Cohesin-dependent regulation of dynamic gene expression during differentiation is lost in Cohesin-mutated myeloid malignancies

The Cohesin complex critically controls interactions between proximal and distal cis-regulatory elements, while Cohesin disruption causes improper gene activation. This process associates with biased hematopoiesis, and Cohesin mutations are common in myeloid neoplasia. In this study, we initially explore Cohesin-associated dynamics and regulation of hematopoietic stem cell renewal and erythropoiesis. Cohesin binding to chromatin increases during erythroid differentiation at active promoters and enhancers only, with pre-binding of Etv6 predicting the subsequent dynamics of Cohesin binding at these elements. Etv6 also binds with the Cohesin complex at chromatin during haematopoiesis. Perturbation of Cohesin members does not alter hematopoietic self-renewal, but severely impairs erythroid differentiation. As in normal erythroid differentiation, the strongest impairment of gene activation in Cohesin-perturbed erythropoiesis occurs at Etv6-pre-bound loci. Taken together these findings propose a mechanism for how the Cohesin complex regulates the induction of gene expression during differentiation and how this may be perturbed in myeloid malignancies.