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Mol Cell Biol, July 1998, p. 4188-4196, Vol. 18, No. 7
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Developmental Specificity of the Interaction between the Locus Control Region and Embryonic or Fetal Globin Genes in Transgenic Mice with an HS3 Core Deletion

Patrick A. Navas, Kenneth R. Peterson, Qiliang Li, Eva Skarpidi, Alex Rohde, Sara E. Shaw, Christopher H. Clegg, Haruhiko Asano, and George Stamatoyannopoulos*

Division of Medical Genetics, University of Washington, Seattle, Washington 98195

Received 8 January 1998/Returned for modification 3 March 1998/Accepted 16 April 1998

The human beta -globin locus control region (LCR) consists of five erythroid-lineage-specific DNase I-hypersensitive sites (HSs) and is required for activation of the beta -globin locus chromatin domain and globin gene expression. Each DNase I-HS of the LCR consists of a highly conserved core element and flanking sequences. To analyze the functional role of the core elements of the HSs, we deleted a 234-bp fragment encompassing the core of HS3 (HS3c) from a beta -globin locus residing on a 248-kb beta -locus yeast artificial chromosome and analyzed its function in F2 progeny of transgenic mice. Human varepsilon -globin gene expression was absent at day 10 and severely reduced in the day 12 embryonic erythropoiesis of mice lacking HS3c. In contrast, gamma -globin gene expression was normal in embryonic erythropoiesis but it was absent in definitive erythropoiesis in the fetal liver. These results indicate that the core element of HS3 is necessary for varepsilon -globin gene transcription in embryonic cells and for gamma -globin gene transcription in definitive cells. Normal gamma -globin gene expression in embryonic cells and the absence of gamma -globin gene expression in definitive cells show that different HSs interact with gamma -globin gene promoters in these two stages of development. Such results provide direct evidence for developmental stage specificity of the interactions between the core elements of HSs and the promoters of the globin genes.

* Corresponding author. Mailing address: University of Washington, Division of Medical Genetics, Box 357720, Seattle, WA 98195. Phone: (206) 543-3526. Fax: (206) 543-3050. E-mail: gstam{at}u.washington.edu.

Mol Cell Biol, July 1998, p. 4188-4196, Vol. 18, No. 7
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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