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Molecular and Cellular Biology, August 2000, p. 5581-5591, Vol. 20, No. 15
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Long-Distance Control of Origin Choice and Replication Timing in
the Human
-Globin Locus Are Independent of the Locus Control
Region
Daniel M.
Cimbora,1
Dirk
Schübeler,1
Andreas
Reik,1
Joan
Hamilton,1
Claire
Francastel,1
Elliot M.
Epner,2 and
Mark
Groudine1,3,*
Division of Basic Sciences, Fred Hutchinson
Cancer Research Center, Seattle, Washington
981091; University of Arizona School of
Medicine, Tucson, Arizona 857242; and
Department of Radiation Oncology, University of Washington
Medical School, Seattle, Washington 981953
Received 3 January 2000/Returned for modification 10 February
2000/Accepted 24 April 2000
DNA replication in the human
-globin locus is subject to
long-distance regulation. In murine and human erythroid cells, the human locus replicates in early S phase from a bidirectional origin located near the
-globin gene. This Hispanic thalassemia deletion removes regulatory sequences located over 52 kb from the origin, resulting in replication of the locus from a different origin, a shift
in replication timing to late S phase, adoption of a closed chromatin
conformation, and silencing of globin gene expression in murine
erythroid cells. The sequences deleted include nuclease-hypersensitive sites 2 to 5 (5'HS2-5) of the locus control region (LCR) plus an
additional 27-kb upstream region. We tested a targeted deletion of
5'HS2-5 in the normal chromosomal context of the human
-globin locus
to determine the role of these elements in replication origin choice
and replication timing. We demonstrate that the 5'HS2-5-deleted locus
initiates replication at the appropriate origin and with normal timing
in murine erythroid cells, and therefore we conclude that 5'HS2-5 in
the classically defined LCR do not control replication in the human
-globin locus. Recent studies also show that targeted deletion of
5'HS2-5 results in a locus that lacks globin gene expression yet
retains an open chromatin conformation. Thus, the replication timing of
the locus is closely correlated with nuclease sensitivity but not
globin gene expression.
*
Corresponding author. Mailing address: Fred Hutchinson
Cancer Research Center, 1100 Fairview Ave N, A3-025, Seattle, WA 98109. Phone: (206) 667-4497. Fax: (206) 667-5894. E-mail:
markg{at}fhcrc.org.
Molecular and Cellular Biology, August 2000, p. 5581-5591, Vol. 20, No. 15
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
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