Long-range genomic loci stochastically assemble into combinatorial forms of chromosome skeleton

Zhang, J.; Wang, S.; Watkins, S. C.; Xing, J.

doi:10.1101/2025.02.10.637328

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bioRxiv · 10.1101/2025.02.10.637328

Long-range genomic loci stochastically assemble into combinatorial forms of chromosome skeleton

Zhang, J.·Wang, S.·Watkins, S. C.·Xing, J.

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Abstract

BackgroundOne fundamental yet open question is how eukaryotic chromosomes fold into segregated territories, a process essential for gene transcription and cell fate. While several models describe how chromosomal loops form at shorter scales, the mechanisms governing large-scale (> 100 Mb) chromosome organization remain poorly understood. ResultsThrough analyzing multiple sequencing- and imaging-based datasets, we identify long-range chromosomal backbone loop structures that span over 100 Mb, extending beyond the reach of several existing DNA loop models. Some long-range loops are stable for at least 10 minutes, as shown by live-cell imaging with sequence-specific CRISPR-dCas9 fluorescent labeling. Biophysical modeling further demonstrates that their formation is driven by a multivalent binding mechanism. Further epigenetic profiling and spatial density analyses indicate that many of the assembly formations are independent of known large-scale nuclear structures. ConclusionsOur findings suggest a redundant, distributed cluster mechanism that ensures chromosomal organization robustness across cell types and against mutations. This mechanism coordinates large-scale chromosome compaction while simultaneously guiding the formation of smaller-scale chromosomal structures, offering a new framework for understanding genome folding and its role in cell identity.

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Zhang, J., Wang, S., Watkins, S. C., Xing, J.. 2025-02-10. Long-range genomic loci stochastically assemble into combinatorial forms of chromosome skeleton. https://doi.org/10.1101/2025.02.10.637328

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