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Blood. 2009 Jan 8;113(2):317-27. doi: 10.1182/blood-2008-02-139741. Epub 2008 Oct 2.

Human C/EBP-epsilon activator and repressor isoforms differentially reprogram myeloid lineage commitment and differentiation.

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  • 1Department of Biochemistry and Molecular Genetics, Section of Hematology-Oncology, College of Medicine, University of Illinois at Chicago, Chicago, IL 60607, USA.


CCAAT enhancer-binding protein-epsilon (C/EBP-epsilon) is required for the terminal differentiation of neutrophils and eosinophils. Human C/EBP-epsilon is expressed as 4 isoforms (32, 30, 27, and 14 kDa) through differential RNA splicing, and alternative promoters and translational start sites. The C/EBP-epsilon(32/30) isoforms are transcriptional activators, whereas C/EBP-epsilon(27) interacts with and represses GATA-1 transactivation of eosinophil promoters. C/EBP-epsilon(14) contains only DNA-binding and -dimerization domains and may function as a dominant-negative regulator. To define functional activities for these C/EBP-epsilon isoforms in myelopoiesis, human CD34(+) progenitors were transduced with internal ribosomal entry site-enhanced green fluorescent protein retroviral vectors encoding the 32/30, 27, and 14-kDa isoforms, purified by fluorescence-activated cell sorter, and analyzed in colony-forming assays and suspension cultures. Progenitors transduced with C/EBP-epsilon(32/30) default exclusively to eosinophil differentiation and gene expression, independent of interleukin-5, and regardless of inclusion of cytokines to induce other lineages. In contrast, the putative repressor C/EBP-epsilon(27) isoform strongly inhibits eosinophil differentiation and gene expression, including GATA-1, promoting granulocyte (neutrophil)-macrophage differen-tiation. The C/EBP-epsilon(14) repressor isoform strongly inhibits eosinophil development and gene expression, promoting erythroid differentiation, an effect enhanced by erythropoietin. Thus, C/EBP-epsilon isoforms can reprogram myeloid lineage commitment and differentiation consistent with their predicted activities based on activator and repressor domains and in vitro functional activities.

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