FIGURE 6.

An example of TAD disruption in cancer and rewiring of promoter-enhancer proximity. The upper panel depicts two distinct TADs, the left containing a gene (depicted with a green box) and two regulatory elements (RE1 and RE2 depicted with red boxes), which can be either an enhancer, or a poised enhancer or a silencer. The right TAD contains one regulatory element (RE3) that would be compatible with the gene. In the upper panel, the gene is located in a confined place with RE1 and RE2 (depicted with round black circles) resulting in its normal transcriptional activation (if RE1 and RE2 are enhancers) or its repression (if RE1 and RE2 are poised enhancers or silencers). Mutation or deletion of the CTCF sites (depicted with yellow) located at the boundary between the TADs, results in the reorganization of the TAD topology and fusion of the two TADs into one. Thus, in the bottom panel, the gene is now in close proximity (and interacts frequently) with RE3 (depicted with round black circle), leading to its expression also by the RE3, if RE3 is an enhancer or its downregulation if RE3 is a silencer. The different combinations of REs could have different results in the expression levels of the gene. Since, RE1 and RE2 contacts are diminished, it could lead to less expression by those two enhancers while the expression levels of the gene remain the same. On the other hand, the combination of RE1, RE2, and RE3 could lead to a super-enhancer and higher levels of expression of the gene.