ATF4 differentially regulates transcriptional activation of myeloid-specific genes by C/EBPepsilon and C/EBPalpha.

Dimerization between different basic region leucine zipper (ZIP) transcription factors is regarded as an important mechanism for integrating various extracellular signals to control specific patterns of gene expression in cells. The activating transcription factor 4 (ATF4) protein was identified as a principal partner for the myeloid-specific transcriptional factor C/EBPepsilon. Dimerization required the ZIP motif of each protein and redirected DNA binding of C/EBPepsilon and ATF4 from their respective symmetric consensus sites to asymmetric C/EBP and cAMP response element sites. The C/EBPepsilon:ATF4 heterodimer bound to the C/EBP sites in the promoters of the myeloid-specific genes encoding neutrophil elastase (NE) and the G-CSF receptor (G-CSFR). Also, the heterodimer bound a previously uncharacterized site in the promoter of the mim-1 gene at nucleotide -174. Coexpression of ATF4 and C/EBPepsilon in the presence of c-Myb synergistically activated the mim-1 and NE promoters compared with C/EBPepsilon plus c-Myb alone. Synergistic activation was not observed for the G-CSFR promoter and only occurred in the presence of c-myb with the NE or mim-1 promoters. In contrast, ATF4:C/EBPalpha dimers bound to the C/EBP sites in the G-CSFR and NE promoters, but transcriptional activation was inhibited by 30-80% in the presence or absence of c-Myb. We propose that ATF4 may regulate myeloid gene expression differentially by potentiating C/EBPepsilon but inhibiting C/EBPalpha-mediated transcriptional activation.