Functional implications of genome topology

Abstract

Although genomes are defined by their sequence, the linear arrangement of nucleotides is only their most basic feature. A fundamental property of genomes is their topological organization in three-dimensional space in the intact cell nucleus. The application of imaging methods and genome-wide biochemical approaches, combined with functional data, is revealing the precise nature of genome topology and its regulatory functions in gene expression and genome maintenance. The emerging picture is one of extensive self-enforcing feedback between activity and spatial organization of the genome, suggestive of a self-organizing and self-perpetuating system that uses epigenetic dynamics to regulate genome function in response to regulatory cues and to propagate cell-fate memory.

Figure 1

A global view of the cell nucleus. Chromatin domain folding is determined by transcriptional activity of genome regions. Boundaries form at the interface of active and inactive parts of the genome. Higher-order domains of similar activity status cluster to form chromatin domains, which assemble into chromosome territories. Repressive regions of chromosomes tend to contact other repressive regions on the same chromosome arm, whereas active domains are more exposed on the outside of chromosome territories and have a higher chance of contacting active domains on the other chromosome arm and on other chromosomes,, giving rise to topological ‘superdomains’ composed of multiple, functionally similar genome domains. The location of territories is constrained by their association with the nuclear periphery, transcription hubs, nuclear bodies and centromere clusters

Figure 2

Four types of transcription regulatory chromatin loops. (a) Intragenic loops joining the 5’ and 3’ end of genes may allow recycling of RNA Pol II and facilitate maintenance of transcriptional directionality. (b) Enhancer- promoter loops—mediated by sequence-specific transcription factors, and possibly assisted by noncoding RNAs or by general DNA binding factors such as CTCF and cohesin—lead to transcriptional activation. (c) Loops between Polycomb-bound regions (PREs) and promoters prevent RNA Pol II recruitment and/or impair transcriptional elongation of promoter-bound RNA polymerases. (d) Insulator-mediated loops may segregate individual loci containing the coding part of the gene and its regulatory regions from the surrounding genome landscape with other regulatory elements.

Figure 3

A model depicting the interplay of genome structure and function. The transcriptional activity of genome regions determines the formation of chromatin domains (red and green). Domains are defined patterns of nucleosome positioning, histone modifications and differential higher-order folding. The activity state of a ‘neutral’ genome region (black) is determined by its physical association with either an active or repressive environment, and these long-range contacts may thus change functional states (indicated by transformation of the portion of the black chromosome closest to a repressive (red) domain of another chromosome to pink). The functional status of the chromatin domain feeds back and reinforces its structural features (self-enforcement). Chromatin structure-function relationships are heritable (self-propagation).However, given the inherent plasticity of the system, even in terminally differentiated states strong physiological or environmental stimuli may switch chromatin domains, allowing for the possibility of cell reprogramming.