Getting the genome in shape: the formation of loops, domains and compartments

Abstract

The hierarchical levels of genome architecture exert transcriptional control by tuning the accessibility and proximity of genes and regulatory elements. Here, we review current insights into the trans-acting factors that enable the genome to flexibly adopt different functionally relevant conformations.

Fig. 1

Cell-to-cell variability in genomic neighborhoods. The upper half shows a simplified overview of chromatin behavior during the cell cycle. Chromosome territory positioning differs between mother cell and daughter cells (but can be fairly similar between two daughter cells owing to symmetric spindle positioning). In the lower half, the zoom view schematically shows the high levels of variation between the genomic neighborhoods of a given topologically associating domain (TAD) of interest (indicated in blue) across the mother cell and the two daughter cells 1 and 2. TADs are represented by colored spheres

Fig. 2

Convergent CTCF sites at topologically associated domain (TAD) boundaries. The linear distribution of CTCF binding sites and regulatory elements across a hypothetical chromosomal segment (top) results in three-dimensional looped configurations (bottom) that will differ between cells and change over time. CTCF-mediated loops can create TADs, within which enhancer-promoter loops are formed. Loops preferentially occur between convergent CTCF sites, which predicts that a TAD boundary needs to have divergent CTCF sites to accommodate looping with its neighboring boundaries. Note that not all CTCF sites form loops, even when associated with CTCF

Fig. 3

Different scenarios for cohesin-mediated chromatin looping. Three hypotheses for the strategy by which the cohesin complex is involved in the formation of chromatin loops. a After initial association of cohesin to one roadblock (such as CTCF), cohesin holds on to this site, and the flanking chromatin is pulled through until a second roadblock is encountered. b The cohesin ring remains open when the complex is attached to one roadblock. Only when a second cognate anchor sequence comes in close proximity does the ring close efficiently. c Cohesin embraces the DNA anchors of a loop that are already held together by other proteins (left-hand cartoons); its embrace stabilizes maintenance of the loops (right-hand cartoons)