{{Short description|Mechanism of nuclear organization}} thumb|386x386px|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<ref>{{Cite journal |last1=Piovesan |first1=Allison |last2=Pelleri |first2=Maria Chiara |last3=Antonaros |first3=Francesca |last4=Strippoli |first4=Pierluigi |last5=Caracausi |first5=Maria |last6=Vitale |first6=Lorenza |date=2019-02-27 |title=On the length, weight and GC content of the human genome |journal=BMC Research Notes |volume=12 |issue=1 |page=106 |doi=10.1186/s13104-019-4137-z |doi-access=free |pmid=30813969 |pmc=6391780 |bibcode=2019BMCRN..12..106P |issn=1756-0500 }}</ref> and is packed into the nucleus with the diameter of 5-20 μm.<ref>{{Cite book |title=Comprehensive Physiology |date=2011-01-31 |publisher=Wiley |isbn=978-0-470-65071-4 |editor-last=Prakash |editor-first=Y. S. |edition=1 |language=en |doi=10.1002/cphy.c100038 |pmc=4600468 |pmid=23737203 |last1=Lammerding |first1=J. |volume=1 |pages=783–807 }}</ref> 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%,<ref name=":0">{{Cite journal |last1=Kim |first1=Yoori |last2=Shi |first2=Zhubing |last3=Zhang |first3=Hongshan |last4=Finkelstein |first4=Ilya J. |last5=Yu |first5=Hongtao |date=2019-12-13 |title=Human cohesin compacts DNA by loop extrusion |journal=Science |volume=366 |issue=6471 |pages=1345–1349 |doi=10.1126/science.aaz4475 |pmid=31780627 |pmc=7387118 |bibcode=2019Sci...366.1345K }}</ref> while condensin achieves a remarkable 10,000-fold compaction of mitotic chromosomes, as evidenced by microscopy, Hi-C, and polymer simulations.<ref name=":1">{{Cite journal |last1=Gibcus |first1=Johan H. |last2=Samejima |first2=Kumiko |last3=Goloborodko |first3=Anton |last4=Samejima |first4=Itaru |last5=Naumova |first5=Natalia |last6=Nuebler |first6=Johannes |last7=Kanemaki |first7=Masato T. |last8=Xie |first8=Linfeng |last9=Paulson |first9=James R. |last10=Earnshaw |first10=William C. |last11=Mirny |first11=Leonid A. |last12=Dekker |first12=Job |date=2018-02-09 |title=A pathway for mitotic chromosome formation |journal=Science |volume=359 |issue=6376 |pages=–6135 |doi=10.1126/science.aao6135 |pmid=29348367 |pmc=5924687 }}</ref>
Another challenge lies in establishing long-range genomic communication, which can span hundreds of thousands of base pairs.<ref>{{Cite journal |last1=Lancho |first1=Olga |last2=Herranz |first2=Daniel |date=December 2018 |title=The MYC Enhancer-ome: Long-Range Transcriptional Regulation of MYC in Cancer |journal=Trends in Cancer |volume=4 |issue=12 |pages=810–822 |doi=10.1016/j.trecan.2018.10.003 |issn=2405-8033 |pmc=6260942 |pmid=30470303}}</ref> Physical encounters between genomic elements are intrinsically random and promiscuous without mechanisms to facilitate them.<ref>{{Cite journal |last1=Yang |first1=Jin H. |last2=Hansen |first2=Anders S. |date=July 2024 |title=Enhancer selectivity in space and time: from enhancer–promoter interactions to promoter activation |journal=Nature Reviews Molecular Cell Biology |language=en |volume=25 |issue=7 |pages=574–591 |doi=10.1038/s41580-024-00710-6 |issn=1471-0080 |pmc=11574175 |pmid=38413840}}</ref> 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.<ref>{{Cite journal |last1=Karpinska |first1=Magdalena A |last2=Oudelaar |first2=Aukje Marieke |date=2023-04-01 |title=The role of loop extrusion in enhancer-mediated gene activation |journal=Current Opinion in Genetics & Development |volume=79 |article-number=102022 |doi=10.1016/j.gde.2023.102022 |pmid=36842325 |issn=0959-437X |doi-access=free }}</ref> thumb|400x400px|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 are thought to play the key role in loading extruder on DNA<ref>{{Cite journal |last1=Alonso-Gil |first1=Dácil |last2=Losada |first2=Ana |date=October 2023 |title=NIPBL and cohesin: new take on a classic tale |journal=Trends in Cell Biology |language=en |volume=33 |issue=10 |pages=860–871 |doi=10.1016/j.tcb.2023.03.006|pmid=37062615 |doi-access=free }}</ref>) ** Unloaders of the extruder, the molecule that facilitates detachment of extruder from DNA (for example, WAPL<ref name=":4">{{cite journal |last1=Kueng |first1=Stephanie |last2=Hegemann |first2=Björn |last3=Peters |first3=Beate H. |last4=Lipp |first4=Jesse J. |last5=Schleiffer |first5=Alexander |last6=Mechtler |first6=Karl |last7=Peters |first7=Jan-Michael |title=Wapl Controls the Dynamic Association of Cohesin with Chromatin |journal=Cell |date=December 2006 |volume=127 |issue=5 |pages=955–967 |doi=10.1016/j.cell.2006.09.040|pmid=17113138 |doi-access=free }}</ref><ref name=":5">{{cite journal |last1=Gandhi |first1=Rita |last2=Gillespie |first2=Peter J. |last3=Hirano |first3=Tatsuya |title=Human Wapl Is a Cohesin-Binding Protein that Promotes Sister-Chromatid Resolution in Mitotic Prophase |journal=Current Biology |date=December 2006 |volume=16 |issue=24 |pages=2406–2417 |doi=10.1016/j.cub.2006.10.061|pmid=17112726 |bibcode=2006CBio...16.2406G |pmc=1850625 }}</ref><ref name=":6">{{cite journal |last1=Tedeschi |first1=Antonio |last2=Wutz |first2=Gordana |last3=Huet |first3=Sébastien |last4=Jaritz |first4=Markus |last5=Wuensche |first5=Annelie |last6=Schirghuber |first6=Erika |last7=Davidson |first7=Iain Finley |last8=Tang |first8=Wen |last9=Cisneros |first9=David A. |last10=Bhaskara |first10=Venugopal |last11=Nishiyama |first11=Tomoko |last12=Vaziri |first12=Alipasha |last13=Wutz |first13=Anton |last14=Ellenberg |first14=Jan |last15=Peters |first15=Jan-Michael |title=Wapl is an essential regulator of chromatin structure and chromosome segregation |journal=Nature |date=September 2013 |volume=501 |issue=7468 |pages=564–568 |doi=10.1038/nature12471|pmid=23975099 |pmc=6080692 |bibcode=2013Natur.501..564T }}</ref>) ** Road-blocks located on DNA that present a hindrance to extruder movement and lead to stalling of the extrusion machinery.
