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

Abstract

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 actively transcribed 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.

Mapping robust multiscale communities in chromosome contact networks

“…Through polymer simulations 17 , we have demonstrated that our generalization effectively partitions spatially proximal monomers into meaningful 3D communities. And by adding the complete scope outlined in this paper, researchers can rate the stability and robustness of these communities by identifying core regions, distinguishing ambiguous nodes, and investigating hierarchical community relationships 18,40 .…”

“…However, recently, there has been an emerging research direction alongside this development that takes advantage of the methods developed in complex network theory. This approach treats the Hi-C data as a weighted network of 3D contacts and groups nodes with above-average connectivity into mesoscale communities [16][17][18][19] . While these and many other community detection methods led to several impactful insights, underneath this approach reside an often overlooked fundamental limitation: in most networks, more than one node partition may represent a feasible network community division.…”

“…Apart from observing stable communities (e.g, the beginning of the chromosome), we note that the 3D folding is not perfectly hierarchical, in which smaller communities form larger and larger super-structures. Albeit small, there are deviations that make the folding structure semi-nested 18 .…”