Extensive mutual influences of SMC complexes shape 3D genome folding

Han Zhao, Lirong Shu, Shiyi Qin, Fangxuan Lyu, Fuhai Liu, En Lin, Sijian Xia, Baiyue Wang, Manzhu Wang, Fengnian Shan, Yinzhi Lin, Lin Zhang, Yufei Gu, Gerd A. Blobel, Kai Huang () and Haoyue Zhang ()
Additional contact information
Han Zhao: Shenzhen Bay Laboratory
Lirong Shu: Shenzhen Bay Laboratory
Shiyi Qin: Shenzhen Bay Laboratory
Fangxuan Lyu: Shenzhen Bay Laboratory
Fuhai Liu: Shenzhen Bay Laboratory
En Lin: Shenzhen Bay Laboratory
Sijian Xia: Shenzhen Bay Laboratory
Baiyue Wang: Shenzhen Bay Laboratory
Manzhu Wang: Shenzhen Bay Laboratory
Fengnian Shan: Shenzhen Bay Laboratory
Yinzhi Lin: Shenzhen Bay Laboratory
Lin Zhang: Shenzhen Bay Laboratory
Yufei Gu: Shenzhen Bay Laboratory
Gerd A. Blobel: The Children’s Hospital of Philadelphia
Kai Huang: Shenzhen Bay Laboratory
Haoyue Zhang: Shenzhen Bay Laboratory

Nature, 2025, vol. 640, issue 8058, 543-553

Abstract: Abstract Mammalian genomes are folded through the distinct actions of structural maintenance of chromosome (SMC) complexes, which include the chromatin loop-extruding cohesin (extrusive cohesin), the sister chromatid cohesive cohesin and the mitotic chromosome-associated condensins1–3. Although these complexes function at different stages of the cell cycle, they exist together on chromatin during the G2-to-M phase transition, when the genome structure undergoes substantial reorganization1,2. Yet, how the different SMC complexes affect each other and how their interactions orchestrate the dynamic folding of the three-dimensional genome remain unclear. Here we engineered all possible cohesin and condensin configurations on mitotic chromosomes to delineate the concerted, mutually influential action of SMC complexes. We show that condensin disrupts the binding of extrusive cohesin at CCCTC-binding factor (CTCF) sites, thereby promoting the disassembly of interphase topologically associating domains (TADs) and loops during mitotic progression. Conversely, extrusive cohesin impedes condensin-mediated mitotic chromosome spiralization. Condensin reduces peaks of cohesive cohesin, whereas cohesive cohesin antagonizes condensin-mediated longitudinal shortening of mitotic chromosomes. The presence of both extrusive and cohesive cohesin synergizes these effects and inhibits mitotic chromosome condensation. Extrusive cohesin positions cohesive cohesin at CTCF-binding sites. However, cohesive cohesin by itself cannot be arrested by CTCF molecules and is insufficient to establish TADs or loops. Moreover, it lacks loop-extrusion capacity, which indicates that cohesive cohesin has nonoverlapping functions with extrusive cohesin. Finally, cohesive cohesin restricts chromatin loop expansion mediated by extrusive cohesin. Collectively, our data describe a three-way interaction among major SMC complexes that dynamically modulates chromatin architecture during cell cycle progression.

Date: 2025
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DOI: 10.1038/s41586-025-08638-3

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