Rules of engagement for condensins and cohesins guide mitotic chromosome formation

Abstract

During mitosis, interphase chromatin is rapidly converted into rod-shaped mitotic chromosomes. Using Hi-C, imaging, proteomics and polymer modeling, we determine how the activity and interplay between loop-extruding SMC motors accomplishes this dramatic transition. Our work reveals rules of engagement for SMC complexes that are critical for allowing cells to refold interphase chromatin into mitotic chromosomes. We find that condensin disassembles interphase chromatin loop organization by evicting or displacing extrusive cohesin. In contrast, condensin bypasses cohesive cohesins, thereby maintaining sister chromatid cohesion while separating the sisters. Studies of mitotic chromosomes formed by cohesin, condensin II and condensin I alone or in combination allow us to develop new models of mitotic chromosome conformation. In these models, loops are consecutive and not overlapping, implying that condensins do not freely pass one another but stall upon encountering each other. The dynamics of Hi-C interactions and chromosome morphology reveal that during prophase loops are extruded in vivo at ~1-3 kb/sec by condensins as they form a disordered discontinuous helical scaffold within individual chromatids.

Extensive mutual influences of SMC complexes shape 3D genome folding

“…3h). Our findings are consistent with a recent study showing that cohesive-cohesin delays chromosome condensation during mitotic progression 38 .…”

“…Finally, a recent study using polymer simulation and immunofluorescence staining predicted that condensin is able to bypass cohesive-cohesin on mitotic chromosomes, suggesting that condensin does not impose direct mechanical influence on cohesive-cohesin (Fig. 7c) 38 . These findings together indicate that disruption of cohesive-cohesin peaks by condensin is a secondary consequence of diminished extrusive-cohesin focal enrichment.…”

“…Furthermore, live cell imaging demonstrated a marked increase in the mitotic enrichment of fluorescently labeled Rad21 when SMC2 was lost (data not shown). Finally, a recent study using chromatin enrichment for proteomics (ChEP) technology reported more rapid cohesin dissociation in the presence of condensin during mitotic progression 38 . These findings collectively support condensin's capacity to unload extrusive-cohesin independently of Wapl.…”