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Blood, 1 October 2001, Vol. 98, No. 7, pp. 2022-2027
PLENARY PAPER
Targeted deletion of 5'HS1 and 5'HS4 of the  -globin locus
control region reveals additive activity of the DNaseI
hypersensitive sites
M. A. Bender,
Julia N. Roach,
Jessica Halow,
Jennie Close,
Raouf Alami,
Eric E. Bouhassira,
Mark Groudine, and
Steven N. Fiering
From the Fred Hutchinson Cancer Research Center; the
Departments of Pediatrics and Radiation Oncology, University of
Washington, Seattle, WA; the Division of Hematology, Department of
Medicine, Albert Einstein College of Medicine, Bronx, NY; and the
Department of Microbiology and Immunology, Dartmouth Medical School,
Hanover, NH.
The mammalian  -globin locus is a multigenic, developmentally
regulated, tissue-specific locus from which gene expression is
regulated by a distal regulatory region, the locus control region
(LCR). The functional mechanism by which the -globin LCR stimulates
transcription of the linked -like globin genes remains unknown. The
LCR is composed of a series of 5 DNaseI hypersensitive sites (5'HSs)
that form in the nucleus of erythroid precursors. These HSs are
conserved among mammals, bind transcription factors that also bind to
other parts of the locus, and compose the functional components of the
LCR. To test the hypothesis that individual HSs have unique properties,
homologous recombination was used to construct 5 lines
of mice with individual deletions of each of the 5'HSs of the
endogenous murine -globin LCR. Here it is reported that deletion of
5'HS1 reduces expression of the linked genes by up to 24%, while
deletion of 5'HS4 leads to reductions of up to 27%. These deletions do
not perturb the normal stage-specific expression of genes from this
multigenic locus. In conjunction with previous studies of deletions of
the other HSs and studies of deletion of the entire LCR, it is
concluded that (1) none of the 5'HSs is essential for nearly
normal expression; (2) none of the HSs is required for proper
developmental expression; and (3) the HSs do not appear to synergize
either structurally or functionally, but rather form independently and
appear to contribute additively to the overall expression from the locus.
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