cycle is mediated by specific conformational dynamics and interface plasticity of SMC1A and SMC3 ATPase domains". Cell Reports. 43 (9). doi:10.1016/j.celrep.2024.114656. ISSN   2211-1247. PMID   39240714.
18. Nomidis, Stefanos K; Carlon, Enrico; Gruber, Stephan; Marko, John F (2022-05-20). "DNA tension-modulated translocation and loop extrusion by SMC complexes revealed by molecular dynamics simulations". Nucleic Acids Research. 50 (9): 4974–4987. doi:10.1093/nar/gkac268. ISSN   0305-1048. PMC   9122525 . PMID   35474142 . Retrieved 2024-11-26.
19. Davidson, Iain F.; Barth, Roman; Horn, Sabrina; Janissen, Richard; Nagasaka, Kota; Wutz, Gordana; Stocsits, Roman R.; Bauer, Benedikt; Dekker, Cees (2024-03-22), Cohesin supercoils DNA during loop extrusion, doi: 10.1101/2024.03.22.586228 , retrieved 2024-11-26
20. Davidson, Iain F.; Barth, Roman; Zaczek, Maciej; van der Torre, Jaco; Tang, Wen; Nagasaka, Kota; Janissen, Richard; Kerssemakers, Jacob; Wutz, Gordana; Dekker, Cees; Peters, Jan-Michael (April 2023). "CTCF is a DNA-tension-dependent barrier to cohesin-mediated loop extrusion". Nature. 616 (7958): 822–827. Bibcode:2023Natur.616..822D. doi:10.1038/s41586-023-05961-5. ISSN   1476-4687. PMC   10132984 . PMID   37076620.
21. Davidson, Iain F.; Bauer, Benedikt; Goetz, Daniela; Tang, Wen; Wutz, Gordana; Peters, Jan-Michael (2019-12-13). "DNA loop extrusion by human cohesin" . Science. 366 (6471): 1338–1345. Bibcode:2019Sci...366.1338D. doi:10.1126/science.aaz3418. PMID   31753851.
22. Ganji, Mahipal; Shaltiel, Indra A.; Bisht, Shveta; Kim, Eugene; Kalichava, Ana; Haering, Christian H.; Dekker, Cees (2018-04-06). "Real-time imaging of DNA loop extrusion by condensin". Science. 360 (6384): 102–105. Bibcode:2018Sci...360..102G. doi:10.1126/science.aar7831. PMC   6329450 . PMID   29472443.
23. van Ruiten, Marjon S.; van Gent, Démi; Sedeño Cacciatore, Ángela; Fauster, Astrid; Willems, Laureen; Hekkelman, Maarten L.; Hoekman, Liesbeth; Altelaar, Maarten; Haarhuis, Judith H. I.; Brummelkamp, Thijn R.; de Wit, Elzo; Rowland, Benjamin D. (June 2022). "The cohesin acetylation cycle controls chromatin loop length through a PDS5A brake mechanism". Nature Structural & Molecular Biology. 29 (6): 586–591. doi:10.1038/s41594-022-00773-z. ISSN   1545-9985. PMC   9205776 . PMID   35710836.
24. Bastié, Nathalie; Chapard, Christophe; Dauban, Lise; Gadal, Olivier; Beckouët, Frédéric; Koszul, Romain (June 2022). "Smc3 acetylation, Pds5 and Scc2 control the translocase activity that establishes cohesin-dependent chromatin loops" . Nature Structural & Molecular Biology. 29 (6): 575–585. doi:10.1038/s41594-022-00780-0. ISSN   1545-9985. PMID   35710835.
25. Wutz, Gordana; Ladurner, Rene; St Hilaire, Brian Glenn; Stocsits, Roman R; Nagasaka, Kota; Pignard, Benoit; Sanborn, Adrian; Tang, Wen; Várnai, Csilla; Ivanov, Miroslav P; Schoenfelder, Stefan; van der Lelij, Petra; Huang, Xingfan; Dürnberger, Gerhard; Roitinger, Elisabeth (2020-02-17). Lee, Jeannie T; Struhl, Kevin; Yu, Hongtao (eds.). "ESCO1 and CTCF enable formation of long chromatin loops by protecting cohesinSTAG1 from WAPL". eLife. 9: e52091. doi: 10.7554/eLife.52091 . ISSN   2050-084X. PMC   7054000 . PMID   32065581.
