NIPBL and WAPL balance cohesin activity to regulate chromatin folding and gene expression

The relationship between cohesin-mediated chromatin looping and gene expression remains unclear. We investigated the roles of NIPBL and WAPL, two regulators of cohesin activity, in chromatin folding and transcription in human cells. Consistent with their opposing roles in cohesin regulation, depletion of these factors showed opposite effects on levels of chromatin-bound cohesin and spatial insulation of neighboring domains. We find that NIPBL or WAPL depletion each alter the expression of ~2,000 genes, most of which are uniquely sensitive to either regulator. We find that each set of differentially expressed genes are enriched at chromatin loop anchors and clustered within the genome, suggesting there are genomic regions sensitive to either more or less cohesin. Remarkably, co-depletion of both regulators rescued chromatin misfolding and gene misexpression compared to either single knockdown. Taken together, we present a model in which the relative, rather than absolute, levels of NIPBL and WAPL are required to balance cohesin activity in chromatin folding to regulate transcription.