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 loop extrusion models. Spatial density analyses point to assembly formation independent of major nuclear structures. A subset of genomic loci serves as nucleation centers, driving 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.