Human Molecular Genetics, 2000, Vol. 9, No. 4 561-574
© 2000 Oxford University Press
Developmentally distinct effects on human 
-, 
- and 
-globin levels caused by the absence or altered position of the human ß-globin gene in YAC transgenic mice
Columbia University, Department of Genetics and Development, 701 West 168th Street, New York, NY 10032, USA
The human ß-globin locus has been an important model system in the study of developmentally regulated transcription in multigene chromosomal domains. In this study, primer extension and sensitive real-time RT–PCR assays were used to quantify the effects of ß-globin sequence modifications on 
-, 
- and 
-globin levels in transgenic mice. E11.5 primitive erythroid cells showed a surprisingly large increase in -globin in the absence of the ß-globin gene (ß– locus), which is weakly expressed at that stage of development. E17.5 fetal liver and adult erythroid cells, in which ß-globin expression approaches its maximum, showed an unexpectedly small, statistically insig- nificant stimulation of - and -globin levels in the absence of ß-globin sequence. Analysis of erythroid colonies produced by in vitro differentiation of embryonic stem cells indicated that the absence of the human ß-globin gene had no effect on -globin expression. These results suggest that competitive influences need not be linked directly to transcription level or distance from the locus control region (LCR), and that the large increases in -globin levels seen in some human deletional ß-thalassemias and hereditary persistence of fetal hemoglobin conditions are most likely to be due to effects other than loss of ß-globin competition. In transgenic mice with ß-globin sequences inserted between and the LCR in a ß-locus (ßup), the expression of -, - and -globins suggested that stage-specific sensitivity to loss of LCR activity may be a more important parameter than position relative to the LCR. The relationship of these measurements of transgenic globin expression to a possible binary model of globin LCR action and to mimicry from red blood cell loss due to transgenic globin imbalances are discussed.
+ To whom correspondence should be addressed. Tel: +1 212 305 6814; Fax: +1 212 923 2090; Email: fdc3@columbia.edu
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