Bridging the resolution gap in structural modeling of 3D genome organization

Abstract

Over the last decade, and especially after the advent of fluorescent in situ hybridization imaging and chromosome conformation capture methods, the availability of experimental data on genome three-dimensional organization has dramatically increased. We now have access to unprecedented details of how genomes organize within the interphase nucleus. Development of new computational approaches to leverage this data has already resulted in the first three-dimensional structures of genomic domains and genomes. Such approaches expand our knowledge of the chromatin folding principles, which has been classically studied using polymer physics and molecular simulations. Our outlook describes computational approaches for integrating experimental data with polymer physics, thereby bridging the resolution gap for structural determination of genomes and genomic domains.

Figure 1. Bridging the resolution gap.

DNA and chromatin have been characterized at diverse resolution scales. The DNA is composed by nucleotides forming base pairs ([A], an AT base-pair from PDB entry 2KV0 [48]), which in turn will form a DNA double helix ([B], DNA structure from PDB entry 2KV0 [48]). The DNA then wraps around histone proteins forming nucleosomes ([C], the complex between nucleosome core particles and DNA from PDB entry 1AOI [49]). It is also known that chromosomes occupy so-called chromosome territories ([F], 3D FISH image from a 3D map of all chromosomes in human male fibroblast nuclei [50]). Between DNA atomic resolution and nuclei chromosome resolution, there have been a plethora of models describing how chromatin folds into the so-called 30 nanometer fiber ([D], image by Richard Wheeler) and then experiences higher-order folding ([E], interchromatin domain and interchromosomal network models of looping interactions between two chromosomes [51]). An integrative approach combining polymer physics with constraint-based modeling will provide important insight about chromatin architecture at the range of resolutions indicated by the dashed rectangle. Length, volume, and resolution scales adapted from .

Figure 2. Main approaches for studying genomic organization.

Two of the most used approaches for experimentally determining features of genome architecture. Light microscopy by fluorescent in situ hybridization (FISH) results in a measured spatial distance (R) (and its distribution in a population of cells or its time course) as function of the genomic linear distance (s). Cell/molecular biology by chromosome conformation capture (3C)-based approaches results in an estimation of the average frequency of contacts between parts of the chromatin in a population of cells.

Figure 3. Two computational approaches for determining the 3D structure of genomic domains and genomes.

(A) The first approach uses polymer models to simulate relevant interactions (both physical and biological) that explain experimental observations. (B) The second approach integrates diverse experimental observations to model a conformational ensemble that satisfies the experimental observations.