26. Andrews, Emily A.; Palecek, Jan; Sergeant, John; Taylor, Elaine; Lehmann, Alan R.; Watts, Felicity Z. (2005-01-01). "Nse2, a Component of the Smc5-6 Complex, Is a SUMO Ligase Required for the Response to DNA Damage". Molecular and Cellular Biology. 25 (1): 185–196. doi:10.1128/MCB.25.1.185-196.2005. PMC   538766 . PMID   15601841.
27. De Piccoli, Giacomo; Cortes-Ledesma, Felipe; Ira, Gregory; Torres-Rosell, Jordi; Uhle, Stefan; Farmer, Sarah; Hwang, Ji-Young; Machin, Felix; Ceschia, Audrey; McAleenan, Alexandra; Cordon-Preciado, Violeta; Clemente-Blanco, Andrés; Vilella-Mitjana, Felip; Ullal, Pranav; Jarmuz, Adam (September 2006). "Smc5–Smc6 mediate DNA double-strand-break repair by promoting sister-chromatid recombination". Nature Cell Biology. 8 (9): 1032–1034. doi:10.1038/ncb1466. ISSN   1476-4679. PMC   4493748 . PMID   16892052.
28. Pradhan, Biswajit; Barth, Roman; Kim, Eugene; Davidson, Iain F.; Bauer, Benedikt; van Laar, Theo; Yang, Wayne; Ryu, Je-Kyung; van der Torre, Jaco; Peters, Jan-Michael; Dekker, Cees (2022-10-18). "SMC complexes can traverse physical roadblocks bigger than their ring size". Cell Reports. 41 (3): 111491. doi:10.1016/j.celrep.2022.111491. ISSN   2211-1247. PMID   36261017.
29. Goloborodko, Anton; Marko, John F.; Mirny, Leonid A. (2016-05-24). "Chromosome Compaction by Active Loop Extrusion". Biophysical Journal. 110 (10): 2162–2168. Bibcode:2016BpJ...110.2162G. doi:10.1016/j.bpj.2016.02.041. ISSN   0006-3495. PMC   4880799 . PMID   27224481.
30. Li, Yan; Haarhuis, Judith H. I.; Sedeño Cacciatore, Ángela; Oldenkamp, Roel; van Ruiten, Marjon S.; Willems, Laureen; Teunissen, Hans; Muir, Kyle W.; de Wit, Elzo; Rowland, Benjamin D.; Panne, Daniel (February 2020). "The structural basis for cohesin–CTCF-anchored loops". Nature. 578 (7795): 472–476. Bibcode:2020Natur.578..472L. doi:10.1038/s41586-019-1910-z. ISSN   1476-4687. PMC   7035113 . PMID   31905366.
31. Davidson, Iain F.; Barth, Roman; Zaczek, Maciej; Torre, Jaco van der; Tang, Wen; Nagasaka, Kota; Janissen, Richard; Kerssemakers, Jacob; Wutz, Gordana; Dekker, Cees; Peters, Jan-Michael (2022-09-11), CTCF is a DNA-tension-dependent barrier to cohesin-mediated DNA loop extrusion, doi: 10.1101/2022.09.08.507093 , retrieved 2022-12-30
32. de Wit, Elzo; Vos, Erica S. M.; Holwerda, Sjoerd J. B.; Valdes-Quezada, Christian; Verstegen, Marjon J. A. M.; Teunissen, Hans; Splinter, Erik; Wijchers, Patrick J.; Krijger, Peter H. L.; de Laat, Wouter (2015-11-19). "CTCF Binding Polarity Determines Chromatin Looping". Molecular Cell. 60 (4): 676–684. doi:10.1016/j.molcel.2015.09.023. ISSN   1097-2765. PMID   26527277.
