Principles of Chromosome Architecture Revealed by Hi-C

Abstract

Chromosomes are folded and compacted in interphase nuclei, but the molecular basis of this folding is poorly understood. Chromosome conformation capture methods, such as Hi-C, combine chemical crosslinking of chromatin with fragmentation, DNA ligation, and high-throughput DNA sequencing to detect neighboring loci genome-wide. Hi-C has revealed the segregation of chromatin into active and inactive compartments and the folding of DNA into self-associating domains and loops. Depletion of CTCF, cohesin, or cohesin-associated proteins was recently shown to affect the majority of domains and loops in a manner that is consistent with a model of DNA folding through extrusion of chromatin loops. Compartmentation was not dependent on CTCF or cohesin. Hi-C contact maps represent the superimposition of CTCF/cohesin-dependent and -independent folding states.

Patterns in the genome

“…Similarly, there is a remarkable correspondence between TADs and TAD boundaries and the bands and inter-bands seen on Drosophila polytene chromosomes (Eagen et al, 2015)., and indeed a correspondence to chromomeres -locally coiled chromatin domains that had been seen decades ago by microscopy on mitotic and meiotic prophase chromosomes (Macgregor, 2012;Eagen, 2018) and which have also now been revealed in the interphase nucleus of diploid cells using FISH and the latest super-resolution optical imaging methods (Szabo et al, 2018).…”

Physics and Biology (of Chromosomes)

“…The emergence of an array of powerful techniques for super-resolution imaging, DNA deep sequencing, use of antibody libraries, and now gene editing has provided us with unprecedented maps, in space and to some degree in time, of where molecules are and how they are juxtaposed or organized inside the cell. Powerful bioinformatics tools (e.g., ENCODE [2] and HiGlass [3]) allow one to play with and combine these maps, which often give striking new insights into biology (e.g., the "topologically associated domains" seen in eukaryote genomes [4]) by just looking. However, given these marvelous mapping methods we should remember that for a truly mechanistic view of cellular machinery, a kinematic description, solely in terms of space and time, is incomplete.…”

Visualising three-dimensional genome organisation in two dimensions

“…These topics have been extensively reviewed elsewhere (e.g. by Eagen, 2018;Fraser et al, 2015;Yu and Ren, 2017), but will be briefly described here to provide context.…”