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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 beta -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 beta -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 beta -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 beta -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 beta -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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