33. Lupiáñez, Darío G.; Kraft, Katerina; Heinrich, Verena; Krawitz, Peter; Brancati, Francesco; Klopocki, Eva; Horn, Denise; Kayserili, Hülya; Opitz, John M.; Laxova, Renata; Santos-Simarro, Fernando; Gilbert-Dussardier, Brigitte; Wittler, Lars; Borschiwer, Marina; Haas, Stefan A.; Osterwalder, Marco; Franke, Martin; Timmermann, Bernd; Hecht, Jochen; Spielmann, Malte; Visel, Axel; Mundlos, Stefan (2015-05-21). "Disruptions of Topological Chromatin Domains Cause Pathogenic Rewiring of Gene-Enhancer Interactions". Cell. 161 (5): 1012–1025. doi:10.1016/j.cell.2015.04.004. ISSN   0092-8674. PMC   4791538 . PMID   25959774.
34. Banigan, Edward J.; Tang, Wen; van den Berg, Aafke A.; Stocsits, Roman R.; Wutz, Gordana; Brandão, Hugo B.; Busslinger, Georg A.; Peters, Jan-Michael; Mirny, Leonid A. (2023-03-14). "Transcription shapes 3D chromatin organization by interacting with loop extrusion". Proceedings of the National Academy of Sciences of the United States of America. 120 (11): e2210480120. Bibcode:2023PNAS..12010480B. doi: 10.1073/pnas.2210480120 . ISSN   1091-6490. PMC   10089175 . PMID   36897969.
35. Brandão, Hugo B.; Paul, Payel; van den Berg, Aafke A.; Rudner, David Z.; Wang, Xindan; Mirny, Leonid A. (2019-10-08). "RNA polymerases as moving barriers to condensin loop extrusion". Proceedings of the National Academy of Sciences of the United States of America. 116 (41): 20489–20499. Bibcode:2019PNAS..11620489B. doi: 10.1073/pnas.1907009116 . ISSN   1091-6490. PMC   6789630 . PMID   31548377.
36. Banigan, Edward J.; Mirny, Leonid A. (2020-06-01). "Loop extrusion: theory meets single-molecule experiments" . Current Opinion in Cell Biology. Cell Nucleus. 64: 124–138. doi:10.1016/j.ceb.2020.04.011. ISSN   0955-0674. PMID   32534241 . Retrieved 2022-04-02.
37. Porter, Hayley; Li, Yang; Neguembor, Maria Victoria; Beltran, Manuel; Varsally, Wazeer; Martin, Laura; Cornejo, Manuel Tavares; Pezić, Dubravka; Bhamra, Amandeep; Surinova, Silvia; Jenner, Richard G; Cosma, Maria Pia; Hadjur, Suzana (2023-04-03). Aguilera, Andrés; Struhl, Kevin; Vannini, Alessandro (eds.). "Cohesin-independent STAG proteins interact with RNA and R-loops and promote complex loading". eLife. 12: e79386. doi: 10.7554/eLife.79386 . ISSN   2050-084X. PMC   10238091 . PMID   37010886.
38. Dequeker, Bart J. H.; Scherr, Matthias J.; Brandão, Hugo B.; Gassler, Johanna; Powell, Sean; Gaspar, Imre; Flyamer, Ilya M.; Lalic, Aleksandar; Tang, Wen; Stocsits, Roman; Davidson, Iain F.; Peters, Jan-Michael; Duderstadt, Karl E.; Mirny, Leonid A.; Tachibana, Kikuë (June 2022). "MCM complexes are barriers that restrict cohesin-mediated loop extrusion". Nature. 606 (7912): 197–203. Bibcode:2022Natur.606..197D. doi:10.1038/s41586-022-04730-0. ISSN   1476-4687. PMC   9159944 . PMID   35585235.
39. Zhang, Hongshan; Shi, Zhubing; Banigan, Edward J.; Kim, Yoori; Yu, Hongtao; Bai, Xiao-chen; Finkelstein, Ilya J. (August 2023). "CTCF and R-loops are boundaries of cohesin-mediated DNA looping". Molecular Cell. 83 (16): 2856–2871.e8. doi:10.1016/j.molcel.2023.07.006. PMID   37536339.
