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Molecular and Cellular Biology, April 1999, p. 3062-3072, Vol. 19, No. 4
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Hypersensitive Site 2 Specifies a Unique Function within the Human beta -Globin Locus Control Region To Stimulate Globin Gene Transcription

Jörg Bungert,* Keiji Tanimoto, Sunil Patel, Qinghui Liu, Mark Fear, and James Douglas Engel

Department of Biochemistry, Molecular Biology and Cell Biology, Northwestern University, Evanston, Illinois 60208-3500

Received 8 September 1998/Returned for modification 20 November 1998/Accepted 20 November 1998

The human beta -globin locus control region (LCR) harbors both strong chromatin opening and enhancer activity when assayed in transgenic mice. To understand the contribution of individual DNase I hypersensitive sites (HS) to the function of the human beta -globin LCR, we have mutated the core elements within the context of a yeast artificial chromosome (YAC) carrying the entire locus and then analyzed the effect of these mutations on the formation of LCR HS elements and expression of the genes in transgenic mice. In the present study, we examined the consequences of two different HS2 mutations. We first generated seven YAC transgenic lines bearing a deletion of the 375-bp core enhancer of HS2. Single-copy HS2 deletion mutants exhibited severely depressed HS site formation and expression of all of the human beta -globin genes at every developmental stage, confirming that HS2 is a vital, integral component of the LCR. We also analyzed four transgenic lines in which the core element of HS2 was replaced by that of HS3 and found that while HS3 is able to restore the chromatin-opening activity of the LCR, it is not able to functionally replace HS2 in mediating high-level globin gene transcription. These results continue to support the hypothesis that HS2, HS3, and HS4 act as a single, integral unit to regulate human globin gene transcription as a holocomplex, but they can also be interpreted to say that formation of a DNase I hypersensitive holocomplex alone is not sufficient for mediating high-level globin gene transcription. We therefore propose that the core elements must productively interact with one another to generate a unique subdomain within the nucleoprotein holocomplex that interacts in a stage-specific manner with individual globin gene promoters.

* Corresponding author. Present address: Department of Biochemistry and Molecular Biology, University of Florida, P.O. Box 100245, Gainesville, FL 32610-0245. Phone: (352) 392-0121. Fax: (352) 392-2953. E-mail: jbungert{at}college.med.ufl.edu.

Molecular and Cellular Biology, April 1999, p. 3062-3072, Vol. 19, No. 4
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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