=== SMC proteins === {{Main|SMC protein}} Loop extrusion is performed by the SMC family of protein-complexes which includes cohesin,<ref name=":7">{{Cite journal |last1=Davidson |first1=Iain F. |last2=Bauer |first2=Benedikt |last3=Goetz |first3=Daniela |last4=Tang |first4=Wen |last5=Wutz |first5=Gordana |last6=Peters |first6=Jan-Michael |date=2019-12-13 |title=DNA loop extrusion by human cohesin |url=https://www.science.org/doi/10.1126/science.aaz3418 |journal=Science |volume=366 |issue=6471 |pages=1338–1345 |doi=10.1126/science.aaz3418|pmid=31753851 |bibcode=2019Sci...366.1338D |url-access=subscription }}</ref> condensin,<ref name=":8">{{Cite journal |last1=Ganji |first1=Mahipal |last2=Shaltiel |first2=Indra A. |last3=Bisht |first3=Shveta |last4=Kim |first4=Eugene |last5=Kalichava |first5=Ana |last6=Haering |first6=Christian H. |last7=Dekker |first7=Cees |date=2018-04-06 |title=Real-time imaging of DNA loop extrusion by condensin |journal=Science |volume=360 |issue=6384 |pages=102–105 |doi=10.1126/science.aar7831 |pmc=6329450 |pmid=29472443|bibcode=2018Sci...360..102G }}</ref> and SMC5/6<ref name=":2">{{Cite journal |last1=Pradhan |first1=Biswajit |last2=Kanno |first2=Takaharu |last3=Umeda Igarashi |first3=Miki |last4=Loke |first4=Mun Siong |last5=Baaske |first5=Martin Dieter |last6=Wong |first6=Jan Siu Kei |last7=Jeppsson |first7=Kristian |last8=Björkegren |first8=Camilla |last9=Kim |first9=Eugene |date=April 2023 |title=The Smc5/6 complex is a DNA loop-extruding motor |journal=Nature |language=en |volume=616 |issue=7958 |pages=843–848 |doi=10.1038/s41586-023-05963-3 |issn=1476-4687 |pmc=10132971 |pmid=37076626|bibcode=2023Natur.616..843P }}</ref> each playing specialized roles depending on the organism, cell cycle phase, and biological context.<ref name=":9">{{Cite journal |last1=Hoencamp |first1=Claire |last2=Rowland |first2=Benjamin D. |date=September 2023 |title=Genome control by SMC complexes |url=https://www.nature.com/articles/s41580-023-00609-8 |journal=Nature Reviews Molecular Cell Biology |language=en |volume=24 |issue=9 |pages=633–650 |doi=10.1038/s41580-023-00609-8 |pmid=37231112 |issn=1471-0080|url-access=subscription }}</ref><ref name=":10">{{Cite journal |last1=Kim |first1=Eugene |last2=Barth |first2=Roman |last3=Dekker |first3=Cees |date=2023-06-20 |title=Looping the Genome with SMC Complexes |journal=Annual Review of Biochemistry |language=en |volume=92 |pages=15–41 |doi=10.1146/annurev-biochem-032620-110506 |pmid=37137166 |issn=0066-4154|doi-access=free }}</ref> 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.<ref name=":9" /><ref name=":10" /> 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,<ref>{{Cite journal |last1=Gomes |first1=Marina Vitoria |last2=Landwerlin |first2=Pauline |last3=Diebold-Durand |first3=Marie-Laure |last4=Shaik |first4=Tajith B. |last5=Durand |first5=Alexandre |last6=Troesch |first6=Edouard |last7=Weber |first7=Chantal |last8=Brillet |first8=Karl |last9=Lemée |first9=Marianne Victoria |last10=Decroos |first10=Christophe |last11=Dulac |first11=Ludivine |last12=Antony |first12=Pierre |last13=Watrin |first13=Erwan |last14=Ennifar |first14=Eric |last15=Golzio |first15=Christelle |date=2024-09-24 |title=The cohesin ATPase cycle is mediated by specific conformational dynamics and interface plasticity of SMC1A and SMC3 ATPase domains |url=https://linkinghub.elsevier.com/retrieve/pii/S2211124724010076 |journal=Cell Reports |language=English |volume=43 |issue=9 |article-number=114656 |doi=10.1016/j.celrep.2024.114656 |issn=2211-1247 |pmid=39240714}}</ref> driving DNA translocation and stepwise loop extrusion.<ref name=":7" /><ref name=":8" /><ref name=":2" /> 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.<ref>{{Cite journal |last1=Nomidis |first1=Stefanos K |last2=Carlon |first2=Enrico |last3=Gruber |first3=Stephan |last4=Marko |first4=John F |date=2022-05-20 |title=DNA tension-modulated translocation and loop extrusion by SMC complexes revealed by molecular dynamics simulations |journal=Nucleic Acids Research |volume=50 |issue=9 |pages=4974–4987 |doi=10.1093/nar/gkac268 |pmid=35474142 |pmc=9122525 |issn=0305-1048 }}</ref><ref>{{cite journal |last1=Davidson |first1=Iain F. |language=en |biorxiv=10.1101/2024.03.22.586228 |last2=Barth |first2=Roman |last3=Horn |first3=Sabrina |last4=Janissen |first4=Richard |last5=Nagasaka |first5=Kota |last6=Wutz |first6=Gordana |last7=Stocsits |first7=Roman R. |last8=Bauer |first8=Benedikt |last9=Dekker |first9=Cees |title=Cohesin supercoils DNA during loop extrusion |journal=Cell Reports |date=2025 |volume=44 |issue=6 |article-number=115856 |doi=10.1016/j.celrep.2025.115856 |pmid=40516048 |doi-access=free }}</ref><ref>{{Cite journal |last1=Davidson |first1=Iain F. |last2=Barth |first2=Roman |last3=Zaczek |first3=Maciej |last4=van der Torre |first4=Jaco |last5=Tang |first5=Wen |last6=Nagasaka |first6=Kota |last7=Janissen |first7=Richard |last8=Kerssemakers |first8=Jacob |last9=Wutz |first9=Gordana |last10=Dekker |first10=Cees |last11=Peters |first11=Jan-Michael |date=April 2023 |title=CTCF is a DNA-tension-dependent barrier to cohesin-mediated loop extrusion |journal=Nature |language=en |volume=616 |issue=7958 |pages=822–827 |doi=10.1038/s41586-023-05961-5 |issn=1476-4687 |pmc=10132984 |pmid=37076620|bibcode=2023Natur.616..822D }}</ref>
=== 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.<ref name=":7"/><ref name=":8"/> PDS5 is thought to pause the extrusion process.<ref>{{Cite journal |last1=van Ruiten |first1=Marjon S. |last2=van Gent |first2=Démi |last3=Sedeño Cacciatore |first3=Ángela |last4=Fauster |first4=Astrid |last5=Willems |first5=Laureen |last6=Hekkelman |first6=Maarten L. |last7=Hoekman |first7=Liesbeth |last8=Altelaar |first8=Maarten |last9=Haarhuis |first9=Judith H. I. |last10=Brummelkamp |first10=Thijn R. |last11=de Wit |first11=Elzo |last12=Rowland |first12=Benjamin D. |date=June 2022 |title=The cohesin acetylation cycle controls chromatin loop length through a PDS5A brake mechanism |journal=Nature Structural & Molecular Biology |language=en |volume=29 |issue=6 |pages=586–591 |doi=10.1038/s41594-022-00773-z |issn=1545-9985 |pmc=9205776 |pmid=35710836}}</ref><ref>{{Cite journal |last1=Bastié |first1=Nathalie |last2=Chapard |first2=Christophe |last3=Dauban |first3=Lise |last4=Gadal |first4=Olivier |last5=Beckouët |first5=Frédéric |last6=Koszul |first6=Romain |date=June 2022 |title=Smc3 acetylation, Pds5 and Scc2 control the translocase activity that establishes cohesin-dependent chromatin loops |url=https://www.nature.com/articles/s41594-022-00780-0 |journal=Nature Structural & Molecular Biology |language=en |volume=29 |issue=6 |pages=575–585 |doi=10.1038/s41594-022-00780-0 |pmid=35710835 |issn=1545-9985|url-access=subscription }}</ref> The SMC can then either restart extruding or be unloaded by the additional binding of WAPL,<ref name=":4" /><ref name=":5" /><ref name=":6" /> 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.