Identification and functional analysis of erythroid-specific genes regulated by heme

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Erythroid cells synthesize and accumulate an enormous amount of hemoglobin in the late stage of their differentiation. It is possible that, in addition to hemoglobin synthesis, heme may also play another important role in the erythroid cell differentiation program. To identify erythroid- specific heme-regulated genes, we performed differential expression analysis between wild-type and heme-deficient erythroblasts, which had been prepared from wild-type and δ-aminolevulinate synthase (ALAS2)-null mouse ES cells, respectively. As a result, the final 4 were considered as the newly identified erythroid-specific heme-regulated genes. These 4 genes were uncoupling protein 2 (UCP2), nucleolar spindle-associated protein (NuSAP), cellular nucleic acid binding protein (CNBP), and a novel acetyltransferase-like protein. Among them, the function of Nusap was further analyzed. NuSAP mRNA was remarkably more abundant in the subset corresponding to immature erythroblasts (TER119^+CD71^<high>) than mature erythroblasts (TER119^+CD7^<low>), and it was significantly increased in TER119^+ cells from in vivo phlebotomized mice. These results suggested that NuSAP gene might contribute to the expansion of immature erythroblast pool. These findings thus suggest that heme may regulate a wide variety of genes in erythroid cell differentiation.