40. Porter, Hayley; Li, Yang; Neguembor, Maria Victoria; Beltran, Manuel; Varsally, Wazeer; Martin, Laura; Cornejo, Manuel Tavares; Pezić, Dubravka; Bhamra, Amandeep; Surinova, Silvia; Jenner, Richard G; Cosma, Maria Pia; Hadjur, Suzana (2023-04-03). Aguilera, Andrés; Struhl, Kevin; Vannini, Alessandro (eds.). "Cohesin-independent STAG proteins interact with RNA and R-loops and promote complex loading". eLife. 12: e79386. doi: 10.7554/eLife.79386 . ISSN   2050-084X. PMC   10238091 . PMID   37010886.
41. Ryu, Je-Kyung; Katan, Allard J.; van der Sluis, Eli O.; Wisse, Thomas; de Groot, Ralph; Haering, Christian H.; Dekker, Cees (December 2020). "The condensin holocomplex cycles dynamically between open and collapsed states" . Nature Structural & Molecular Biology. 27 (12): 1134–1141. doi:10.1038/s41594-020-0508-3. ISSN   1545-9993. PMID   32989304.
42. Bauer, Benedikt W.; Davidson, Iain F.; Canena, Daniel; Wutz, Gordana; Tang, Wen; Litos, Gabriele; Horn, Sabrina; Hinterdorfer, Peter; Peters, Jan-Michael (October 2021). "Cohesin mediates DNA loop extrusion by a "swing and clamp" mechanism". Cell. 184 (21): 5448–5464.e22. doi:10.1016/j.cell.2021.09.016. ISSN   0092-8674. PMC   8563363 . PMID   34624221.
43. Ganji, Mahipal; Shaltiel, Indra A.; Bisht, Shveta; Kim, Eugene; Kalichava, Ana; Haering, Christian H.; Dekker, Cees (2018-04-06). "Real-time imaging of DNA loop extrusion by condensin". Science. 360 (6384): 102–105. Bibcode:2018Sci...360..102G. doi:10.1126/science.aar7831. PMC   6329450 . PMID   29472443.
44. Davidson, Iain F.; Bauer, Benedikt; Goetz, Daniela; Tang, Wen; Wutz, Gordana; Peters, Jan-Michael (2019-12-13). "DNA loop extrusion by human cohesin" . Science. 366 (6471): 1338–1345. Bibcode:2019Sci...366.1338D. doi:10.1126/science.aaz3418. PMID   31753851 . Retrieved 2022-06-15.
45. Golfier, S.; Quail, T.; Kimura, H.; Brugués, J. (2020). "Cohesin and condensin extrude DNA loops in a cell-cycle dependent manner". eLife. 9: 1–34. doi: 10.7554/eLife.53885 . ISSN   2050-084X. PMC   7316503 . PMID   32396063.
46. Mallik, Roop; Gross, Steven P. (November 2004). "Molecular Motors: Strategies to Get Along". Current Biology. 14 (22): R971 –R982. Bibcode:2004CBio...14.R971M. doi: 10.1016/j.cub.2004.10.046 . PMID   15556858.
47. Rao, Suhas S. P.; Huang, Su-Chen; Glenn St Hilaire, Brian; Engreitz, Jesse M.; Perez, Elizabeth M.; Kieffer-Kwon, Kyong-Rim; Sanborn, Adrian L.; Johnstone, Sarah E.; Bascom, Gavin D.; Bochkov, Ivan D.; Huang, Xingfan; Shamim, Muhammad S.; Shin, Jaeweon; Turner, Douglass; Ye, Ziyi; Omer, Arina D.; Robinson, James T.; Schlick, Tamar; Bernstein, Bradley E.; Casellas, Rafael; Lander, Eric S.; Aiden, Erez Lieberman (2017-10-05). "Cohesin Loss Eliminates All Loop Domains". Cell. 171 (2): 305–320.e24. doi:10.1016/j.cell.2017.09.026. ISSN   0092-8674. PMC   5846482 . PMID   28985562.
