Maturational globin switching in primiaxy primitive erythroid cells

Mammals have 2 distinct erythrold lineages. The primitive erythroid lineage originates in the yolk sac and generates a cohort of large erythroblasts that terminally differentiate in the bloodstream. The definitive erythroid lineage generates smaller enucleated erythrocytes that become the predominant cell in fetal and postnatal circulation. These lineages also have distinct globin expression patterns. Our studies in primary murine primitive erythroid cells indicate that beta H1 is the predominant beta-globin transcript in the early yolk sac. Thus, unlike the human, murine P-globin genes are not up-regulated in the order of their chromosomal arrangement. As primitive erythroblasts mature from proerythroblasts to reticulocytes, they undergo a beta H1- to epsilon y-globin switch, up-regulate adult beta 1- and beta 2-globins, and down-regulate zeta-globin. These changes in transcript levels correlate with changes in RNA polymerase 11 density at their promoters and transcribed regions. Furthermore, the epsilon y- and beta H1-globin genes in primitive erythro-blasts reside within a single large hyperacetylated domain. These data suggest that this maturational beta H1-to epsilon y-globin switch is dynamically regulated at the transcriptional level. Globin switching during ontogeny is due not only to the sequential appearance of primitive and definitive lineages but also to changes in globin expression as primitive erythroblasts mature in the bloodstream.