Journal Article

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

Robert Bauchwitz and Frank Costantini

in Human Molecular Genetics

Volume 9, issue 4, pages 561-574
Published in print March 2000 | ISSN: 0964-6906
Published online March 2000 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/9.4.561
Developmentally distinct effects on human ε-, γ- and δ-globin levels caused by the absence or altered position of the human β-globin gene in YAC transgenic mice

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The human β-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 β-globin sequence modifications on ε-, γ- and δ-globin levels in transgenic mice. E11.5 primitive erythroid cells showed a surprisingly large increase in ε-globin in the absence of the β-globin gene (β locus), which is weakly expressed at that stage of development. E17.5 fetal liver and adult erythroid cells, in which β-globin expression approaches its maximum, showed an unexpectedly small, statistically insig‐ nificant stimulation of γ- and δ-globin levels in the absence of β-globin sequence. Analysis of erythroid colonies produced by in vitro differentiation of embryonic stem cells indicated that the absence of the human β-globin gene had no effect on γ-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 γ-globin levels seen in some human deletional β-thalassemias and hereditary persistence of fetal hemoglobin conditions are most likely to be due to effects other than loss of β‐globin competition. In transgenic mice with β-globin sequences inserted between ε and the LCR in a βlocus (βup), the expression of ε-, γ- and δ-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.

Journal Article.  11320 words.  Illustrated.

Subjects: Genetics and Genomics

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