Nonlinear mechanics of human mitotic chromosomes

Anna E.C. Meijering, Kata Sarlós, Christian F. Nielsen, Hannes Witt, Janni Harju, Emma Kerklingh, Guus H. Haasnoot, Anna H. Bizard, Iddo Heller, Chase P. Broedersz*, Ying Liu, Erwin J.G. Peterman, Ian D. Hickson, Gijs J.L. Wuite

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review


In preparation for mitotic cell division, the nuclear DNA of human cells is compacted into individualized, X-shaped chromosomes1. 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 models4. 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 TOP2A5 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.

Original languageEnglish
Pages (from-to)545-550
Number of pages6
Issue number7910
Early online date4 May 2022
Publication statusPublished - 19 May 2022

Bibliographical note

Funding Information:
We thank I. Samejima and W. Earnshaw for providing training in chromosome isolation; R. O’Sullivan for the U2OS TRF1-BirA cell line; S. Acar for help with cell culture; V. Bjerregaard for help with the lentiviral transduction; and A. Biebricher for help with optical tweezers. This work was supported by European Union Horizon 2020 grants (Chromavision 665233 to G.J.L.W., I.D.H., E.J.G.P. and Y.L.; and Antihelix 859853 to Y.L. and I.D.H.), the European Research Council under the European Union’s Horizon 2020 research and innovation program (MONOCHROME, grant agreement no. 883240 to G.J.L.W.), the Novo Nordisk Foundation (NNF18OC0034948 to I.D.H. and G.J.L.W.), the Deutsche Forschungsgemeinschaft (WI 5434/1-1 to H.W.), the Dutch Research Council (NWO Vidi 640-47-555 to I.H.), the Nordea Foundation (to I.D.H.) and the Danish National Research Foundation (DNRF115 to Y.L. and I.D.H.).

Publisher Copyright:
© 2022, The Author(s).


Dive into the research topics of 'Nonlinear mechanics of human mitotic chromosomes'. Together they form a unique fingerprint.

Cite this