<ref>{{Cite journal |last1=Wutz |first1=Gordana |last2=Ladurner |first2=Rene |last3=St Hilaire |first3=Brian Glenn |last4=Stocsits |first4=Roman R |last5=Nagasaka |first5=Kota |last6=Pignard |first6=Benoit |last7=Sanborn |first7=Adrian |last8=Tang |first8=Wen |last9=Várnai |first9=Csilla |last10=Ivanov |first10=Miroslav P |last11=Schoenfelder |first11=Stefan |last12=van der Lelij |first12=Petra |last13=Huang |first13=Xingfan |last14=Dürnberger |first14=Gerhard |last15=Roitinger |first15=Elisabeth |date=2020-02-17 |editor-last=Lee |editor-first=Jeannie T |editor2-last=Struhl |editor2-first=Kevin |editor3-last=Yu |editor3-first=Hongtao |title=ESCO1 and CTCF enable formation of long chromatin loops by protecting cohesinSTAG1 from WAPL |journal=eLife |volume=9 |article-number=e52091 |doi=10.7554/eLife.52091 |doi-access=free |issn=2050-084X |pmc=7054000 |pmid=32065581}}</ref> 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.<ref>{{Cite journal |last1=Andrews |first1=Emily A. |last2=Palecek |first2=Jan |last3=Sergeant |first3=John |last4=Taylor |first4=Elaine |last5=Lehmann |first5=Alan R. |last6=Watts |first6=Felicity Z. |date=2005-01-01 |title=Nse2, a Component of the Smc5-6 Complex, Is a SUMO Ligase Required for the Response to DNA Damage |journal=Molecular and Cellular Biology |volume=25 |issue=1 |pages=185–196 |doi=10.1128/MCB.25.1.185-196.2005 |pmc=538766 |pmid=15601841}}</ref><ref>{{Cite journal |last1=De Piccoli |first1=Giacomo |last2=Cortes-Ledesma |first2=Felipe |last3=Ira |first3=Gregory |last4=Torres-Rosell |first4=Jordi |last5=Uhle |first5=Stefan |last6=Farmer |first6=Sarah |last7=Hwang |first7=Ji-Young |last8=Machin |first8=Felix |last9=Ceschia |first9=Audrey |last10=McAleenan |first10=Alexandra |last11=Cordon-Preciado |first11=Violeta |last12=Clemente-Blanco |first12=Andrés |last13=Vilella-Mitjana |first13=Felip |last14=Ullal |first14=Pranav |last15=Jarmuz |first15=Adam |date=September 2006 |title=Smc5–Smc6 mediate DNA double-strand-break repair by promoting sister-chromatid recombination |journal=Nature Cell Biology |language=en |volume=8 |issue=9 |pages=1032–1034 |doi=10.1038/ncb1466 |issn=1476-4679 |pmc=4493748 |pmid=16892052}}</ref>
=== 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.<ref>{{Cite journal |last1=Pradhan |first1=Biswajit |last2=Barth |first2=Roman |last3=Kim |first3=Eugene |last4=Davidson |first4=Iain F. |last5=Bauer |first5=Benedikt |last6=van Laar |first6=Theo |last7=Yang |first7=Wayne |last8=Ryu |first8=Je-Kyung |last9=van der Torre |first9=Jaco |last10=Peters |first10=Jan-Michael |last11=Dekker |first11=Cees |date=2022-10-18 |title=SMC complexes can traverse physical roadblocks bigger than their ring size |url=https://www.sciencedirect.com/science/article/pii/S2211124722013419 |journal=Cell Reports |volume=41 |issue=3 |article-number=111491 |doi=10.1016/j.celrep.2022.111491 |pmid=36261017 |issn=2211-1247}}</ref>
# '''Other cohesin and condensin molecules:''' Extruding cohesins and condensins has been found to be obstacle to other extruders that they encounter on the way.<ref name="John F 2016">{{Cite journal |last1=Goloborodko |first1=Anton |last2=Marko |first2=John F. |last3=Mirny |first3=Leonid A. |date=2016-05-24 |title=Chromosome Compaction by Active Loop Extrusion |journal=Biophysical Journal |volume=110 |issue=10 |pages=2162–2168 |doi=10.1016/j.bpj.2016.02.041 |pmid=27224481 |pmc=4880799 |bibcode=2016BpJ...110.2162G |issn=0006-3495 }}</ref><ref name=":1" /> As such, they present a fundamental road-block that can be randomly encountered on the DNA. # '''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<ref>{{Cite journal |last1=Li |first1=Yan |last2=Haarhuis |first2=Judith H. I. |last3=Sedeño Cacciatore |first3=Ángela |last4=Oldenkamp |first4=Roel |last5=van Ruiten |first5=Marjon S. |last6=Willems |first6=Laureen |last7=Teunissen |first7=Hans |last8=Muir |first8=Kyle W. |last9=de Wit |first9=Elzo |last10=Rowland |first10=Benjamin D. |last11=Panne |first11=Daniel |date=February 2020 |title=The structural basis for cohesin–CTCF-anchored loops |journal=Nature |language=en |volume=578 |issue=7795 |pages=472–476 |doi=10.1038/s41586-019-1910-z |pmid=31905366 |pmc=7035113 |bibcode=2020Natur.578..472L |issn=1476-4687}}</ref> with recent evidence suggesting a tension-dependence to the interaction.<ref>{{cite bioRxiv |last1=Davidson |first1=Iain F. |title=CTCF is a DNA-tension-dependent barrier to cohesin-mediated DNA loop extrusion |date=2022-09-11 |biorxiv=10.1101/2022.09.08.507093 |last2=Barth |first2=Roman |last3=Zaczek |first3=Maciej |last4=Torre |first4=Jaco van der |last5=Tang |first5=Wen |last6=Nagasaka |first6=Kota |last7=Janissen |first7=Richard |last8=Kerssemakers |first8=Jacob |last9=Wutz |first9=Gordana |last10=Dekker |first10=Cees |last11=Peters |first11=Jan-Michael}}</ref> 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.<ref>{{Cite journal |last1=de Wit |first1=Elzo |last2=Vos |first2=Erica S. M. |last3=Holwerda |first3=Sjoerd J. B. |last4=Valdes-Quezada |first4=Christian |last5=Verstegen |first5=Marjon J. A. M. |last6=Teunissen |first6=Hans |last7=Splinter |first7=Erik |last8=Wijchers |first8=Patrick J. |last9=Krijger |first9=Peter H. L. |last10=de Laat |first10=Wouter |date=2015-11-19 |title=CTCF Binding Polarity Determines Chromatin Looping |url=https://www.sciencedirect.com/science/article/pii/S1097276515007625 |journal=Molecular Cell |volume=60 |issue=4 |pages=676–684 |doi=10.1016/j.molcel.2015.09.023 |pmid=26527277 |issn=1097-2765|hdl=20.500.11755/03de164b-acbe-4937-b734-f281e94c593c |hdl-access=free }}</ref> 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.