Condensation by folding

To understand how chromosomes condense for mitosis, most researchers pick apart DNA's most compact form: metaphase chromosomes. On page 775, Kireeva et al. work from the other end and watch condensation as it occurs. From this perspective, condensation looks like a folding continuum with intermediates that do not fit the favored radial loop model.

The authors used serial section microscopy to examine chromosomes at stages of prophase, when most condensation occurs. At even the earliest stages, 10- and 30-nm chromatin fibers are folded into larger ∼100-nm fibers. In middle prophase, chromatids of 200–250 nm are present that appear to form from the folding of the 100-nm fibers. A further doubling in diameter occurs by late prophase.

Radial loop models propose that chromatin loops of fixed size are the repeating subunit of condensed chromosomes. Loops were imagined to be pulled together by a protein scaffold (including topoisomerase II and condensin), to which the loops were attached. But Kireeva et al. see that topoisomerase II and condensin are dispersed unevenly in foci on the chromosomes until condensation is nearly complete, at late prophase.

The authors do not contest that metaphase chromosomes decondensed in vitro show chromatin loops that likely result from the cross-linking of fibers by scaffold proteins. But they stress that formation of the scaffold axis and its cross-linking to chromatin occur after chromatid axis formation and most condensation, which they propose is driven by levels of folding. Topoisomerase II and condensin may lock these folds into a stable structure. ▪