Structure determination of genomic domains by satisfaction of spatial restraints

Abstract

The three-dimensional (3D) architecture of a genome is non-random and known to facilitate the spatial colocalization of regulatory elements with the genes they regulate. Determining the 3D structure of a genome may therefore probe an essential step in characterizing how genes are regulated. Currently, there are several experimental and theoretical approaches that aim at determining the 3D structure of genomes and genomic domains; however, approaches integrating experiments and computation to identify the most likely 3D folding of a genome at medium to high resolutions have not been widely explored. Here, we review existing methodologies and propose that the integrative modeling platform (http://www.integrativemodeling. org), a computational package developed for structurally characterizing protein assemblies, could be used for integrating diverse experimental data towards the determination of the 3D architecture of genomic domains and entire genomes at unprecedented resolution. Our approach, through the visualization of looping interactions between distal regulatory elements, will allow for the characterization of global chromatin features and their relation to gene expression. We illustrate our work by outlining the recent determination of the 3D architecture of the α-globin domain in the human genome.Keywords chromosome conformation . chromatin structure . integrative modeling . computational structural biology Abbreviations 1DOne-dimensional 3D

Defined chromosome structure in the genome-reduced bacterium Mycoplasma pneumoniae

“…Briefly, based on the hypothesis that chromatin interaction frequencies are a proxy for spatial proximities between loci15, we used TADbit164748 to convert the contact frequencies of genomic loci into spatial distances. Then we searched for the 3D conformations that best satisfied the spatial distances between genomic loci inferred from the frequencies of our Hi-C matrix.…”

“…However, more recent developments in super-resolution localization microscopy89101112 and chromosome conformation capture (3C)-based techniques13 have enabled the determination of the global chromosome organization of some bacteria14. High-throughput derivations of genome-wide 3C-based assays such as Hi-C technologies15 have been used to generate high-resolution contact maps of genomes, which when combined with modelling, can provide three-dimensional (3D) representations of genome structures16171819. Studies of bacterial chromosome organization and regulation using these afore mentioned combinatorial techniques have been carried out in Caulobacter crescentus, resulting in a Hi-C map with a 13 kb resolution17, in Escherichia coli with a 20 kb resolution20, and in Bacillus subtilis with 30, 10 and 4 kb resolutions212223.…”

Population-based 3D genome structure analysis reveals driving forces in spatial genome organization

“…These methods relate Hi-C contact frequencies to distances, assuming that a lower contact frequency corresponds to a larger distance between loci in 3D space, which requires additional (often arbitrary) assumptions (6,12,(24)(25)(26)(27)(28)(29)(30). The major limitation of these methods is that the generated consensus structures do not represent single instances of actual genome structures and cannot capture the variable nature of long-range and trans chromatin interactions in different structural states.…”

Understanding spatial organizations of chromosomes via statistical analysis of Hi‐C data

“…[102]) (Table 1). These methods design a target function to measure the goodness-of-fit of a 3D model with respect to the Hi-C data, and search the model space to optimize the target function with some pre-specified constraints (e.g., the spatial distance between two loci must fall into a certain range).…”