Modeling chromosomes: Beyond pretty pictures

Abstract

Recently, Chromosome Conformation Capture (3C) based experiments have highlighted the importance of computational models for the study of chromosome organization. In this review, we propose that current computational models can be grouped into roughly four classes, with two classes of data-driven models: consensus structures and data-driven ensembles, and two classes of de novo models: structural ensembles and mechanistic ensembles. Finally, we highlight specific questions mechanistic ensembles can address.

Keywords: Chromatin; Hi-C; Model; Polymer; Simulation.

Figure 1

Left: Data-driven spatial models being with Hi-C maps. Then they usually convert the Hi-C map to a map of average pairwise distances or constraints. From the distance map, a single spatial conformation (consensus structure), or a set of spatial conformations is generated (data-driven ensemble). Some ensemble data-driven models then calculate the simulated Hi-C contact map and compare it to the original. Right: De novo approaches begin with a hypothesis, which is then used to develop a spatial model. This spatial model has hypothesis-dependent interactions in addition to basic polymer constraints. This model is then used to generate a set of conformations. These in turn can be used to calculate a simulated contact map by performing in silico Hi-C, which can be compared with the relevant experimental Hi-C map. This leads to either rejection of the initial hypothesis, or modification of the hypothesis or model parameters (e.g. loop length).

Figure 2

Mechanistic ensembles based on loop extrusion can explain interphase and metaphase chromosomal organization. Left: In a model of loop extrusion, Loop Extruding Factors (LEFs) bind to chromatin and extrude a progressively larger loop [52]. Top: In interphase, a TAD organization can be achieved with a low density of LEFs that stall at boundary elements, potentially inwards-oriented CTCF sites [55]. Bottom: In metaphase, a homogeneous contact map with a slowly-decaying contact probability in agreement with experimental Hi-C maps can be achieved via loop extrusion as well. However, in this case the density of LEFs is higher and boundary elements are no longer present. In this case, LEFs extrude all available chromatin fiber, and form an array of consecutive loops [20].