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, 14 a process essential for gene transcription and cell fate. Through analyzing Hi-C and chromatin15 tracing DNA-FISH data, we identify long-range chromo skeleton loop structures that span over 16 100 Mb, extending beyond the reach of loop extrusion models. Spatial density analyses point to 17 assembly formation independent of major nuclear structures. A subset of genomic loci serves as 18 nucleation centers, driving loop clustering. These complexes are highly stable, as shown by live19 cell imaging with sequence-specific fluorescent labeling, and biophysical model analyses reveal a 20 multivalent binding mechanism. Our findings suggest a redundant, distributed cluster mechanism 21 that ensures robustness across cell types and against mutations, guiding both chromosome 22 compaction and the formation of smaller-scale chromosomal structures.