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Mapping the semi-nested community structure of 3D chromosome contact networks
Umeå University, Faculty of Science and Technology, Department of Physics.ORCID iD: 0000-0002-6618-8232
Department of Physics and Research Institute of Natural Science, Jinju, Gyeongsang National University, South Korea; Future Convergence Technology Research Institute, Jinju, Gyeongsang National University, South Korea.
Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
Umeå University, Faculty of Science and Technology, Department of Physics.ORCID iD: 0000-0003-3174-8145
2023 (English)In: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 19, no 7, article id e1011185Article in journal (Refereed) Published
Abstract [en]

Mammalian DNA folds into 3D structures that facilitate and regulate genetic processes such as transcription, DNA repair, and epigenetics. 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' 3D organization: loop extrusion and phase separation. This paper aims to map out the chromosome's 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.

Place, publisher, year, edition, pages
Public Library of Science (PLoS), 2023. Vol. 19, no 7, article id e1011185
National Category
Genetics and Genomics
Identifiers
URN: urn:nbn:se:umu:diva-212472DOI: 10.1371/journal.pcbi.1011185ISI: 001024553700001PubMedID: 37432974Scopus ID: 2-s2.0-85165521366OAI: oai:DiVA.org:umu-212472DiVA, id: diva2:1785702
Funder
Swedish Research Council, 2017-03848Swedish Research Council, 2021-04080Knut and Alice Wallenberg Foundation, 2014-0018Available from: 2023-08-04 Created: 2023-08-04 Last updated: 2025-02-07Bibliographically approved

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Bernenko, DoloresStenberg, PerLizana, Ludvig

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