48. Schwarzer, Wibke; Abdennur, Nezar; Goloborodko, Anton; Pekowska, Aleksandra; Fudenberg, Geoffrey; Loe-Mie, Yann; Fonseca, Nuno A.; Huber, Wolfgang; Haering, Christian H.; Mirny, Leonid; Spitz, Francois (2017-11-02). "Two independent modes of chromatin organization revealed by cohesin removal". Nature. 551 (7678): 51–56. Bibcode:2017Natur.551...51S. doi:10.1038/nature24281. ISSN   1476-4687. PMC   5687303 . PMID   29094699.
49. Calderon, Lesly; Weiss, Felix D; Beagan, Jonathan A; Oliveira, Marta S; Georgieva, Radina; Wang, Yi-Fang; Carroll, Thomas S; Dharmalingam, Gopuraja; Gong, Wanfeng; Tossell, Kyoko; de Paola, Vincenzo; Whilding, Chad; Ungless, Mark A; Fisher, Amanda G; Phillips-Cremins, Jennifer E (2022-04-26). Day, Jeremy J; Struhl, Kevin (eds.). "Cohesin-dependence of neuronal gene expression relates to chromatin loop length". eLife. 11: e76539. doi: 10.7554/eLife.76539 . ISSN   2050-084X. PMC   9106336 . PMID   35471149.
50. Adams, Nicholas M.; Galitsyna, Aleksandra; Tiniakou, Ioanna; Esteva, Eduardo; Lau, Colleen M.; Reyes, Jojo; Abdennur, Nezar; Shkolikov, Alexey; Yap, George S. (2024-10-30), "Cohesin-mediated chromatin remodeling controls the differentiation and function of conventional dendritic cells", BioRxiv: The Preprint Server for Biology, doi:10.1101/2024.09.18.613709, PMC   11430140 , PMID   39345451 , retrieved 2024-11-26
51. Wang, Xindan; Brandão, Hugo B.; Le, Tung B. K.; Laub, Michael T.; Rudner, David Z. (2017-02-03). "Bacillus subtilis SMC complexes juxtapose chromosome arms as they travel from origin to terminus". Science. 355 (6324): 524–527. Bibcode:2017Sci...355..524W. doi:10.1126/science.aai8982. PMC   5484144 . PMID   28154080.
52. Rao, Suhas S.P.; Huntley, Miriam H.; Durand, Neva C.; Stamenova, Elena K.; Bochkov, Ivan D.; Robinson, James T.; Sanborn, Adrian L.; Machol, Ido; Omer, Arina D.; Lander, Eric S.; Aiden, Erez Lieberman (December 2014). "A 3D Map of the Human Genome at Kilobase Resolution Reveals Principles of Chromatin Looping". Cell. 159 (7): 1665–1680. doi:10.1016/j.cell.2014.11.021. PMC   5635824 . PMID   25497547.
53. Peters, Jan-Michael (2021-06-01). "How DNA loop extrusion mediated by cohesin enables V(D)J recombination". Current Opinion in Cell Biology. Cell Nucleus. 70: 75–83. doi: 10.1016/j.ceb.2020.11.007 . ISSN   0955-0674. PMID   33422934.
54. Zhang, Yu; Zhang, Xuefei; Dai, Hai-Qiang; Hu, Hongli; Alt, Frederick W. (September 2022). "The role of chromatin loop extrusion in antibody diversification". Nature Reviews Immunology. 22 (9): 550–566. doi:10.1038/s41577-022-00679-3. ISSN   1474-1741. PMC   9376198 . PMID   35169260.
55. Ba, Zhaoqing; Lou, Jiangman; Ye, Adam Yongxin; Dai, Hai-Qiang; Dring, Edward W.; Lin, Sherry G.; Jain, Suvi; Kyritsis, Nia; Kieffer-Kwon, Kyong-Rim; Casellas, Rafael; Alt, Frederick W. (October 2020). "CTCF orchestrates long-range cohesin-driven V(D)J recombinational scanning". Nature. 586 (7828): 305–310. Bibcode:2020Natur.586..305B. doi:10.1038/s41586-020-2578-0. ISSN   1476-4687. PMC   7554077 . PMID   32717742.
