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

Marco Di Stefano,Jonas Paulsen,Tonje G Lien,Cristian Micheletti,Eivind Hovig

doi:10.1038/srep35985

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.

Highlights

Heterogeneity of the chromosomal conformational ensemble that is probed experimentally
We employ steered molecular dynamics simulations to drive the formation of these constitutive contacts in a physical model of the human diploid genome, where chromosomes are coarse-grained at the 30 nm level
We mostly focus on lung fibroblasts (IMR90) with phenomenologically placed chromosomes and point out the relevant analogies with the human embryonic stem cells in specific contexts

Summary

Introduction

Heterogeneity of the chromosomal conformational ensemble that is probed experimentally. We employ steered molecular dynamics simulations to drive the formation of these constitutive contacts in a physical model of the human diploid genome, where chromosomes are coarse-grained at the 30 nm level. The viability of this general strategy is here explored for two distinct human cell lines: lung fibroblasts (IMR90) and embryonic stem cells (hESC). Some of these studies have addressed the architecture of specific, local functional domains[21,24,28], including the formation and plasticity of topologically associated domains (TADs)[29,30,31,32,33,34]. The two main challenges of these approaches are: the use of suitable data analysis strategies for inferring pairwise distances from the phenomenological data, such as Hi-C21,23,36,40–42, and the optimal use of the distances as phenomenological constraints for three-dimensional models[21,23,25,40,42]

Methods

Results

Conclusion