Housed in a nucleus only a few microns wide, the human genome, roughly 2 m long, is folded into loops and contact domains of chromatin, which composes chromosomes.
Advances in high-throughput techniques have helped unravel genome architecture. Building on an existing 3D map of the human genome annotated with around 9,000 contact domains and 10,000 loops, researchers evaluated theoretical models for the formation of these chromatin structures.
The analysis suggests that an extrusion model, previously proposed to explain loop formation during a stage of cell division called metaphase, closely comports with simulation data from high-resolution spatial maps of chromosomes at the interphase stage.
In the model, a complex composed of the DNA-binding proteins CCCTC-binding factor (CTCF) and cohesin is thought to extrude loops as the two proteins slide in opposite directions along chromatin.
The model explains not only why loops are unknotted and nonoverlapping but also why they tend to lie between CTCF-binding motifs that are oriented facing each other. Editing the CTCF-binding motifs found at the loop anchors—including insertion of even a single base pair—reengineered loops and contact domains, and the model accurately predicted the positions of loops and domains using only information about CTCF-binding sites in human cells.
According to the authors, genome editing can help probe and alter how the human genome is folded.