In cohesin wild-type (+/+) cells, HSPC differentiation down the erythroid lineage requires a gradual increase in cohesin protein levels (top). This increase in cohesin evicts the transcriptional repressor Etv6 (purple circle) from genes required for erythroid differentiation (blue box). In addition, it facilitates the formation of chromatin loops permitting distal cis-regulatory elements (yellow box) and erythroid differentiation genes to interact, resulting in gene activation. In cohesin haploinsufficient cells (+/−), cohesin levels cannot increase during erythroid commitment (bottom). This prevents the eviction of Etv6 and induction of genes required for erythroid differentiation.