Characterizing the variation in chromosome structure ensembles in the context of the nuclear microenvironment

P Das and TY Shen and RP McCord, PLOS COMPUTATIONAL BIOLOGY, 18, e1010392 (2022).

DOI: 10.1371/journal.pcbi.1010392

Inside the nucleus, chromosomes are subjected to direct physical interaction between different components, active forces, and thermal noise, leading to the formation of an ensemble of three-dimensional structures. However, it is still not well understood to what extent and how the structural ensemble varies from one chromosome region or cell- type to another. We designed a statistical analysis technique and applied it to single-cell chromosome imaging data to reveal the heterogeneity of individual chromosome structures. By analyzing the resulting structural landscape, we find that the largest dynamic variation is the overall radius of gyration of the chromatin region, followed by domain reorganization within the region. By comparing different human cell-lines and experimental perturbation data using this statistical analysis technique and a network-based similarity quantification approach, we identify both cell-type and condition- specific features of the structural landscapes. We identify a relationship between epigenetic state and the properties of chromosome structure fluctuation and validate this relationship through polymer simulations. Overall, our study suggests that the types of variation in a chromosome structure ensemble are cell-type as well as region-specific and can be attributed to constraints placed on the structure by factors such as variation in epigenetic state. Author summaryRecent work has revealed principles of how chromosomes are folded and structured inside the human nucleus. It is now even possible to microscopically trace the path of chromosomes in 3D in individual cells. With this data, we can start to examine how much variation exists in chromosome structure and what biological factors may restrict or enhance this variation. Are chromosomes stuck in just a few possible positions or do they move around more freely, sampling many configurations? Here, we use a mathematical approach to compare chromosome structure variation in different cell types, at different locations along the genome, and when key structural proteins are removed. Through these comparisons and dynamic simulations of chromosome behavior, we identify factors that may constrain or promote variation in chromosome structure.

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