Hi-C-constrained physical models of human chromosomes recover functionally-related properties of genome organization

TL;DR

This study integrates chromosome contact data into physical models of the human genome, revealing functional organization features like gene-rich regions at the nuclear center, without prior explicit modeling of these properties.

Contribution

It introduces a novel approach combining genome-wide contact data with physical modeling to uncover emergent functional properties of genome organization.

Findings

Gene-rich regions localize centrally in the nucleus

Gene-poor and lamina-associated domains are peripheral

Models remain minimally entangled and consistent with in vivo data

Abstract

Combining genome-wide structural models with phenomenological data is at the forefront of efforts to understand the organizational principles regulating the human genome. Here, we use chromosome-chromosome contact data as knowledge-based constraints for large-scale three-dimensional models of the human diploid genome. The resulting models remain minimally entangled and acquire several functional features that are observed in vivo and that were never used as input for the model. We find, for instance, that gene-rich, active regions are drawn towards the nuclear center, while gene poor and lamina-associated domains are pushed to the periphery. These and other properties persist upon adding local contact constraints, suggesting their compatibility with non-local constraints for the genome organization. The results show that suitable combinations of data analysis and physical modelling can expose the unexpectedly rich functionally-related properties implicit in chromosome-chromosome contact data. Specific directions are suggested for further developments based on combining experimental data analysis and genomic structural modelling.