Developmentally regulated and erythroid-specific expression of the human embryonic β-globin gene in transgenic mice

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Abstract
Transgenic mice have proven to be an effective expression system for studying developmental control of the human fetal and adult β-globin genes. In the current work we are interested in developing the transgenic mouse system for the study of the human embryonic β-globin gene, ε. An ε-globin gene construction (HSII,I,ε) containing the human ε-globin gene with 0.2 kb of 3′ flanking sequence and 13.7 kb of extended 5′ flanking region including the erythroidspecific DNase I super-hypersensitive sites HSI and HSII was made. This construction was injected into fertilized mouse ova, and its expression was analyzed in peripheral blood, brain, and her samples of 13.5 day transgenic fetuses. Fetuses carrying intact copies of the transgene expressed human ε-globin mRNA in their peripheral blood. Levels of expression of human ε-globin mRNA in these transgenic mice ranged from 2% to 26% per gene copy of the endogenous mouse embryonic εγ-globin mRNA level. Furthermore, the human ε-globin transgene was expressed specifically in peripheral blood but not in brain or in liver which is an adult erythroid tissue at this stage. Thus, the HSII,I,ε transgene was expressed in an erythroid-specific and embryonic stage-specific manner in the transgenic mice. A human ε-globin gene construction that did not contain the distal upstream flanking region which includes the HSI and HSII sites, was not expressed in the embryos of transgenic mice. These data indicate that the human ε-globin gene with 5′ flanking region extending to include DNase I super-hypersensitive sites HSI and HSII is sufficient for the developmentally specific activation of the human ε-globin gene in erythroid tissue of transgenic mice.