CyEBP« mediates myeloid differentiation and is regulated by the CCAAT displacement protein (CDPycut)

Neutrophils from CCAAT enhancer binding protein epsilon (Cy EBP«) knockout mice have morphological and biochemical features similar to those observed in patients with an extremely rare congenital disorder called neutrophil-specific secondary granule deficiency (SGD). SGD is characterized by frequent bacterial infections attributed, in part, to the lack of neutrophil secondary granule proteins (SGP). A mutation that results in loss of functional CyEBP« activity has recently been described in an SGD patient, and has been postulated to be the cause of the disease in this patient. We have previously demonstrated that overexpression of CCAAT displacement protein (CDPycut), a highly conserved transcriptional repressor of developmentally regulated genes, suppresses expression of SGP genes in 32Dcl3 cells. This phenotype resembles that observed in both CyEBP«2y2 mice and in SGD patients. Based on these observations we investigated potential interactions between CyEBP« and CDPycut during neutrophil maturation. In this study, we demonstrate that inducible expression of CyEBP« in 32Dcl3ytet cells results in granulocytic differentiation. Furthermore, Northern blot analysis of G-CSF-induced CDPycut overexpressing 32Dcl3 cells revealed absence of CyEBP« mRNA. We therefore hypothesize that CyEBP« positively regulates SGP gene expression, and that CyEBP« is itself negatively regulated by CDPycut during neutrophil maturation. We further demonstrate that the CyEBP« promoter is regulated by CDPycut during myeloid differentiation.