Fig. 5

The non-random packaging of chromatin inside the nucleus. A On the nuclear scale, each chromosome occupies individual regions, termed chromosomal territories [135]. B Within these chromosomes, chromatin clusters into transcriptionally active (“A”) and inactive (“B”) compartments [136]. C Within these compartments, further organization occurs in the form of megabase-long loop structures called “topologically associating domains” (TADs) [137]. TADs are highly conserved between cell types and tend to insulate enhancers and genes contained within it from elements outside of the TAD, thereby preventing inappropriate enhancer–promoter contacts [138]. D Finally, TADs are further compartmentalized into smaller sub-TAD loops that frequently facilitate enhancer–promoter interactions. Unlike TADs, these smaller loops are more cell-type specific [139]. Generally, it is thought that TAD and sub-TAD loops are formed by the interaction of CTCF DNA binding proteins and cohesin ring-shaped complexes that bring distant chromatin regions into physical proximity [140]. However, even this is a simplistic model as further evidence suggest the involvement of many other factors. For example, recent evidence suggest that sub-TAD loops are more commonly stabilized by YY1 proteins in a manner analogous to CTCF [141]. Another evidence shows the involvement of ZNF143 as a chromatin-looping factor that bind to promoter and establish loops through interaction with enhancer-bound CTCF and cohesin [142]. Overall, the mechanisms behind chromatin looping are still an active area of research