Interferon regulatory factor 2 binding protein 2b regulates neutrophil versus macrophage fate during zebrafish definitive myelopoiesis

Proper cell fate choice of neutrophil-macrophage progenitor is essential for adequate myeloid sub-populations during embryonic development and in adulthood. The network governing neutrophil-macrophage progenitor cell fate is composed of several key determinants such as myeloid master regulators CCAAT enhancer binding protein alpha (C/EBPα) and spleen focus forming virus proviral integration oncogene (PU.1). Nevertheless, more regulators remain to be identified and characterized. To ensure balanced commitment of neutrophil-macrophage progenitor toward each lineage, the interplay among these determinants is not only synergistic, but also antagonistic. Depletion of Interferon regulatory factor 2 binding protein 2b (Irf2bp2b), a well known negative transcription regulator, results in a bias in neutrophil-macrophage progenitor cell fate choice which favors macrophages at the expense of neutrophils during the zebrafish definitive myelopoiesis stage in deficient embryos. Mechanistic studies indicate that Interferon regulatory factor 2 binding protein 2b acts as a downstream target of CCAAT enhancer binding protein alpha, to repress spleen focus forming virus proviral integration oncogene expression, and that SUMOylation confers the repressive function of Interferon regulatory factor 2 binding protein 2b. Thus, Interferon regulatory factor 2 binding protein 2b is a novel determinant in the cell fate choice of neutrophil-macrophage progenitor.