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

One fundamental yet open question is how eukaryotic chromosomes fold into segregated territories, a process essential for gene transcription and cell fate. Through analyzing Hi-C and chromatin-tracing DNA-FISH data, we identify long-range chromo skeleton loop structures that span over 100 Mb, extending beyond the reach of many existing DNA loop models. Further spatial density analyses point to assembly formation also independent of major nuclear structures. Some long-range loops share a subset of genomic loci, which serve as nucleation centers and drive loop clustering. These complexes are highly stable, as shown by live-cell imaging with sequence-specific fluorescent labeling, and biophysical model analyses reveal a multivalent binding mechanism. Our findings suggest a redundant, distributed cluster mechanism that ensures robustness across cell types and against mutations, guiding both chromosome compaction and the formation of smaller-scale chromosomal structures.