NIPBL dosage shapes genome folding by tuning the rate of cohesin loop extrusion

Cohesin loop extrusion is a major driver of chromosome folding, but how its dynamics are controlled to shape the genome remains elusive. Here we disentangle the contributions of the cohesin cofactors NIPBL, WAPL and PDS5 to loop extrusion kinetics using titrated perturbations and calibrated biophysical models. We demonstrate that beyond contributing to cohesin loading, cellular NIPBL dosage quantitatively controls the rate of loop extrusion. This role explains how lowering NIPBL abundance compensates for elevated cohesin lifetime caused by inactivation of WAPL, the cohesin unloader, and how the NIPBL:PDS5 balance in cells sets the net rate of extrusion. We validate the predicted consequences of altered extrusion rate on chromosome morphology and cohesin dynamics in single cells and demonstrate its impact on compartmentalization and transcription. These findings provide a mechanistic basis for the genetic interactions between cohesin cofactors and the molecular origin of haploinsufficiency in cohesinopathies, such as Cornelia de Lange syndrome.