High-throughput Pore-C reveals the single-allele topology and cell type-specificity of 3D genome folding

Canonical three-dimensional (3D) genome structures represent the ensemble average of pairwise chromatin interactions but not the single-allele topologies in populations of cells. Recently developed Pore-C can capture multiway chromatin contacts that reflect regional topologies of single chromosomes. By carrying out high-throughput Pore-C, we reveal extensive but regionally restricted clusters of single-allele topologies that aggregate into canonical 3D genome structures in two human cell types. We show that fragments in multi-contact reads generally coexist in the same TAD. In contrast, a concurrent significant proportion of multi-contact reads span multiple compartments of the same chromatin type over megabase distances. Synergistic chromatin looping between multiple sites in multi-contact reads is rare compared to pairwise interactions. Interestingly, the single-allele topology clusters are cell type-specific even inside highly conserved TADs in different types of cells. In summary, HiPore-C enables global characterization of single-allele topologies at an unprecedented depth to reveal elusive genome folding principles. Here the authors establish a high throughput Pore-C (HiPore-C) method increasing the sequencing output of multi-way chromatin contacts and reveal single-allele topology diversity and cell type-specificity of 3D genome folding.

Automated summary

By using the high-throughput Pore-C technique, researchers have discovered extensive and regionally restricted clusters of single-allele topologies in two human cell types, which aggregate into canonical 3D genome structures. They also observed a significant portion of multi-contact reads spanning multiple compartments of the same chromatin type over long distances. Moreover, the single-allele topology clusters are cell type-specific. These findings provide global characterization of single-allele topologies and reveal the principles of genome folding.