Nonlinear mechanics of human mitotic chromosomes 作者：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, et al. Nature 2022/05/04 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.
目前尚不完全清楚有丝分裂染色体的结构组织。本研究介绍一种基于光学捕获和操控的人类染色体组织探索流程，在严格可控实验条件下实现细胞分裂中期天然染色体的高分辨率力测量和荧光成像。研究人员使用该方法发现在增加机械负荷的情况下，染色体表现出非线性僵化行为，并提供证据证明TOP2A发挥作用保持染色体的紧凑性。该方法为调查正常或疾病相关染色体结构与动态学提供新途径。
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