Developmentally distinct effects on human -, - and -globin levels caused by the absence or altered position of the human -globin gene in YAC transgenic mice

Authors: Bauchwitz, Robert; Costantini, Frank

Source: Human Molecular Genetics, Volume 9, Number 4, 1 March 2000 , pp. 561-574(14)

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Abstract:

The human -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 -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 -globin gene (^– locus), which is weakly expressed at that stage of development. E17.5 fetal liver and adult erythroid cells, in which -globin expression approaches its maximum, showed an unexpectedly small, statistically insig- nificant stimulation of - and -globin levels in the absence of -globin sequence. Analysis of erythroid colonies produced by in vitro differentiation of embryonic stem cells indicated that the absence of the human -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 -thalassemias and hereditary persistence of fetal hemoglobin conditions are most likely to be due to effects other than loss of -globin competition. In transgenic mice with -globin sequences inserted between and the LCR in a ^-locus (^up), 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.

Document Type: Research article

Publication date: 2000-03-01

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Developmentally distinct effects on human -, - and -globin levels caused by the absence or altered position of the human -globin gene in YAC transgenic mice

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