A transient definitive erythroid lineage with unique regulation of the β-globin locus in the mammalian embryo

A transient erythromyeloid wave of definitive hematopoietic progenitors (erythroid/myeloid progenitors [EMPs]) emerges in the yolk sac beginning at embryonic day 8.25 (E8.25) and colonizes the liver by E10.5, before adult-repopulating hematopoietic stem cells. At E11.5, we observe all maturational stages of erythroid precursors in the liver and the first definitive erythrocytes in the circulation. These early fetal liver erythroblasts express predominantly adult beta-globins and the definitive erythroid-specific transcriptional modifiers c-myb, Sox6, and Bcl11A. Surprisingly, they also express low levels of embryonic beta H1-, but not epsilon y-, globin transcripts. Consistent with these results, RNA polymerase and highly modified histones are found associated with beta H1-and adult globin, but not epsilon y-globin, genes. E11.5 definitive proerythroblasts from mice transgenic for the human beta-globin locus, like human fetal erythroblasts, express predominately human gamma-, low beta-, and no epsilon-globin transcripts. Significantly, E9.5 yolk sac-derived EMPs cultured in vitro have similar murine and human transgenic globin expression patterns. Later liver proerythroblasts express low levels of gamma-globin, while adult marrow proerythroblasts express only beta-globin transcripts. We conclude that yolk sac-derived EMPs, the first of 2 origins of definitive erythropoiesis, express a unique pattern of globin genes as they generate the first definitive erythrocytes in the liver of the mammalian embryo. (Blood. 2011; 117(17):4600-4608)