<ref>{{Cite journal |last1=Lupiáñez |first1=Darío G. |last2=Kraft |first2=Katerina |last3=Heinrich |first3=Verena |last4=Krawitz |first4=Peter |last5=Brancati |first5=Francesco |last6=Klopocki |first6=Eva |last7=Horn |first7=Denise |last8=Kayserili |first8=Hülya |last9=Opitz |first9=John M. |last10=Laxova |first10=Renata |last11=Santos-Simarro |first11=Fernando |last12=Gilbert-Dussardier |first12=Brigitte |last13=Wittler |first13=Lars |last14=Borschiwer |first14=Marina |last15=Haas |first15=Stefan A. |date=2015-05-21 |title=Disruptions of Topological Chromatin Domains Cause Pathogenic Rewiring of Gene-Enhancer Interactions |journal=Cell |volume=161 |issue=5 |pages=1012–1025 |doi=10.1016/j.cell.2015.04.004 |issn=0092-8674 |last16=Osterwalder |first16=Marco |last17=Franke |first17=Martin |last18=Timmermann |first18=Bernd |last19=Hecht |first19=Jochen |last20=Spielmann |first20=Malte |last21=Visel |first21=Axel |last22=Mundlos |first22=Stefan|pmid=25959774 |pmc=4791538 |bibcode=2015Cell..161.1012L }}</ref> # '''RNA polymerase/transcription''': 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.<ref>{{Cite journal |last1=Banigan |first1=Edward J. |last2=Tang |first2=Wen |last3=van den Berg |first3=Aafke A. |last4=Stocsits |first4=Roman R. |last5=Wutz |first5=Gordana |last6=Brandão |first6=Hugo B. |last7=Busslinger |first7=Georg A. |last8=Peters |first8=Jan-Michael |last9=Mirny |first9=Leonid A. |date=2023-03-14 |title=Transcription shapes 3D chromatin organization by interacting with loop extrusion |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=120 |issue=11 |article-number=e2210480120 |doi=10.1073/pnas.2210480120 |doi-access=free |issn=1091-6490 |pmid=36897969|pmc=10089175 |bibcode=2023PNAS..12010480B }}</ref><ref>{{Cite journal |last1=Brandão |first1=Hugo B. |last2=Paul |first2=Payel |last3=van den Berg |first3=Aafke A. |last4=Rudner |first4=David Z. |last5=Wang |first5=Xindan |last6=Mirny |first6=Leonid A. |date=2019-10-08 |title=RNA polymerases as moving barriers to condensin loop extrusion |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=116 |issue=41 |pages=20489–20499 |doi=10.1073/pnas.1907009116 |doi-access=free |issn=1091-6490 |pmc=6789630 |pmid=31548377|bibcode=2019PNAS..11620489B }}</ref> 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,<ref>{{Cite journal |last1=Banigan |first1=Edward J. |last2=Mirny |first2=Leonid A. |date=2020-06-01 |title=Loop extrusion: theory meets single-molecule experiments |url=https://www.sciencedirect.com/science/article/pii/S0955067420300570 |journal=Current Opinion in Cell Biology |series=Cell Nucleus |volume=64 |pages=124–138 |doi=10.1016/j.ceb.2020.04.011 |pmid=32534241 |issn=0955-0674 |access-date=2022-04-02|url-access=subscription }}</ref> allowing for effective barrier function by polymerase. Furthermore, it has been found that RNA can directly interact with cohesin subunits.<ref name="ReferenceA">{{Cite journal |last1=Porter |first1=Hayley |last2=Li |first2=Yang |last3=Neguembor |first3=Maria Victoria |last4=Beltran |first4=Manuel |last5=Varsally |first5=Wazeer |last6=Martin |first6=Laura |last7=Cornejo |first7=Manuel Tavares |last8=Pezić |first8=Dubravka |last9=Bhamra |first9=Amandeep |last10=Surinova |first10=Silvia |last11=Jenner |first11=Richard G |last12=Cosma |first12=Maria Pia |last13=Hadjur |first13=Suzana |date=2023-04-03 |editor-last=Aguilera |editor-first=Andrés |editor2-last=Struhl |editor2-first=Kevin |editor3-last=Vannini |editor3-first=Alessandro |title=Cohesin-independent STAG proteins interact with RNA and R-loops and promote complex loading |journal=eLife |volume=12 |article-number=e79386 |doi=10.7554/eLife.79386 |doi-access=free |pmid=37010886 |pmc=10238091 |issn=2050-084X}}</ref> # '''DNA replication:''' Replication forks and replisomes have been shown to restrict loop extrusion activity<ref>{{Cite journal |last1=Jeppsson |first1=K. |last2=Sakata |first2=T. |last3=Nakato |first3=R. |last4=Milanova |first4=S. |last5=Shirahige |first5=K. |last6=Björkegren |first6=C. |title=Science |url=https://www.science.org/action/cookieAbsent |access-date=2026-03-11 |journal=Science Advances |date=2022 |volume=8 |issue=23 |article-number=eabn7063 |language=en |doi=10.1126/sciadv.abn7063 |pmc=9187231 |pmid=35687682}}</ref><ref>{{cite bioRxiv |last1=Liao |first1=Qin |title=Replisomes restrict SMC-mediated DNA-loop extrusion in vivo |date=2025-02-23 |language=en |biorxiv=10.1101/2025.02.23.639750 |last2=Brandão |first2=Hugo B. |last3=Ren |first3=Zhongqing |last4=Wang |first4=Xindan }}</ref>. Additionally, the MCM helicase, which is associated with origins of replication, has been found to counteract the extrusion of cohesin on DNA.<ref>{{Cite journal |last1=Dequeker |first1=Bart J. H. |last2=Scherr |first2=Matthias J. |last3=Brandão |first3=Hugo B. |last4=Gassler |first4=Johanna |last5=Powell |first5=Sean |last6=Gaspar |first6=Imre |last7=Flyamer |first7=Ilya M. |last8=Lalic |first8=Aleksandar |last9=Tang |first9=Wen |last10=Stocsits |first10=Roman |last11=Davidson |first11=Iain F. |last12=Peters |first12=Jan-Michael |last13=Duderstadt |first13=Karl E. |last14=Mirny |first14=Leonid A. |last15=Tachibana |first15=Kikuë |date=June 2022 |title=MCM complexes are barriers that restrict cohesin-mediated loop extrusion |journal=Nature |language=en |volume=606 |issue=7912 |pages=197–203 |doi=10.1038/s41586-022-04730-0 |pmid=35585235 |pmc=9159944 |bibcode=2022Natur.606..197D |issn=1476-4687}}</ref> # '''R-loops''': Some evidence suggests that R-loops can also act as barriers to loop extrusion,<ref>{{Cite journal |last1=Zhang |first1=Hongshan |last2=Shi |first2=Zhubing |last3=Banigan |first3=Edward J. |last4=Kim |first4=Yoori |last5=Yu |first5=Hongtao |last6=Bai |first6=Xiao-chen |last7=Finkelstein |first7=Ilya J. |date=August 2023 |title=CTCF and R-loops are boundaries of cohesin-mediated DNA looping |url=https://linkinghub.elsevier.com/retrieve/pii/S1097276523005208 |journal=Molecular Cell |language=en |volume=83 |issue=16 |pages=2856–2871.e8 |doi=10.1016/j.molcel.2023.07.006|pmid=37536339 |url-access=subscription }}</ref> and R-loops have been shown to interact with cohesin subunits.<ref name="ReferenceA"/> However, other evidence suggests that R-loops may instead act as cohesin loaders.