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 threedimensional (3D) folding of chromatin from Hi-C data. The 3D chromosome structures generated from our heterogeneous loop model (HLM) are used to visualize chromosome organizations that can substantiate the measurements from FISH, ChIA-PET, and RNA-Seq signals. We demonstrate the utility of HLM with several case studies. Specifically, the HLM-generated chromosome structures, which reproduce the spatial distribution of topologically associated domains (TADs) from FISH measurement, show the phase segregation between two types of TADs 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 HLM to discuss how the chromatin folding and gene expression level of Pax6 loci, associated with mouse neural development, is modulated by interactions with two enhancers. Finally, HLM-generated structures of chromosome 19 of mouse embryonic stem cells (mESCs), 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, which can complement interpreting other experimental data.

Revisiting the organization of Polycomb-repressed domains: 3D chromatin models from Hi-C compared with super-resolution imaging

“…To elaborate more on the differences between three epigenetic states other than γ, we modeled 3D structures of A-23, I-14 and R-11 domains by employing the HLM approach ( 30 ) and visualized them (Figure 3A ).…”

“…Details about the original HLM can be found in Ref. ( 30 ). Each monomer of our chromatin polymer model in this study represents 5 kb genome.…”

“…To visualize a structural ensemble of modeled chromatin domain ( 30 ), the geometric centers of three or four (sub)domains, if any, were first selected from the whole domain, and next the distribution of the interdomain distances were computed based on the ensemble of structures. Several chromatin conformations were then randomly selected from the most populated cluster determined based on the interdomain distances, and were aligned and rendered.…”

“…To gain better understanding to different epigenetic states, 3D modeling and visualization of each state would be of great help. To this end, we applied a recently developed, polymer-based chromosome modeling approach, termed the heterogeneous loop model (HLM) ( 30 ) ( https://github.com/leiliu2015/HLM , see Supplementary Information and Supplementary Figure S1 ), on Hi-C data of Drosophila Kc 167 cells ( 9 ) and generated 3D structures of active, inactive, and Polycomb-repressed domains.…”

Toward understanding the dynamic state of 3D genome

“…(3) states that the contact probability is a function of the variety of chromosome structures. Also, another contact kernel represented by the step function states that is a function of the variance [34] , [35] : …”