Analysis of long-range contacts across cell types outlines a core sequence determinant of 3D genome organization

The sequence-driven organizing principles of the 3D genome are crucial for interpreting the core effects of genomic variation and understanding the evolution of genome organization and function. We investigated these by isolating and analysing cell-type-persistent contacts, heavily dependent on the similarly cell-type-persistent genomic sequence. We stratified long-range contacts from a diverse set of human tissues and cell lines based on contact persistence, c_p, reflecting their presence across cell or tissue types, and present them as an atlas of contacts and cell-type invariant (CETI) hubs they form across human chromosomes. Our survey of >300 chromatin and genome features revealed their association with c_p, contrasting variable from persistent contacts in terms of co-localization with genes, 3D architectural domains, and epigenetic and sequence elements. We found persistent contacts to be predominantly comprised of adenine and thymine (AT)-rich sequences and related to heterochromatin. A key outcome is finding a link between the experimental genomic contacts and the complementarity between pairs of contacting DNA loci. This work provides evidence for a sequence determinant of genomic contacts contributing to the decoding of the relationship between sequence and structure that is crucial for functional and evolutionary studies concerning 3D genome organization.