Molecular Mechanisms Regulating Chromatin Looping

Enhancer-promoter contacts appear to be largely restricted to occur within Topologically Associating Domains (TADs). TADs are formed by the DNA-binding protein CTCF (panel A) and cohesin (panel B). At the molecular level, CTCF binds specific DNA sites and recruits cohesin, which is thought to hold together TADs as a chromatin loop inside its lumen (panel C). Thus, at least two different types of loops shape 3D genome organization: structural loops that form TADs and enhancer-promoter loops that are thought to form inside TADs (panel C). The structural loops are thought to be formed through cohesin-mediated loop extrusion, where cohesin-extrusion is eventually blocked by CTCF (panel D). Consistently, loss of CTCF or cohesin causes loss of most TADs and loops. And functionally, loss of CTCF boundaries can results in human developmental disorders and oncogene activation in (e.g. in glioma) by enabling aberrant enhancer-promoter contacts.

However, we have shown that CTCF and cohesin bind chromatin with very different residence times, suggesting that the complex formed by CTCF and cohesin is unlikely to be a stable complex and thus that TADs and loops are also unlikely to be stable structures inside the cell.