Background

Three major SMC-complex activities shape chromosome architecture in mammalian cells: extrusive cohesin, which drives loop extrusion and supports TADs/loops in interphase; cohesive cohesin, which holds sister chromatids together; and condensins, which organize mitotic chromosomes. These complexes coexist during the G2-to-M transition, when genome architecture is dramatically rebuilt, but how they influence one another during this transition had remained unclear.

Notes: 

Extrusive cohesin builds the 3D genome architecture (loops, TADs) by pulling DNA into loops. Cohesive cohesin ensures accurate chromosome segregation by gluing sister chromatids together.

Question

how do extrusive cohesin, cohesive cohesin, and condensin interact with each other on chromatin, and how do these interactions collectively drive the reorganization of 3D genome structure during mitotic entry?

Main findings

The study shows that genome reorganization during mitotic entry is not controlled by each SMC complex acting independently, but by strong mutual antagonism and coordination among all three. Condensin removes focal binding of extrusive cohesin from CTCF sites, helping dismantle interphase TADs and loops. In the opposite direction, extrusive cohesin resists condensin-driven spiralization of mitotic chromosomes. Condensin also reduces peaks of cohesive cohesin, whereas cohesive cohesin counteracts condensin-mediated chromosome shortening. Extrusive cohesin helps position cohesive cohesin at CTCF sites, but cohesive cohesin alone cannot be halted by CTCF and cannot generate TADs or loops, indicating that it lacks loop-extrusion activity and serves a distinct role. The authors therefore conclude that mitotic genome folding is shaped by a three-way interaction among SMC complexes, rather than by a simple handoff from cohesin to condensin.

Key methods used

The authors engineered all possible cohesin-condensin configurations on mitotic chromosomes to dissect their functional interplay. They used acute degradation systems and cell-cycle synchronization to selectively remove or retain each SMC activity. They didn’t just remove cohesin—they bias it toward specific functional states.  They then used Hi-C to measure 3D genome architecture, ChIP-seq to map chromatin occupancy of cohesin/condensin-related factors, and polymer simulations to model the structural consequences of these interactions. The paper also integrates newly generated sequencing datasets deposited as GSE269952, along with comparison to external Hi-C and ChIP-seq datasets. 

Notes:

When discussing this topic, "configuration" often refers to the structural shape or binding mode of the cohesin complex itself.

Ring configuration: The classic model where cohesin forms a closed ring that encircles one or two DNA molecules (for cohesion).

Extrusion configuration: A more recent model where cohesin is not just a static ring but adopts a dynamic, motor-like configuration that actively pulls DNA loops.

Open vs. closed configuration: Whether the cohesin ring is transiently open (to load DNA) or closed (to hold DNA).

Research article link: https://doi.org/10.1038/s41586-025-08638-3