Restraint‐based three‐dimensional modeling of genomes and genomic domains

Abstract

a b s t r a c tChromosomes are large polymer molecules composed of nucleotides. In some species, such as humans, this polymer can sum up to meters long and still be properly folded within the nuclear space of few microns in size. The exact mechanisms of how the meters long DNA is folded into the nucleus, as well as how the regulatory machinery can access it, is to a large extend still a mystery. However, and thanks to newly developed molecular, genomic and computational approaches based on the Chromosome Conformation Capture (3C) technology, we are now obtaining insight on how genomes are spatially organized. Here we review a new family of computational approaches that aim at using 3C-based data to obtain spatial restraints for modeling genomes and genomic domains.

The second decade of 3C technologies: detailed insights into nuclear organization

“…These two separate approaches are explained in detail by Dekker et al (2013), Ay and Noble (2015), and Serra et al (2015). Explaining the physical details underlying polymer simulations is beyond the scope of this review; we therefore only want to provide a few examples illustrating the two major strategies that have been employed in restraint-based modeling.…”

Genome-wide mapping and analysis of chromosome architecture

“…Owing to space limitations, this Review does not cover alternative applications of C-data, such as haplotype phasing 28–30 , genome assembly 31–33 , metagenomic applications 34–36 and three-dimensional (3D) chromosome modelling 22,24,37,38 . Readers can find excellent reviews on these topics elsewhere 5,39–42 . We conclude by providing perspective on the challenges that remain ahead.…”

Multiscale simulation of DNA

“…Techniques such as Hi-C [165] provide low resolution (at best 1 kb with in-situ Hi-C [166]) information on prevalent contacts of the chromatin fiber which, transformed into distance or spatial contact restraints, can be used to visualize the target chromatin region. There are in general two modeling strategies to convert the experimental output into a three-dimensional object (recently reviewed in [167]). …”

“…One category of models directly transforms the contacts analytically into a single 3D structure while another set of models uses optimization-based methods to generate multiple possible configurations [167]. Introduction of higher level of detail can be achieved by the intermediate chain-of-beads approach, which involves two features: small-scale chromatin properties and overall genome organization based on experimental results, for example from Hi-C [165], FISH [168] or cryo-EM [159] Hi-C contacts) [171][172][173].…”