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

Abstract

The globin chain synthetic pattern and the extent of DNA methylation within embryonic, fetal and adult .beta.-like globin gene domains were evaluated in .gtoreq. 90% purified human erythroblasts from yolk sacs and fetal livers in the 6- to 12-wk gestational period as well as from adult marrows. The 6-wk erythroblasts produce essentially embryonic .epsilon. chains, whereas the 12-wk erythroblasts synthesize largely fetal .gamma. globin and the adult marrow erythroblasts synthesize almost exclusively adult .beta. 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. Modulation of the methylation pattern may represent a key mechanism for regulating expression of human globin genes during embryonic .fwdarw. fetal and fetal .fwdarw. adult Hb switches in humans. In ontogenic development this mechanism might in turn correlate with a gradual modification of chromatin structure in the non-.alpha. gene cluster, thus leading to a 5'' .fwdarw. 3'' activation of globin genes in a balanced fashion.