Heterogeneous Loop Model to Infer 3D Chromosome Structures from Hi-C

Abstract

Adapting a well-established formalism in polymer physics, we develop a minimalist approach to infer three-dimensional folding of chromatin from Hi-C data. The three-dimensional chromosome structures generated from our heterogeneous loop model (HLM) are used to visualize chromosome organizations that can substantiate the measurements from fluorescence in situ hybridization, chromatin interaction analysis by paired-end tag sequencing, and RNA-seq signals. We demonstrate the utility of the HLM with several case studies. Specifically, the HLM-generated chromosome structures, which reproduce the spatial distribution of topologically associated domains from fluorescence in situ hybridization measurement, show the phase segregation between two types of topologically associated domains explicitly. We discuss the origin of cell-type-dependent gene-expression level by modeling the chromatin globules of α-globin and SOX2 gene loci for two different cell lines. We also use the HLM to discuss how the chromatin folding and gene-expression level of Pax6 loci, associated with mouse neural development, are modulated by interactions with two enhancers. Finally, HLM-generated structures of chromosome 19 of mouse embryonic stem cells, based on single-cell Hi-C data collected over each cell-cycle phase, visualize changes in chromosome conformation along the cell-cycle. Given a contact frequency map between chromatic loci supplied from Hi-C, HLM is a computationally efficient and versatile modeling tool to generate chromosome structures that can complement interpreting other experimental data.