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Globin gene switching in transgenic mice carrying HS2-globin gene
constructs
NA Roberts, JA Sloane-Stanley, JA Sharpe, SJ Stanworth and WG Wood
MRC Molecular Haematology Unit, University of Oxford, John Radcliffe
Hospital, United Kingdom.
We have examined the pattern of human globin gene switching in transgenic
mice containing three different gamma and beta gene constructs (HS2G gamma
A gamma delta beta, HS2A gamma beta neo, and HS2A gamma en beta) and
compared the results with previously described transgenics (HS2A gamma
beta, HS2G gamma A gamma-117 delta beta, and LCR epsilon G gamma A gamma
delta beta). Developmental regulation was observed in all cases with
identical patterns in lines bearing the same construct. Three different
patterns of switching were observed: LCR epsilon G gamma A gamma delta beta
and HS2A gamma beta neo mice switched rapidly, HS2G gamma A gamma delta
beta and HS2G gamma A gamma- 117 delta beta at an intermediate rate, and
HS2A gamma beta and HS2A gamma en beta mice showed delayed switching, with
a plateau in late fetal-early neonatal life and readily detectable levels
of gamma mRNA in adults. No difference was observed in the time of
switching of the HS2G gamma A gamma delta beta mice compared with those
with the A gamma- 117 hereditary persistence of fetal hemoglobin mutation,
but adult levels of gamma mRNA were significantly higher (approximately 5%)
in lines carrying the mutation than in those without (approximately 1%).
Reversion to the rapid switch of the LCR epsilon G gamma A gamma delta beta
mice was observed in three lines with the HS2A gamma beta neo construct in
which expression of the tk-neo gene was approximately equal to that of the
globin genes. The inclusion of the A gamma enhancer in HS2A gamma beta mice
did not alter the pattern of switching, or reduce the relatively high
levels of gamma mRNA in these lines. However, unlike other HS2 mice, the
combination of HS2 and the A gamma enhancer resulted in copy
number-dependent expression in HS2A gamma en beta lines, with intrauterine
death at approximately 12.5 days gestation at high copy numbers. These
results demonstrate that numerous elements throughout the beta globin gene
cluster interact to produce the correct pattern of developmental regulation
of these genes. Furthermore, extinction of gamma gene expression in adult
life is not completely autonomous and is incomplete when HS2 is the only
LCR element present.
Volume 89,
Issue 2,
pp. 713-723,
01/15/1997
Copyright © 1997 by The American Society of Hematology
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