Shaping of the 3D genome by the ATPase machine cohesin

Kim, Yoori; Yu, Hongtao

doi:10.1038/s12276-020-00526-2

Cited by 26 publications

(22 citation statements)

References 84 publications

(96 reference statements)

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“…There are indications that TAD formation and phase separation are counteracting processes (Y. Kim & Yu, 2020), raising the question whether the loading of cohesin at Scc2/4-mediated DNA-condensates determines whether cohesin promotes loop extrusion or sister chromatid cohesion. As cohesin degradation in vivo leads to the loss of all DNA loops but not of the condensation-mediated compartmentalization of chromatin (Rao et al, 2017), it is likely that phase separation does not cause loop extrusion but both processes co-exist.…”

Section: Ideas and Speculationmentioning

confidence: 99%

“…Different histone modifications furthermore regulate accessibility of the DNA leading to the less densely packed gene-rich euchromatin and the more densely packed transcriptional inactive heterochromatin (Y. Kim & Yu, 2020). Additionally, the chromatin fiber is folded by loop formation into topologically associated domains (TADs), which exhibit high self-interaction and bring far-distance regions of the genome into close proximity (Dixon et al,3 and higher cohesin stability when it is loaded at these sites, suggesting a loading mechanism primed by phase separation.…”

Section: Introductionmentioning

confidence: 99%

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The loader complex Scc2/4 forms co-condensates with DNA as loading sites for cohesin

Zernia

Kamp

Stigler

2021

Preprint

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The genome is organized by diverse packaging mechanisms like nucleosome formation, loop extrusion and phase separation, which all compact DNA in a dynamic manner. Phase separation additionally drives protein recruitment to condensed DNA sites and thus regulates gene transcription. The cohesin complex is a key player in chromosomal organization that extrudes loops to connect distant regions of the genome and ensures sister chromatid cohesion after S-phase. For stable loading onto the DNA and for activation, cohesin requires the loading complex Scc2/4. As the precise loading mechanism remains unclear, we investigated whether phase separation might be the initializer of the cohesin recruitment process. We found that, in absence of cohesin, budding yeast Scc2/4 forms phase separated co-condensates with DNA, which comprise liquid-like properties shown by droplet shape, fusion ability and reversibility. We reveal in DNA curtain and optical tweezer experiments that these condensates are built by DNA bridging and bending through Scc2/4. Importantly, Scc2/4-mediated condensates recruit cohesin efficiently and increase the stability of the cohesin complex. We conclude that phase separation properties of Scc2/4 enhance cohesin loading by molecular crowding, which might then provide a starting point for the recruitment of additional factors and proteins.

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Section: Ideas and Speculationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The loader complex Scc2/4 forms co-condensates with DNA as loading sites for cohesin

Zernia

Kamp

Stigler

2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Several groups have shown that cohesin extrudes loops in a two-sided manner [29,30]. Although theoretical considerations suggest, that two-sided LE by dimers of cohesin rings should take place in living mammalian cells [31], there are contradictory reports on whether this is actually the case in in vitro models [28,29].…”

Section: Introductionmentioning

confidence: 99%

Sensitivity of cohesin–chromatin association to high-salt treatment corroborates non-topological mode of loop extrusion

Golov

Golova

Гаврилов

et al. 2021

Epigenetics & Chromatin

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Cohesin is a key organizer of chromatin folding in eukaryotic cells. The two main activities of this ring-shaped protein complex are the maintenance of sister chromatid cohesion and the establishment of long-range DNA–DNA interactions through the process of loop extrusion. Although the basic principles of both cohesion and loop extrusion have been described, we still do not understand several crucial mechanistic details. One of such unresolved issues is the question of whether a cohesin ring topologically embraces DNA string(s) during loop extrusion. Here, we show that cohesin complexes residing on CTCF-occupied genomic sites in mammalian cells do not interact with DNA topologically. We assessed the stability of cohesin-dependent loops and cohesin association with chromatin in high-ionic-strength conditions in G1-synchronized HeLa cells. We found that increased salt concentration completely displaces cohesin from those genomic regions that correspond to CTCF-defined loop anchors. Unsurprisingly, CTCF-anchored cohesin loops also dissipate in these conditions. Because topologically engaged cohesin is considered to be salt resistant, our data corroborate a non-topological model of loop extrusion. We also propose a model of cohesin activity throughout the interphase, which essentially equates the termination of non-topological loop extrusion with topological loading of cohesin. This theoretical framework enables a parsimonious explanation of various seemingly contradictory experimental findings.

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“…This biological event is mediated by a ring-shaped complex cohesin which consists of four core components: SMC1, SMC3, SCC1 and SCC3 [10][11][12]. Besides sister chromatid cohesion and chromosome segregation, cohesin and its regulatory factors also exert functions in a variety of other biological processes such as DNA damage repair, transcriptional regulation and chromatin architecture organization [11][12][13][14][15]. Chromosome cohesion involves multiple steps including cohesin loading, cohesion establishment, cohesion maintenance and cohesion dissolution [11].…”

Section: Introductionmentioning

confidence: 99%

WAPL orchestrates porcine oocyte meiotic progression via control of spindle assembly checkpoint activity

Zhou

Miao

Zhang

et al. 2021

Reprod Biol Endocrinol

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Background In mitotic cells, WAPL acts as a cohesin release factor to remove cohesin complexes from chromosome arms during prophase to allow the accurate chromosome segregation in anaphase. However, we have recently documented that Wapl exerts a unique meiotic function in the spindle assembly checkpoint (SAC) control through maintaining Bub3 stability during mouse oocyte meiosis I. Whether this noncanonical function is conserved among species is still unknown. Methods We applied RNAi-based gene silencing approach to deplete WAPL in porcine oocytes, validating the conserved roles of WAPL in the regulation of SAC activity during mammalian oocyte maturation. We also employed immunostaining, immunoblotting and image quantification analyses to test the WAPL depletion on the meiotic progression, spindle assembly, chromosome alignment and dynamics of SAC protein in porcine oocytes. Results We showed that depletion of WAPL resulted in the accelerated meiotic progression by displaying the precocious polar body extrusion and compromised spindle assembly and chromosome alignment. Notably, we observed that the protein level of BUB3 was substantially reduced in WAPL-depleted oocytes, especially at kinetochores. Conclusions Collectively, our data demonstrate that WAPL participates in the porcine oocyte meiotic progression through maintenance of BUB3 protein levels and SAC activity. This meiotic function of WAPL in oocytes is highly conserved between pigs and mice.

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Shaping of the 3D genome by the ATPase machine cohesin

Cited by 26 publications

References 84 publications

The loader complex Scc2/4 forms co-condensates with DNA as loading sites for cohesin

The loader complex Scc2/4 forms co-condensates with DNA as loading sites for cohesin

Sensitivity of cohesin–chromatin association to high-salt treatment corroborates non-topological mode of loop extrusion

WAPL orchestrates porcine oocyte meiotic progression via control of spindle assembly checkpoint activity

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