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Several insights derive from chromosome capture methods, such as Hi-C, which allow researchers to construct contact maps depicting 3D interactions among all DNA segment pairs. These maps show a complex cross-scale organization spanning megabase-pair compartments to short-ranged DNA loops. To better understand the organizing principles, several groups analyzed Hi-C data assuming a Russian-doll-like nested hierarchy where DNA regions of similar sizes merge into larger and larger structures. Apart from being a simple and appealing description, this model explains, e.g., the omnipresent chequerboard pattern seen in Hi-C maps, known as A\/B compartments, and foreshadows the co-localization of some functionally similar DNA regions. However, while successful, this model is incompatible with the two competing mechanisms that seem to shape a significant part of the chromosomes\u2019 3D organization: loop extrusion and phase separation. This paper aims to map out the chromosome\u2019s actual folding hierarchy from empirical data. To this end, we take advantage of Hi-C experiments and treat the measured DNA-DNA interactions as a weighted network. From such a network, we extract 3D communities using the generalized Louvain algorithm. This algorithm has a resolution parameter that allows us to scan seamlessly through the community size spectrum, from A\/B compartments to topologically associated domains (TADs). By constructing a hierarchical tree connecting these communities, we find that chromosomes are more complex than a perfect hierarchy. Analyzing how communities nest relative to a simple folding model, we found that chromosomes exhibit a significant portion of nested and non-nested community pairs alongside considerable randomness. In addition, by examining nesting and chromatin types, we discovered that nested parts are often associated with active chromatin. These results highlight that cross-scale relationships will be essential components in models aiming to reach a deep understanding of the causal mechanisms of chromosome folding.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1011185","type":"journal-article","created":{"date-parts":[[2023,7,11]],"date-time":"2023-07-11T17:33:34Z","timestamp":1689096814000},"page":"e1011185","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["Mapping the semi-nested community structure of 3D chromosome contact networks"],"prefix":"10.1371","volume":"19","author":[{"given":"Dolores","family":"Bernenko","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3079-5679","authenticated-orcid":true,"given":"Sang 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