A CTCF Code for 3D Genome Architecture

Abstract

The architectural protein CTCF plays a complex role in decoding the functional output of the genome. Guo et al. now show that the orientation of a CTCF site restricts its choice of interacting partner, thus creating a code that predicts the three-dimensional organization of the genome. We propose a DNA extrusion model to account for orientation-specific loop formation.

Figure 1. Model of Orientation Biased CTCF Looping

(A) CTCF mediated loops in convergent and divergent orientations only differ in how they are connected by the DNA. The loop on the left occurs much more frequently than the loop on the right, suggesting the mechanism of loop formation must be able to distinguish the two cases. (B) A loop-extrusion model would explain the orientation bias seen in CTCF mediated looping. CTCF bends DNA and could be capable of forming a loop on one side of its binding site only, due to the manner in which the DNA is bent. This loop could then be expanded in one direction via the action of cohesin and possibly also transcription, causing the CTCF site to contact other DNA elements such as other CTCF sites, cohesin-associated Mediator complexes, and cohesin-associated gene promoters more frequently in one orientation. Homodimerization of CTCF complexes in anti-parallel orientations may not be favored, leading to continued, rather than completed loop formation when two CTCF binding sites encounter each other during loop extrusions, accounting for the paucity of these interactions observed in genome interaction data.