<ref>{{Cite journal |last1=Porter |first1=Hayley |last2=Li |first2=Yang |last3=Neguembor |first3=Maria Victoria |last4=Beltran |first4=Manuel |last5=Varsally |first5=Wazeer |last6=Martin |first6=Laura |last7=Cornejo |first7=Manuel Tavares |last8=Pezić |first8=Dubravka |last9=Bhamra |first9=Amandeep |last10=Surinova |first10=Silvia |last11=Jenner |first11=Richard G |last12=Cosma |first12=Maria Pia |last13=Hadjur |first13=Suzana |date=2023-04-03 |editor-last=Aguilera |editor-first=Andrés |editor2-last=Struhl |editor2-first=Kevin |editor3-last=Vannini |editor3-first=Alessandro |title=Cohesin-independent STAG proteins interact with RNA and R-loops and promote complex loading |journal=eLife |volume=12 |article-number=e79386 |doi=10.7554/eLife.79386 |doi-access=free |issn=2050-084X |pmc=10238091 |pmid=37010886}}</ref>
== 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,<ref>{{Cite journal |last1=Ryu |first1=Je-Kyung |last2=Katan |first2=Allard J. |last3=van der Sluis |first3=Eli O. |last4=Wisse |first4=Thomas |last5=de Groot |first5=Ralph |last6=Haering |first6=Christian H. |last7=Dekker |first7=Cees |date=December 2020 |title=The condensin holocomplex cycles dynamically between open and collapsed states |url=https://www.nature.com/articles/s41594-020-0508-3 |journal=Nature Structural & Molecular Biology |language=en |volume=27 |issue=12 |pages=1134–1141 |doi=10.1038/s41594-020-0508-3 |pmid=32989304 |issn=1545-9993|url-access=subscription }}</ref> the Brownian-ratchet model, the DNA-segment capture model/DNA-pumping model<ref>{{Cite journal |last1=Marko |first1=John F |last2=De Los Rios |first2=Paolo |last3=Barducci |first3=Alessandro |last4=Gruber |first4=Stephan |date=2019-07-26 |title=DNA-segment-capture model for loop extrusion by structural maintenance of chromosome (SMC) protein complexes |url=https://academic.oup.com/nar/article/47/13/6956/5512983 |journal=Nucleic Acids Research |language=en |volume=47 |issue=13 |pages=6956–6972 |doi=10.1093/nar/gkz497 |issn=0305-1048 |pmc=6649773 |pmid=31175837}}</ref>, the hold-and-feed model and the swing-and-clamp model.<ref>{{Cite journal |last1=Bauer |first1=Benedikt W. |last2=Davidson |first2=Iain F. |last3=Canena |first3=Daniel |last4=Wutz |first4=Gordana |last5=Tang |first5=Wen |last6=Litos |first6=Gabriele |last7=Horn |first7=Sabrina |last8=Hinterdorfer |first8=Peter |last9=Peters |first9=Jan-Michael |date=October 2021 |title=Cohesin mediates DNA loop extrusion by a "swing and clamp" mechanism |journal=Cell |volume=184 |issue=21 |pages=5448–5464.e22 |doi=10.1016/j.cell.2021.09.016 |issn=0092-8674 |pmc=8563363 |pmid=34624221}}</ref>
== Evidence for loop extrusion ==
=== Evidence for loop extruding molecules and their properties ===
==== Direct visualization ''in vitro'' ==== The first direct evidence of loop extrusion came from in vitro imaging studies on fluorescently labeled DNA with condensin<ref name=":3">{{Cite journal |last1=Ganji |first1=Mahipal |last2=Shaltiel |first2=Indra A. |last3=Bisht |first3=Shveta |last4=Kim |first4=Eugene |last5=Kalichava |first5=Ana |last6=Haering |first6=Christian H. |last7=Dekker |first7=Cees |date=2018-04-06 |title=Real-time imaging of DNA loop extrusion by condensin |journal=Science |volume=360 |issue=6384 |pages=102–105 |doi=10.1126/science.aar7831 |pmid=29472443 |pmc=6329450 |bibcode=2018Sci...360..102G }}</ref> or cohesin.<ref name=":0" /><ref>{{Cite journal |last1=Davidson |first1=Iain F. |last2=Bauer |first2=Benedikt |last3=Goetz |first3=Daniela |last4=Tang |first4=Wen |last5=Wutz |first5=Gordana |last6=Peters |first6=Jan-Michael |date=2019-12-13 |title=DNA loop extrusion by human cohesin |url=https://www.science.org/doi/10.1126/science.aaz3418 |journal=Science |volume=366 |issue=6471 |pages=1338–1345 |doi=10.1126/science.aaz3418 |pmid=31753851 |bibcode=2019Sci...366.1338D |access-date=2022-06-15|url-access=subscription }}</ref><ref>{{Cite journal |last1=Golfier |first1=Stefan |last2=Quail |first2=Thomas |last3=Kimura |first3=Hiroshi |last4=Brugués |first4=Jan |date=2020-05-12 |title=Cohesin and condensin extrude DNA loops in a cell cycle-dependent manner |journal=eLife |language=en |volume=9 |article-number=e53885 |doi=10.7554/eLife.53885 |doi-access=free|issn=2050-084X |pmc=7316503 |pmid=32396063}}</ref> Extrusion was found to be ATP-dependent and happened at ~1-3kb/s. The stall force was measured to be around 0.1-1pN<ref>{{Cite journal |last1=Golfier |first1=S. |last2=Quail |first2=T. |last3=Kimura |first3=H. |last4=Brugués |first4=J. |date=2020 |title=Cohesin and condensin extrude DNA loops in a cell-cycle dependent manner |journal=eLife |volume=9 |pages=1–34 |article-number=e53885 |doi=10.7554/eLife.53885 |doi-access=free |pmid=32396063 |pmc=7316503 |issn=2050-084X}}</ref><ref name=":3" /> which is small compared to other molecular motors.<ref>{{Cite journal |last1=Mallik |first1=Roop |last2=Gross |first2=Steven P. |date=November 2004 |title=Molecular Motors: Strategies to Get Along |journal=Current Biology |language=en |volume=14 |issue=22 |pages=R971–R982 |doi=10.1016/j.cub.2004.10.046|pmid=15556858 |bibcode=2004CBio...14.R971M |doi-access=free }}</ref>
==== ''In vivo'' evidence ==== Loop extrusion by the SMC complex cohesin was suggested on the basis of chromatin contact maps from Hi-C experiments. These maps displayed genomic domains of self-contact of a few hundred kb in size, referred to as topologically associating domains (TADs).<ref>{{Cite journal |last1=Sofueva |first1=Sevil |last2=Yaffe |first2=Eitan |last3=Chan |first3=Wen-Ching |last4=Georgopoulou |first4=Dimitra |last5=Vietri Rudan |first5=Matteo |last6=Mira-Bontenbal |first6=Hegias |last7=Pollard |first7=Steven M. |last8=Schroth |first8=Gary P. |last9=Tanay |first9=Amos |last10=Hadjur |first10=Suzana |date=2013-12-01 |title=Cohesin-mediated interactions organize chromosomal domain architecture |journal=The EMBO Journal |language=en |volume=32 |issue=24 |pages=3119–3129 |doi=10.1038/emboj.2013.237 |issn=1460-2075 |pmc=4489921 |pmid=24185899}}</ref><ref name=":11" /><ref>{{Cite journal |last1=Dixon |first1=Jesse R. |last2=Selvaraj |first2=Siddarth |last3=Yue |first3=Feng |last4=Kim |first4=Audrey |last5=Li |first5=Yan |last6=Shen |first6=Yin |last7=Hu |first7=Ming |last8=Liu |first8=Jun S. |last9=Ren |first9=Bing |date=May 2012 |title=Topological domains in mammalian genomes identified by analysis of chromatin interactions |journal=Nature |language=en |volume=485 |issue=7398 |pages=376–380 |doi=10.1038/nature11082 |issn=1476-4687 |pmc=3356448 |pmid=22495300 |bibcode=2012Natur.485..376D }}</ref><ref>{{Cite journal |last1=Nora |first1=Elphège P. |last2=Lajoie |first2=Bryan R. |last3=Schulz |first3=Edda G. |last4=Giorgetti |first4=Luca |last5=Okamoto |first5=Ikuhiro |last6=Servant |first6=Nicolas |last7=Piolot |first7=Tristan |last8=van Berkum |first8=Nynke L. |last9=Meisig |first9=Johannes |last10=Sedat |first10=John |last11=Gribnau |first11=Joost |last12=Barillot |first12=Emmanuel |last13=Blüthgen |first13=Nils |last14=Dekker |first14=Job |last15=Heard |first15=Edith |date=May 2012 |title=Spatial partitioning of the regulatory landscape of the X-inactivation centre |journal=Nature |language=en |volume=485 |issue=7398 |pages=381–385 |doi=10.1038/nature11049 |issn=1476-4687 |pmc=3555144 |pmid=22495304 |bibcode=2012Natur.485..381N }}</ref> These domains are generally bordered by binding sites for the CTCF protein, which are oriented in a convergent manner such that CTCF proteins "point" toward each other.