Spinning the threads of life

Physicists discover a biophysical model relating to looped DNA in chromosomes, which assumes diffusive sliding of cohesin along DNA, without any motor activity, and the loading of multiple cohesins on the same piece of chromosome.

Every living cell contains chromosomes - very long DNA molecules encoding the genetic information needed for its function. A cell then needs to find a compromise between storing such large molecules in its interior in a compact state and being able to access any part of this information. As part of the solution of this packing puzzle, DNA in chromosomes is often looped. Chromosome loops are not only important because they reduce the 3D size of the genome, but also because they regulate gene expression, by enabling regions of the DNA which are far apart in 1D sequence, but are functionally related, to come together in 3D and interact.

Many chromosome loops are associated with cohesin - a ring-like protein that clips onto a chromosomal fibre much like a carabiner onto a climber's rope (in polymer physics this is known as a "slip-link").  By embracing the fibre at two adjacent points, it can fold it into a mini-loop, and then travel down the fibre to enlarge the loop. What mechanism drives loop enlargement? The popular "loop-extrusion model" sees cohesin as a powerful motor, but to generate the large loops observed in experiments, it has to travel faster and further than most known molecular motors. In our work we instead suggest a different biophysical model, which assumes simply diffusive sliding of cohesin along DNA, without any motor activity. Our simulations show that this mechanism is, perhaps surprisingly, fast enough to create loops of hundreds of thousands of base pairs, as seen experimentally, even within the crowded environment which constitutes the cell nucleus. We also find it is also crucial that the binding dynamics of cohesin on DNA requires ATP, so cannot be described by thermodynamics alone. We finally uncover an intriguing "ratchet effect", which can boost loop enlargement by exploiting the loading of multiple cohesins (carabiners) on the same piece of chromosome (rope).