Autonomous Developmental Control of Human Embryonic Globin Gene Switching in Transgenic Mice

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Abstract
The mechanisms by which expression of the β-like globin genes are developmentally regulated are under intense investigation. The temporal control of human embryonic (ε) globin expression was analyzed. A 3.7-kilobase (kb) fragment that contained the entire human ε-globin gene was linked to a 2.5-kb cassette of the locus control region (LCR), and the developmental time of expression of this construct was studied in transgenic mice. The human ε-globin transgene was expressed in yolk sac-derived primitive erythroid cells, but not in fetal liver or bone marrow-derived definitive erythroid cells. The absence of ε gene expression in definitive erythroid cells suggests that the developmental regulation of the ε-globin gene depends only on the presence of the LCR and the ε-globin gene itself (that is, an autonomous negative control mechanism). The autonomy of ε-globin gene developmental control distinguishes it from the competitive mechanism of regulation of γ and β-globin genes, and therefore, suggests that at least two distinct mechanisms function in human hemoglobin switching.

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