<ref name=":11" /> This observation suggested that this aspect of chromatin organization must be executed by a 1-dimensional, linear scanning mechanism, rather than a 3-dimensional mechanism involving random encounters, which would exhibit CTCF orientations (convergent, divergent, and two parallel orientations) in equal probabilities. Subsequent quantitative simulation models proposing loop extrusion by cohesin were able to reproduce patterns of chromatin contacts observed in Hi-C.<ref>{{Cite journal |last1=Fudenberg |first1=Geoffrey |last2=Imakaev |first2=Maxim |last3=Lu |first3=Carolyn |last4=Goloborodko |first4=Anton |last5=Abdennur |first5=Nezar |last6=Mirny |first6=Leonid A. |date=May 2016 |title=Formation of Chromosomal Domains by Loop Extrusion |journal=Cell Reports |volume=15 |issue=9 |pages=2038–2049 |doi=10.1016/j.celrep.2016.04.085 |issn=2211-1247 |pmc=4889513 |pmid=27210764 |bibcode=2016CellR..15.2038F }}</ref><ref>{{Cite journal |last1=Sanborn |first1=Adrian L. |last2=Rao |first2=Suhas S. P. |last3=Huang |first3=Su-Chen |last4=Durand |first4=Neva C. |last5=Huntley |first5=Miriam H. |last6=Jewett |first6=Andrew I. |last7=Bochkov |first7=Ivan D. |last8=Chinnappan |first8=Dharmaraj |last9=Cutkosky |first9=Ashok |last10=Li |first10=Jian |last11=Geeting |first11=Kristopher P. |last12=Gnirke |first12=Andreas |last13=Melnikov |first13=Alexandre |last14=McKenna |first14=Doug |last15=Stamenova |first15=Elena K. |date=2015-11-24 |title=Chromatin extrusion explains key features of loop and domain formation in wild-type and engineered genomes |journal=Proceedings of the National Academy of Sciences |volume=112 |issue=47 |pages=E6456–E6465 |doi=10.1073/pnas.1518552112 |doi-access=free |pmc=4664323 |pmid=26499245 |bibcode=2015PNAS..112E6456S }}</ref>
More recent evidence comes from imaging of chromatin dynamics in the presence and absence of cohesin. Experiments with fluorescently tagged genomic loci analyzed by mathematical inference techniques indicate that these loci into come into spatial proximity more frequently in the presence of cohesin.<ref>{{Cite journal |last1=Gabriele |first1=M. |last2=Brandão |first2=H. B. |last3=Grosse-Holz |first3=S. |last4=Jha |first4=A. |last5=Dailey |first5=G. M. |last6=Cattoglio |first6=C. |last7=Hsieh |first7=T. S. |last8=Mirny |first8=L. |last9=Zechner |first9=C. |last10=Hansen |first10=A. S. |title=Dynamics of CTCF- and cohesin-mediated chromatin looping revealed by live-cell imaging |url=https://www.science.org/action/cookieAbsent |access-date=2026-03-11 |journal=Science |date=2022 |volume=376 |issue=6592 |pages=496–501 |language=en |doi=10.1126/science.abn6583 |pmc=9069445 |pmid=35420890 |bibcode=2022Sci...376..496G }}</ref><ref>{{Cite journal |last1=Mach |first1=Pia |last2=Kos |first2=Pavel I. |last3=Zhan |first3=Yinxiu |last4=Cramard |first4=Julie |last5=Gaudin |first5=Simon |last6=Tünnermann |first6=Jana |last7=Marchi |first7=Edoardo |last8=Eglinger |first8=Jan |last9=Zuin |first9=Jessica |last10=Kryzhanovska |first10=Mariya |last11=Smallwood |first11=Sebastien |last12=Gelman |first12=Laurent |last13=Roth |first13=Gregory |last14=Nora |first14=Elphège P. |last15=Tiana |first15=Guido |date=December 2022 |title=Cohesin and CTCF control the dynamics of chromosome folding |journal=Nature Genetics |language=en |volume=54 |issue=12 |pages=1907–1918 |doi=10.1038/s41588-022-01232-7 |issn=1546-1718 |pmc=9729113 |pmid=36471076}}</ref> Associated simulation modeling again indicates that chromatin loop extrusion can explain these observations.
=== 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.<ref>{{Cite journal |last1=Rao |first1=Suhas S. P. |last2=Huang |first2=Su-Chen |last3=Glenn St Hilaire |first3=Brian |last4=Engreitz |first4=Jesse M. |last5=Perez |first5=Elizabeth M. |last6=Kieffer-Kwon |first6=Kyong-Rim |last7=Sanborn |first7=Adrian L. |last8=Johnstone |first8=Sarah E. |last9=Bascom |first9=Gavin D. |last10=Bochkov |first10=Ivan D. |last11=Huang |first11=Xingfan |last12=Shamim |first12=Muhammad S. |last13=Shin |first13=Jaeweon |last14=Turner |first14=Douglass |last15=Ye |first15=Ziyi |date=2017-10-05 |title=Cohesin Loss Eliminates All Loop Domains |journal=Cell |volume=171 |issue=2 |pages=305–320.e24 |doi=10.1016/j.cell.2017.09.026 |issn=0092-8674 |last16=Omer |first16=Arina D. |last17=Robinson |first17=James T. |last18=Schlick |first18=Tamar |last19=Bernstein |first19=Bradley E. |last20=Casellas |first20=Rafael |last21=Lander |first21=Eric S. |last22=Aiden |first22=Erez Lieberman|pmid=28985562 |pmc=5846482 |bibcode=2017Cell..171..305R }}</ref><ref>{{Cite journal |last1=Schwarzer |first1=Wibke |last2=Abdennur |first2=Nezar |last3=Goloborodko |first3=Anton |last4=Pekowska |first4=Aleksandra |last5=Fudenberg |first5=Geoffrey |last6=Loe-Mie |first6=Yann |last7=Fonseca |first7=Nuno A. |last8=Huber |first8=Wolfgang |last9=Haering |first9=Christian H. |last10=Mirny |first10=Leonid |last11=Spitz |first11=Francois |date=2017-11-02 |title=Two independent modes of chromatin organization revealed by cohesin removal. |journal=Nature |volume=551 |issue=7678 |pages=51–56 |bibcode=2017Natur.551...51S |doi=10.1038/nature24281 |issn=1476-4687 |pmc=5687303 |pmid=29094699}}</ref> In more specific settings, inhibition of cohesin has been found to inhibit neuronal maturation<ref>{{Cite journal |last1=Calderon |first1=Lesly |last2=Weiss |first2=Felix D |last3=Beagan |first3=Jonathan A |last4=Oliveira |first4=Marta S |last5=Georgieva |first5=Radina |last6=Wang |first6=Yi-Fang |last7=Carroll |first7=Thomas S |last8=Dharmalingam |first8=Gopuraja |last9=Gong |first9=Wanfeng |last10=Tossell |first10=Kyoko |last11=de Paola |first11=Vincenzo |last12=Whilding |first12=Chad |last13=Ungless |first13=Mark A |last14=Fisher |first14=Amanda G |last15=Phillips-Cremins |first15=Jennifer E |date=2022-04-26 |editor-last=Day |editor-first=Jeremy J |editor2-last=Struhl |editor2-first=Kevin |title=Cohesin-dependence of neuronal gene expression relates to chromatin loop length |journal=eLife |volume=11 |article-number=e76539 |doi=10.7554/eLife.76539 |doi-access=free |issn=2050-084X |pmc=9106336 |pmid=35471149}}</ref> and differentiation and function of dendritic cells.<ref>{{cite bioRxiv |last1=Adams |first1=Nicholas M. |title=Cohesin-mediated chromatin remodeling controls the differentiation and function of conventional dendritic cells |date=2024-10-30 |language=en |biorxiv=10.1101/2024.09.18.613709 |last2=Galitsyna |first2=Aleksandra |last3=Tiniakou |first3=Ioanna |last4=Esteva |first4=Eduardo |last5=Lau |first5=Colleen M. |last6=Reyes |first6=Jojo |last7=Abdennur |first7=Nezar |last8=Shkolikov |first8=Alexey |last9=Yap |first9=George S.}}</ref> Depletion of either condensin I or condensin II at the entry into mitosis leads to abnormal chromosome formation and improper segregation of sister chromatids.<ref name=":1" />