56. Dai, Hai-Qiang; Hu, Hongli; Lou, Jiangman; Ye, Adam Yongxin; Ba, Zhaoqing; Zhang, Xuefei; Zhang, Yiwen; Zhao, Lijuan; Yoon, Hye Suk; Chapdelaine-Williams, Aimee M.; Kyritsis, Nia; Chen, Huan; Johnson, Kerstin; Lin, Sherry; Conte, Andrea (February 2021). "Loop extrusion mediates physiological Igh locus contraction for RAG scanning". Nature. 590 (7845): 338–343. Bibcode:2021Natur.590..338D. doi:10.1038/s41586-020-03121-7. ISSN   1476-4687. PMC   9037962 . PMID   33442057.
57. Zhang, Yu; Zhang, Xuefei; Ba, Zhaoqing; Liang, Zhuoyi; Dring, Edward W.; Hu, Hongli; Lou, Jiangman; Kyritsis, Nia; Zurita, Jeffrey; Shamim, Muhammad S.; Presser Aiden, Aviva; Lieberman Aiden, Erez; Alt, Frederick W. (September 2019). "The fundamental role of chromatin loop extrusion in physiological V(D)J recombination". Nature. 573 (7775): 600–604. Bibcode:2019Natur.573..600Z. doi:10.1038/s41586-019-1547-y. ISSN   1476-4687. PMC   6867615 . PMID   31511698.
58. Tasic, Bosiljka; Nabholz, Christoph E.; Baldwin, Kristin K.; Kim, Youngwook; Rueckert, Erroll H.; Ribich, Scott A.; Cramer, Paula; Wu, Qiang; Axel, Richard; Maniatis, Tom (July 2002). "Promoter Choice Determines Splice Site Selection in Protocadherin α and γ Pre-mRNA Splicing". Molecular Cell. 10 (1): 21–33. doi:10.1016/S1097-2765(02)00578-6. PMID   12150904.
59. Monahan, Kevin; Rudnick, Noam D.; Kehayova, Polina D.; Pauli, Florencia; Newberry, Kimberly M.; Myers, Richard M.; Maniatis, Tom (2012-06-05). "Role of CCCTC binding factor (CTCF) and cohesin in the generation of single-cell diversity of Protocadherin-α gene expression". Proceedings of the National Academy of Sciences. 109 (23): 9125–9130. Bibcode:2012PNAS..109.9125M. doi: 10.1073/pnas.1205074109 . ISSN   0027-8424. PMC   3384188 . PMID   22550178.
60. Guo, Ya; Monahan, Kevin; Wu, Haiyang; Gertz, Jason; Varley, Katherine E.; Li, Wei; Myers, Richard M.; Maniatis, Tom; Wu, Qiang (2012-12-18). "CTCF/cohesin-mediated DNA looping is required for protocadherin α promoter choice". Proceedings of the National Academy of Sciences. 109 (51): 21081–21086. Bibcode:2012PNAS..10921081G. doi: 10.1073/pnas.1219280110 . ISSN   0027-8424. PMC   3529044 . PMID   23204437.
61. Kiefer, Lea; Chiosso, Anna; Langen, Jennifer; Buckley, Alex; Gaudin, Simon; Rajkumar, Sandy M.; Servito, Gabrielle Isabelle F.; Cha, Elizabeth S.; Vijay, Akshara; Yeung, Albert; Horta, Adan; Mui, Michael H.; Canzio, Daniele (2023-06-23). "WAPL functions as a rheostat of Protocadherin isoform diversity that controls neural wiring" . Science. 380 (6651): eadf8440. doi:10.1126/science.adf8440. ISSN   0036-8075. PMID   37347873.
62. Banigan, Edward J; van den Berg, Aafke A; Brandão, Hugo B; Marko, John F; Mirny, Leonid A (2020-04-06). "Chromosome organization by one-sided and two-sided loop extrusion". eLife. 9. doi: 10.7554/eLife.53558 . ISSN   2050-084X. PMC   7295573 . PMID   32250245.