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Mapping the semi-nested community structure of 3D chromosome contact networks

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 s...

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Detalles Bibliográficos
Autores principales: Bernenko, Dolores, Lee, Sang Hoon, Stenberg, Per, Lizana, Ludvig
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10361492/
https://www.ncbi.nlm.nih.gov/pubmed/37432974
http://dx.doi.org/10.1371/journal.pcbi.1011185
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author Bernenko, Dolores
Lee, Sang Hoon
Stenberg, Per
Lizana, Ludvig
author_facet Bernenko, Dolores
Lee, Sang Hoon
Stenberg, Per
Lizana, Ludvig
author_sort Bernenko, Dolores
collection PubMed
description 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.
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spelling pubmed-103614922023-07-22 Mapping the semi-nested community structure of 3D chromosome contact networks Bernenko, Dolores Lee, Sang Hoon Stenberg, Per Lizana, Ludvig PLoS Comput Biol Research Article 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. Public Library of Science 2023-07-11 /pmc/articles/PMC10361492/ /pubmed/37432974 http://dx.doi.org/10.1371/journal.pcbi.1011185 Text en © 2023 Bernenko et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Bernenko, Dolores
Lee, Sang Hoon
Stenberg, Per
Lizana, Ludvig
Mapping the semi-nested community structure of 3D chromosome contact networks
title Mapping the semi-nested community structure of 3D chromosome contact networks
title_full Mapping the semi-nested community structure of 3D chromosome contact networks
title_fullStr Mapping the semi-nested community structure of 3D chromosome contact networks
title_full_unstemmed Mapping the semi-nested community structure of 3D chromosome contact networks
title_short Mapping the semi-nested community structure of 3D chromosome contact networks
title_sort mapping the semi-nested community structure of 3d chromosome contact networks
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10361492/
https://www.ncbi.nlm.nih.gov/pubmed/37432974
http://dx.doi.org/10.1371/journal.pcbi.1011185
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