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EED is essential for regulating the repressive histone modification, histone 3 lysine 27 tri-methylation (H3K27me3) at many developmental genes. EED depletion significantly impeded erythroid maturation. EED depletion impaired the generation of hematopoietic stem cells. The function of EED within polycomb repressive complex 2 (PRC2) is mediated by a complex network of protein-protein interactions. The targeted disruption of EED's reader function can lead to allosteric inhibition of PRC2 catalytic activity. Eed(Delta/Delta) HSPCs exhibited increased attachment to a major extracellular matrix component, fibronectin. Thus, EED deficiency increases proliferation on one side but promotes quiescence possibly by enhanced adhesion to the hematopoietic niche on the other, and these conflicting events would lead to abnormal differentiation and functional defect of Eed(Delta/Delta) HSPCs.