The cellular balance of NIPBL and PDS5 tunes the rate of cohesin loop extrusion and shapes chromosome organization across scales [HiC]

Cohesin loop extrusion has emerged as a major contributor to chromosome folding, enabling essential genomic functions from transcriptional regulation to DNA recombination and repair. Despite its requirement for extrusion, the co-factor NIPBL binds cohesin only intermittently. By combining in vivo experimental and in silico modeling approaches, we discovered that limiting NIPBL abundance causes chromosome folding defects that are best explained by reduced extrusion rates. Reduced extrusion rates, but not reduced loading, can counteract an increase in cohesin lifetime brought on by WAPL depletion. Depleting the NIPBL competitors PDS5A and PDS5B increases extrusion rates, in a way that can be shunted by NIPBL-co-depletion. Finally, we observed that extrusion rate and cohesin lifetime, although equally contributing to cohesin processivity, differentially impact genomic compartmentalization. In addition to shedding light on unappreciated roles of NIPBL beyond cohesin loading, in regulating the rate of cohesin loop extrusion, our work provides an experimentally calibrated computational framework to investigate the molecular mechanisms edifying genome architecture and function. Overall design: Hi-C using in various mouse embryonic stem cell lines with auxin- or dTAG-inducible degrons inserted on endogenous NIPBL, RAD21, WAPL, PDS5A and PDS5B.