Molecular mechanisms of human hemoglobin switching: Selective undermethylation and expression of globin genes in embryonic, fetal, and adult erythroblasts

The globin chain synthetic pattern and the extent of DNA methylation within embryonic, fetal, and adult β-like globin gene domains were evaluated in ≥90% purified human erythroblasts from yolk sacs and fetal livers in the 6- to 12-week gestational period as well as from adult marrows. The 6-wk erythroblasts produce essentially embryonic ε chains, whereas the 12-wk erythroblasts synthesize largely fetal gamma globin and the adult marrow erythroblasts synthesize almost exclusively adult β chains. In all phases of ontogenic development, a strong correlation exists between DNA hypomethylation in the close flanking sequences of globin genes and their expression. These results suggest that modulation of the methylation pattern may represent a key mechanism for regulating expression of human globin genes during embryonic → fetal and fetal → adult Hb switches in humans. In ontogenic development this mechanism might in turn correlate with a gradual modification of chromatin structure in the non-α gene cluster, thus leading to a 5' → 3' activation of globin genes in a balanced fashion.