Publication
Nonlinear mechanics of human mitotic chromosomes
Publisher:
Springer Science and Business Media LLC
Date:
04-05-2022
DOI:
10.1038/S41586-022-04666-5
Abstract: In preparation for mitotic cell ision, the nuclear DNA of human cells is compacted into in idualized, X-shaped chromosomes 1 . This metamorphosis is driven mainly by the combined action of condensins and topoisomerase IIα (TOP2A) 2,3 , and has been observed using microscopy for over a century. Nevertheless, very little is known about the structural organization of a mitotic chromosome. Here we introduce a workflow to interrogate the organization of human chromosomes based on optical trapping and manipulation. This allows high-resolution force measurements and fluorescence visualization of native metaphase chromosomes to be conducted under tightly controlled experimental conditions. We have used this method to extensively characterize chromosome mechanics and structure. Notably, we find that under increasing mechanical load, chromosomes exhibit nonlinear stiffening behaviour, distinct from that predicted by classical polymer models 4 . To explain this anomalous stiffening, we introduce a hierarchical worm-like chain model that describes the chromosome as a heterogeneous assembly of nonlinear worm-like chains. Moreover, through inducible degradation of TOP2A 5 specifically in mitosis, we provide evidence that TOP2A has a role in the preservation of chromosome compaction. The methods described here open the door to a wide array of investigations into the structure and dynamics of both normal and disease-associated chromosomes.