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Molecular and Cellular Biology, August 2005, p. 7033-7041, Vol. 25, No. 16
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.16.7033-7041.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Synergistic and Additive Properties of the Beta-Globin Locus Control Region (LCR) Revealed by 5'HS3 Deletion Mutations: Implication for LCR Chromatin Architecture

Xiangdong Fang,¹ Jin Sun,^1, Ping Xiang,¹ Man Yu,¹ Patrick A. Navas,¹ Kenneth R. Peterson,² George Stamatoyannopoulos,¹ and Qiliang Li^1*

Division of Medical Genetics, School of Medicine, University of Washington, Seattle, Washington 98195,¹ Department of Biochemistry & Molecular Biology, University of Kansas Medical Center, Kansas City, Kansas 66160²

Received 8 February 2005/ Returned for modification 24 March 2005/ Accepted 19 May 2005

Deletion of the 234-bp core element of the DNase I hypersensitive site 3 (5'HS3) of the locus control region (LCR) in the context of a human beta-globin locus yeast artificial chromosome (ß-YAC) results in profound effects on globin gene expression in transgenic mice. In contrast, deletion of a 2.3-kb 5'HS3 region, which includes the 234-bp core sequence, has a much milder phenotype. Here we report the effects of these deletions on chromatin structure in the beta-globin locus of adult erythroblasts. The 234-bp 5'HS3 deletion abolished histone acetylation throughout the ß-globin locus; recruitment of RNA polymerase II (pol II) to the LCR and beta-globin gene promoter was reduced to a basal level; and formation of all the 5' DNase I hypersensitive sites of the LCR was disrupted. The 2.3-kb 5'HS3 deletion mildly reduced the level of histone acetylation but did not change the profile across the whole locus; the 5' DNase I hypersensitive sites of the LCR were formed, but to a lesser extent; and recruitment of pol II was reduced, but only marginally. These data support the hypothesis that the LCR forms a specific chromatin structure and acts as a single entity. Based on these results we elaborate on a model of LCR chromatin architecture which accommodates the distinct phenotypes of the 5'HS3 and HS3 core deletions.

Present address: Division of Hematology and Oncology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210.

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