Insights about genome function from spatial organization of the genome

Abstract

Over the last 15 years, development of chromosome conformation capture (3C) and its subsequent high-throughput variants in conjunction with the fast development of sequencing technology has allowed investigators to generate large volumes of data giving insights into the spatial three-dimensional (3D) architecture of the genome. This huge data has been analyzed and validated using various statistical, mathematical, genomics, and biophysical tools in order to examine the chromosomal interaction patterns, understand the organization of the chromosome, and find out functional implications of the interactions. This review summarizes the data generated by several large-scale high-throughput chromosome conformation capture studies and the functional implications obtained from the data analyses. We also discuss emerging results on factors (both CCCTC binding factor (CTCF) related and CTCF independent) that could contribute to looping interactions.

Keywords: Chromatin looping; Chromosome conformation capture (3C); Genome architecture; Hi-C; Histone modifications; Topologically associated domains (TAD); Transcription.

Fig. 1

Schematic representation of how smaller TAD-like structures (sub-TADs) emerge from Hi-C contact matrix and how they might be forming in three dimensions. Dynamic loop extrusion by factors like Cohesin might lead to looping and higher interactions in the extruded loci leading to emergence of sub-TADs

Fig. 2

Frequency distribution of interactions (above cutoff of 10 units of interaction value for a pair of loci) with distance between the interacting loci by analyzing intra-chromosomal Hi-C contact matrix of human chromosome 5 (analysis was done using normalized interaction values from Hi-C data given in Rao et al. [8])

Fig. 3

Schematic representation to show that TAD boundary restricts the spread of heterochromatinization

Fig. 4

Schematic representation showing coordinated expression of genes mediated by an enhancer interacting with multiple promoters within the same TAD and a TAD boundary restricts enhancer interaction and activity only to target genes within the same TAD