Long-Distance Control of Origin Choice and Replication Timing in the Human beta -Globin Locus Are Independent of the Locus Control Region

doi:10.1128/MCB.20.15.5581-5591.2000

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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, thehuman locus replicates in early S phase from a bidirectional originlocated near the $beta$ -globin gene. This Hispanic thalassemia deletionremoves 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 closedchromatin conformation, and silencing of globin gene expressionin murine erythroid cells. The sequences deleted include nuclease-hypersensitivesites 2 to 5 (5'HS2-5) of the locus control region (LCR) plusan additional 27-kb upstream region. We tested a targeted deletionof 5'HS2-5 in the normal chromosomal context of the human $beta$ -globinlocus to determine the role of these elements in replication originchoice and replication timing. We demonstrate that the 5'HS2-5-deletedlocus initiates replication at the appropriate origin and withnormal timing in murine erythroid cells, and therefore we concludethat 5'HS2-5 in the classically defined LCR do not control replicationin the human $beta$ -globin locus. Recent studies also show that targeteddeletion of 5'HS2-5 results in a locus that lacks globin geneexpression yet retains an open chromatin conformation. Thus, thereplication timing of the locus is closely correlated with nucleasesensitivity but not globin geneexpression.

^* 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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Long-Distance Control of Origin Choice and Replication Timing in the Human -Globin Locus Are Independent of the Locus Control Region

Long-Distance Control of Origin Choice and Replication Timing in the Human $beta$ -Globin Locus Are Independent of the Locus Control Region