== 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.<ref name=":1" /> * '''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.<ref>{{Cite journal |last1=Wang |first1=Xindan |last2=Brandão |first2=Hugo B. |last3=Le |first3=Tung B. K. |last4=Laub |first4=Michael T. |last5=Rudner |first5=David Z. |date=2017-02-03 |title=Bacillus subtilis SMC complexes juxtapose chromosome arms as they travel from origin to terminus |journal=Science |volume=355 |issue=6324 |pages=524–527 |doi=10.1126/science.aai8982 |pmid=28154080 |pmc=5484144 |bibcode=2017Sci...355..524W }}</ref> * '''Enhancer–promoter communication:''' During interphase, cohesin-mediated loop extrusion has been proposed to facilitate communication between distal enhancers and promoters that regulate gene transcription<ref>{{Cite journal |last1=Rittenhouse |first1=Natalie L |last2=Dowen |first2=Jill M |date=2024-04-01 |title=Cohesin regulation and roles in chromosome structure and function |journal=Current Opinion in Genetics & Development |volume=85 |article-number=102159 |doi=10.1016/j.gde.2024.102159 |issn=0959-437X |pmc=10947815 |pmid=38382406}}</ref>. As cohesin extrudes loops of chromatin, it can transiently bring regulatory elements separated by tens to hundreds of kilobases into proximity, enabling enhancer-bound transcription factors to interact with promoter-associated transcriptional machinery. CTCF binding sites can modulate this process by blocking or stabilizing extrusion, thereby constraining which enhancers can contact which promoters<ref>{{Cite journal |last1=Rinzema |first1=Niels J. |last2=Sofiadis |first2=Konstantinos |last3=Tjalsma |first3=Sjoerd J. D. |last4=Verstegen |first4=Marjon J. A. M. |last5=Oz |first5=Yuva |last6=Valdes-Quezada |first6=Christian |last7=Felder |first7=Anna-Karina |last8=Filipovska |first8=Teodora |last9=van der Elst |first9=Stefan |last10=de Andrade dos Ramos |first10=Zaria |last11=Han |first11=Ruiqi |last12=Krijger |first12=Peter H. L. |last13=de Laat |first13=Wouter |date=June 2022 |title=Building regulatory landscapes reveals that an enhancer can recruit cohesin to create contact domains, engage CTCF sites and activate distant genes |journal=Nature Structural & Molecular Biology |language=en |volume=29 |issue=6 |pages=563–574 |doi=10.1038/s41594-022-00787-7 |issn=1545-9993 |pmc=9205769 |pmid=35710842}}</ref><ref>{{Cite journal |last1=Kubo |first1=Naoki |last2=Ishii |first2=Haruhiko |last3=Xiong |first3=Xiong |last4=Bianco |first4=Simona |last5=Meitinger |first5=Franz |last6=Hu |first6=Rong |last7=Hocker |first7=James D. |last8=Conte |first8=Mattia |last9=Gorkin |first9=David |last10=Yu |first10=Miao |last11=Li |first11=Bin |last12=Dixon |first12=Jesse R. |last13=Hu |first13=Ming |last14=Nicodemi |first14=Mario |last15=Zhao |first15=Huimin |date=February 2021 |title=Promoter-proximal CTCF binding promotes distal enhancer-dependent gene activation |journal=Nature Structural & Molecular Biology |language=en |volume=28 |issue=2 |pages=152–161 |doi=10.1038/s41594-020-00539-5 |issn=1545-9985 |pmc=7913465 |pmid=33398174}}</ref>. Through this mechanism CTCF and cohesin have been shown to enable complex developmental and regulatory programs: ** '''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<ref>{{Cite journal |last=Peters |first=Jan-Michael |date=2021-06-01 |title=How DNA loop extrusion mediated by cohesin enables V(D)J recombination |journal=Current Opinion in Cell Biology |series=Cell Nucleus |volume=70 |pages=75–83 |doi=10.1016/j.ceb.2020.11.007 |pmid=33422934 |issn=0955-0674|doi-access=free }}</ref><ref>{{Cite journal |last1=Zhang |first1=Yu |last2=Zhang |first2=Xuefei |last3=Dai |first3=Hai-Qiang |last4=Hu |first4=Hongli |last5=Alt |first5=Frederick W. |date=September 2022 |title=The role of chromatin loop extrusion in antibody diversification |journal=Nature Reviews Immunology |language=en |volume=22 |issue=9 |pages=550–566 |doi=10.1038/s41577-022-00679-3 |issn=1474-1741 |pmc=9376198 |pmid=35169260}}</ref> as depletion of cohesin inhibits V(D)J recombination.<ref>{{Cite journal |last1=Ba |first1=Zhaoqing |last2=Lou |first2=Jiangman |last3=Ye |first3=Adam Yongxin |last4=Dai |first4=Hai-Qiang |last5=Dring |first5=Edward W. |last6=Lin |first6=Sherry G. |last7=Jain |first7=Suvi |last8=Kyritsis |first8=Nia |last9=Kieffer-Kwon |first9=Kyong-Rim |last10=Casellas |first10=Rafael |last11=Alt |first11=Frederick W. |date=October 2020 |title=CTCF orchestrates long-range cohesin-driven V(D)J recombinational scanning |journal=Nature |language=en |volume=586 |issue=7828 |pages=305–310 |doi=10.1038/s41586-020-2578-0 |issn=1476-4687 |pmc=7554077 |pmid=32717742|bibcode=2020Natur.586..305B }}</ref> 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.<ref>{{Cite journal |last1=Dai |first1=Hai-Qiang |last2=Hu |first2=Hongli |last3=Lou |first3=Jiangman |last4=Ye |first4=Adam Yongxin |last5=Ba |first5=Zhaoqing |last6=Zhang |first6=Xuefei |last7=Zhang |first7=Yiwen |last8=Zhao |first8=Lijuan |last9=Yoon |first9=Hye Suk |last10=Chapdelaine-Williams |first10=Aimee M. |last11=Kyritsis |first11=Nia |last12=Chen |first12=Huan |last13=Johnson |first13=Kerstin |last14=Lin |first14=Sherry |last15=Conte |first15=Andrea |date=February 2021 |title=Loop extrusion mediates physiological Igh locus contraction for RAG scanning |journal=Nature |language=en |volume=590 |issue=7845 |pages=338–343 |doi=10.1038/s41586-020-03121-7 |issn=1476-4687 |pmc=9037962 |pmid=33442057|bibcode=2021Natur.590..338D }}</ref><ref>{{Cite journal |last1=Zhang |first1=Yu |last2=Zhang |first2=Xuefei |last3=Ba |first3=Zhaoqing |last4=Liang |first4=Zhuoyi |last5=Dring |first5=Edward W. |last6=Hu |first6=Hongli |last7=Lou |first7=Jiangman |last8=Kyritsis |first8=Nia |last9=Zurita |first9=Jeffrey |last10=Shamim |first10=Muhammad S. |last11=Presser Aiden |first11=Aviva |last12=Lieberman Aiden |first12=Erez |last13=Alt |first13=Frederick W. |date=September 2019 |title=The fundamental role of chromatin loop extrusion in physiological V(D)J recombination |journal=Nature |language=en |volume=573 |issue=7775 |pages=600–604 |doi=10.1038/s41586-019-1547-y |issn=1476-4687 |pmc=6867615 |pmid=31511698|bibcode=2019Natur.573..600Z }}</ref> ** '''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.