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 multiple sequencing-and imaging-based datasets, we identify long-range chromosomal skeleton loop structures that span over 100 Mb, extending beyond the reach of several existing DNA loop models. Further epigenetic and spatial density analyses point to assembly formation 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.