Regulation of embryonic/fetal globin genes by nuclear hormone receptors: anovel perspective on hemoglobin switching

The CCAAT box is one of the conserved motifs found in globin promoters. It binds the CP1 protein. We noticed that the CCAAT-box region of embryonic/fe tal, but not adult, globin promoters also contains one or two direct repeat s of a short motif analogous to DR-1 binding sites for non-steroid nuclear hormone receptors. We show that a complex previously named NF-E3 binds to t hese repeats. In transgenic mice, destruction of the CCAAT motif within the human epsilon-globin promoter leads to substantial reduction in epsilon ex pression in embryonic erythroid cells, indicating that CP1 activates epsilo n expression; in contrast, destruction of the DR-1 elements yields striking epsilon expression in definitive erythropoiesis, indicating that the NF-E3 complex acts as a developmental repressor of the epsilon gene. We also sho w that NF-E3 is immunologically related to COUP-TF orphan nuclear receptors . One of these, COUP-TF II, is expressed in embryonic/fetal erythroid cell lines, murine yolk sac, intra-embryonic splanchnopleura and fetal liver. In addition, the structure and abundance of NF-E3/COUP-TF complexes vary duri ng fetal liver development, These results elucidate the structure as well a s the role of NF-E3 in globin gene expression and provide evidence that nuc lear hormone receptors are involved in the control of globin gene switching .