Nucleic Acids Research, 2000, Vol. 28, No. 14 2736-2740
© 2000 Oxford University Press
Human 
-globin gene promoter element regulates human ß-globin gene developmental specificity
Department of Biochemistry and Molecular Genetics, School of Medicine and Dentistry, University of Alabama at Birmingham, Birmingham, AL 35294, USA
The persistence of fetal hemoglobin in many patients with deletion type ß thalassemias and the expression patterns of human globin genes in transgenic mice suggest that 
- to ß-globin gene switching results primarily from competition of - and ß-globin genes for interaction with the ß-globin locus control region (LCR). To define regulatory sequences that are essential for the competitive advantage of the gene at early developmental stages, stable transgenic mouse lines were produced with LCR -ß constructs containing deletions of 5'-flanking DNA. All constructs contained the full 22 kb LCR, a 4.1 kb ß-globin gene and a -globin gene with 1348, 383, 202, 130, 72 or 52 bp of 5'-flanking sequence. Primer extension analysis of yolk sac, fetal liver and blood RNA from these lines demonstrated that a region between –202 and –130 of the human -globin gene promoter was required to suppress ß-globin gene expression at early developmental stages. Four transcription factor binding sites within this region [GATA(p), Oct1, GATA(d) and CACCC] were mutated independently in LCR -ß constructs and transgenic mouse lines were produced. Only the CACCC box mutation resulted in high levels of ß-globin gene expression in early embryos. These results demonstrate that the CACCC box of the human -globin gene plays a critical role in human ß-globin gene developmental specificity. The data also suggest that CACCC box binding factors mediate LCR– interactions which normally enhance -globin and suppress ß-globin gene expression in fetal erythroid cells.
* To whom correspondence should be addressed. Tel: +1 205 934 5294; Fax: +1 205 934 2889; Email: ttownes@uab.edu The authors wish it to be known that, in their opinion, the first two authors should be considered as joint First Authors
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