<ref>{{Cite journal |last1=Tasic |first1=Bosiljka |last2=Nabholz |first2=Christoph E. |last3=Baldwin |first3=Kristin K. |last4=Kim |first4=Youngwook |last5=Rueckert |first5=Erroll H. |last6=Ribich |first6=Scott A. |last7=Cramer |first7=Paula |last8=Wu |first8=Qiang |last9=Axel |first9=Richard |last10=Maniatis |first10=Tom |date=July 2002 |title=Promoter Choice Determines Splice Site Selection in Protocadherin α and γ Pre-mRNA Splicing |url=https://linkinghub.elsevier.com/retrieve/pii/S1097276502005786 |journal=Molecular Cell |language=en |volume=10 |issue=1 |pages=21–33 |doi=10.1016/S1097-2765(02)00578-6|pmid=12150904 }}</ref> The choice of protocadherins rely on cohesin, which bridges alternative promoters of protocadherin with the enhancer in a CTCF-dependent manner.<ref>{{Cite journal |last1=Monahan |first1=Kevin |last2=Rudnick |first2=Noam D. |last3=Kehayova |first3=Polina D. |last4=Pauli |first4=Florencia |last5=Newberry |first5=Kimberly M. |last6=Myers |first6=Richard M. |last7=Maniatis |first7=Tom |date=2012-06-05 |title=Role of CCCTC binding factor (CTCF) and cohesin in the generation of single-cell diversity of Protocadherin-α gene expression |journal=Proceedings of the National Academy of Sciences |language=en |volume=109 |issue=23 |pages=9125–9130 |doi=10.1073/pnas.1205074109 |doi-access=free |issn=0027-8424 |pmc=3384188 |pmid=22550178|bibcode=2012PNAS..109.9125M }}</ref> This process involves intricate regulation by CTCF<ref>{{Cite journal |last1=Guo |first1=Ya |last2=Monahan |first2=Kevin |last3=Wu |first3=Haiyang |last4=Gertz |first4=Jason |last5=Varley |first5=Katherine E. |last6=Li |first6=Wei |last7=Myers |first7=Richard M. |last8=Maniatis |first8=Tom |last9=Wu |first9=Qiang |date=2012-12-18 |title=CTCF/cohesin-mediated DNA looping is required for protocadherin α promoter choice |journal=Proceedings of the National Academy of Sciences |language=en |volume=109 |issue=51 |pages=21081–21086 |doi=10.1073/pnas.1219280110 |doi-access=free |issn=0027-8424 |pmc=3529044 |pmid=23204437|bibcode=2012PNAS..10921081G }}</ref> and WAPL.<ref>{{Cite journal |last1=Kiefer |first1=Lea |last2=Chiosso |first2=Anna |last3=Langen |first3=Jennifer |last4=Buckley |first4=Alex |last5=Gaudin |first5=Simon |last6=Rajkumar |first6=Sandy M. |last7=Servito |first7=Gabrielle Isabelle F. |last8=Cha |first8=Elizabeth S. |last9=Vijay |first9=Akshara |last10=Yeung |first10=Albert |last11=Horta |first11=Adan |last12=Mui |first12=Michael H. |last13=Canzio |first13=Daniele |date=2023-06-23 |title=WAPL functions as a rheostat of Protocadherin isoform diversity that controls neural wiring |url=https://www.science.org/doi/10.1126/science.adf8440 |journal=Science |language=en |volume=380 |issue=6651 |article-number=eadf8440 |doi=10.1126/science.adf8440 |pmid=37347873 |bibcode=2023Sci...380f8440K |issn=0036-8075|url-access=subscription }}</ref> * '''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.<ref name=":11">{{Cite journal |last1=Rao |first1=Suhas S.P. |last2=Huntley |first2=Miriam H. |last3=Durand |first3=Neva C. |last4=Stamenova |first4=Elena K. |last5=Bochkov |first5=Ivan D. |last6=Robinson |first6=James T. |last7=Sanborn |first7=Adrian L. |last8=Machol |first8=Ido |last9=Omer |first9=Arina D. |last10=Lander |first10=Eric S. |last11=Aiden |first11=Erez Lieberman |date=December 2014 |title=A 3D Map of the Human Genome at Kilobase Resolution Reveals Principles of Chromatin Looping |journal=Cell |language=en |volume=159 |issue=7 |pages=1665–1680 |doi=10.1016/j.cell.2014.11.021 |pmc=5635824 |pmid=25497547}}</ref> CTCF sites at TAD boundaries act as barriers to loop extrusion, preventing cohesin from extruding loops across domain borders. As a result, enhancers and promoters located in different TADs are less likely to be brought together by cohesin-mediated looping, making TADs function as regulatory neighborhoods that constrain enhancer–promoter communication within the same domain.
== 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.<ref>{{Cite journal |last1=Banigan |first1=Edward J |last2=van den Berg |first2=Aafke A |last3=Brandão |first3=Hugo B |last4=Marko |first4=John F |last5=Mirny |first5=Leonid A |date=2020-04-06 |title=Chromosome organization by one-sided and two-sided loop extrusion |journal=eLife |language=en |volume=9 |article-number=e53558 |doi=10.7554/eLife.53558 |issn=2050-084X |pmc=7295573 |pmid=32250245 |doi-access=free}}</ref> * '''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.<ref name="John F 2016" /><ref name=":1" /> * '''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:<ref name="John F 2016" />
* '''Processivity''' (<math display="inline">\lambda = 2v\tau</math>): Average size of a loop extruded by an unobstructed LEF before dissociating. This characteristic loop size depends on the extrusion speed <math>v</math> and the residence time <math>\tau</math> of the LEF on the chromatin. * '''Separation''' (<math>d= L / N</math>)''':''' Average distance between LEFs on the chromatin fiber. It is determined by the total number of LEFs <math>N</math> and the length of the chromatin <math>L</math>. 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 <math>\lambda/d</math>, defines two states of chromatin organization:
* '''Sparse State''' (<math>\lambda /d \ll 1</math>): LEFs operate independently, forming isolated loops with large gaps between them. This state results in minimal compaction of the chromatin fiber. * '''Dense State''' (<math>\lambda /d \gg 1</math>): LEFs are abundant enough to form a continuous, gapless array of loops. This leads to significant chromatin compaction, as seen during mitosis.
== References == {{Reflist}}
Category:Nuclear organization Category:Extrusion